Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer.
Oncogene
The mitochondrial unfolded protein response (UPR) maintains mitochondrial quality control and proteostasis under stress conditions. However, the role of UPR in aggressive and resistant prostate cancer is not clearly defined. We show that castration-resistant neuroendocrine prostate cancer (CRPC-NE) harbored highly dysfunctional oxidative phosphorylation (OXPHOS) Complexes. However, biochemical and protein analyses of CRPC-NE tumors showed upregulation of nuclear-encoded OXPHOS proteins and UPR in this lethal subset of prostate cancer suggestive of compensatory upregulation of stress signaling. Genetic deletion and pharmacological inhibition of the main chaperone of UPR heat shock protein 60 (HSP60) reduced neuroendocrine prostate cancer (NEPC) growth in vivo as well as reverted NEPC cells to a more epithelial-like state. HSP60-dependent aggressive NEPC phenotypes was associated with upregulation of β-catenin signaling both in cancer cells and in vivo tumors. HSP60 expression rendered enrichment of aggressive prostate cancer signatures and metastatic potential were inhibited upon suppression of UPR. We discovered that UPR promoted OXPHOS functions including mitochondrial bioenergetics in CRPC-NE via regulation of β-catenin signaling. Mitochondrial biogenesis facilitated cisplatin resistance and inhibition of UPR resensitizes CRPC-NE cells to cisplatin. Together, our findings demonstrated that UPR promotes mitochondrial health via upregulating β-catenin signaling and UPR represents viable therapeutic target for NEPC.
10.1038/s41388-024-03261-4
Chitotriosidase, a marker of innate immunity, is elevated in patients with primary breast cancer.
Thein Mya Sanda,Kohli Anita,Ram Rohit,Ingaramo Maria Clara,Jain Alka,Fedarko Neal S
Cancer biomarkers : section A of Disease markers
BACKGROUND:Cancer progression has been associated with altered immune cell function and activation. Neopterin, which is secreted by interferon-γ stimulated macrophages, exhibits an association with multiple cancer types and metastatic disease. Chitotriosidase, which is secreted by chronically activated macrophages and granulocyte-macrophage colony-stimulating factor stimulated neutrophils has not been studied in the setting of cancer. OBJECTIVE:The goal of this discovery study was to screen chitotriosidase for diagnostic capacity in detecting cancer and compare its operating characteristics with those of neopterin. METHODS:Serum from subjects with breast (n= 66) or prostate (n= 70) cancer, and from 204 subjects free of malignant disease were studied. Chitotriosidase was measured by enzyme activity assay, while neopterin was measured by a competitive enzyme immunoassay. Statistical analyses included group comparisons by Mann Whitney U test, diagnostic capacity by receiver operating characteristics (ROC) curve analysis and biomarker associations with physiologic and clinical measures by Spearman correlation. RESULTS:Chitotriosidase activity was significantly higher in both cancer types compared with gender matched controls, though only in breast cancer was the diagnostic capacity significant (area under the ROC curve of 0.97 ± 0.01). In contrast, neopterin was significantly elevated in prostate cancer and exhibited discriminatory capacity (area under the ROC curve of 0.76 ± 0.05). Age, BMI, % body fat and metastasis were variables that correlated with neopterin, but not chitotriosidase levels. CONCLUSIONS:The operating characteristics of serum chitotriosidase were different from neopterin and further analysis of chitotriosidase as a biomarker for breast cancer is warranted.
10.3233/CBM-160101
An evaluation of current prostate cancer diagnostic approaches with emphasis on liquid biopsies and prostate cancer.
Mollica Veronica,Di Nunno Vincenzo,Santoni Matteo,Cimadamore Alessia,Scarpelli Marina,Lopez-Beltran Antonio,Cheng Liang,Mariani Cinzia,Battelli Nicola,Montironi Rodolfo,Massari Francesco
Expert review of molecular diagnostics
: Knowledge of the complex biology of prostate cancer is constantly growing, opening the field up to new therapeutic advances. The selection of patients on the basis of prognostic and predictive biomarkers is a challenging and emerging clinical need, not yet completely fulfilled. In this scenario, liquid biopsy offers a noninvasive and attractive approach to give important information about tumor biology and eventual resistance to treatments.: The aim of this review of the literature is to evaluate the current knowledge and the promising value of liquid biopsy in prostate cancer. Circulating tumor cells and circulating tumor DNA identified by liquid biopsies are currently under evaluation to guide therapeutic decisions in prostate cancer management, even though practical applications of these approaches are still very limited. We examined the current areas of interest in which circulating tumor cells and circulating tumor DNA are being investigated, such as their prognostic and predictive role in response to chemotherapy or androgen receptor signaling inhibition, especially in the castration-resistant setting.: As the body of knowledge on liquid biopsy rapidly grows, we need to identify which can be the real applications of this technique in clinical practice and to overcome the problems that are limiting its routinely use.
10.1080/14737159.2019.1684265
Noncanonical Wnt as a prognostic marker in prostate cancer: "you can't always get what you Wnt".
Fisher Rebecca R,Pleskow Haley M,Bedingfield Kathleen,Miyamoto David T
Expert review of molecular diagnostics
: Wnt signaling is important for normal development, cell proliferation, and cell differentiation. However, aberrations in the pathway can lead to tumorigenesis and cancer progression. Recent genome-wide studies have demonstrated the frequent occurrence of Wnt pathway alterations in prostate cancer. Although alterations in the Wnt pathway in prostate cancer may have an impact on prognosis, recent studies suggest that the Wnt pathway also plays an important role in disease progression and treatment resistance.: We review the literature with regard to the potential prognostic significance of noncanonical Wnt signaling in prostate cancer. After a brief overview of the canonical and noncanonical Wnt pathways, we discuss the preclinical and clinical evidence for activation of Wnt signaling in prostate cancer. We focus on clinical evidence for noncanonical Wnt pathway components to serve as potential prognostic biomarkers.: Although many therapeutic options are available for men with prostate cancer, there remains an unmet need for prognostic and predictive biomarkers to precisely guide clinical management. Early evidence suggests that components of the noncanonical Wnt pathway may serve as prognostic biomarkers. However, prospective validation studies are necessary before these biomarkers can be routinely applied in the clinic.
10.1080/14737159.2020.1702522
Oncogenic ETS Factors in Prostate Cancer.
Nicholas Taylor R,Strittmatter Brady G,Hollenhorst Peter C
Advances in experimental medicine and biology
Prostate cancer is unique among carcinomas in that a fusion gene created by a chromosomal rearrangement is a common driver of the disease. The TMPRSS2/ERG rearrangement drives aberrant expression of the ETS family transcription factor ERG in 50% of prostate tumors. Similar rearrangements promote aberrant expression of the ETS family transcription factors ETV1 and ETV4 in another 10% of cases. Together, these three ETS factors are thought to promote tumorigenesis in the majority of prostate cancers. A goal of precision medicine is to be able to apply targeted therapeutics that are specific to disease subtypes. ETS gene rearrangement positive tumors represent the largest molecular subtype of prostate cancer, but to date there is no treatment specific to this marker. In this chapter we will review the latest findings regarding the molecular mechanisms of ETS factor function in the prostate. These molecular details may provide a path towards new therapeutic targets for this subtype of prostate cancer. Further, we will describe efforts to target the oncogenic functions of ETS family transcription factors directly as well as indirectly.
10.1007/978-3-030-32656-2_18
Tumour innervation and neurosignalling in prostate cancer.
March Brayden,Faulkner Sam,Jobling Phillip,Steigler Allison,Blatt Alison,Denham Jim,Hondermarck Hubert
Nature reviews. Urology
Prostate cancer progression has been shown to be dependent on the development of autonomic nerves into the tumour microenvironment. Sympathetic nerves activate adrenergic neurosignalling that is necessary in early stages of tumour progression and for initiating an angiogenic switch, whereas parasympathetic nerves activate cholinergic neurosignalling resulting in tumour dissemination and metastasis. The innervation of prostate cancer seems to be initiated by neurotrophic growth factors, such as the precursor to nerve growth factor secreted by tumour cells, and the contribution of brain-derived neural progenitor cells has also been reported. Current experimental, epidemiological and clinical evidence shows the stimulatory effect of tumour innervation and neurosignalling in prostate cancer. Using nerves and neurosignalling could have value in the management of prostate cancer by predicting aggressive disease, treating localized disease through denervation and relieving cancer-associated pain in bone metastases.
10.1038/s41585-019-0274-3
Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers. I. Molecular Biomarkers in Prostate Cancer.
Lotan Tamara L,Tomlins Scott A,Bismar Tarek A,Van der Kwast Theodorus H,Grignon David,Egevad Lars,Kristiansen Glen,Pritchard Colin C,Rubin Mark A,Bubendorf Lukas
The American journal of surgical pathology
The combined clinical and molecular heterogeneity of prostate cancer necessitates the use of prognostic, predictive, and diagnostic biomarkers to assist the clinician with treatment selection. The pathologist plays a critical role in guiding molecular biomarker testing in prostate cancer and requires a thorough knowledge of the current testing options. In the setting of clinically localized prostate cancer, prognostic biomarkers such as Ki-67 labeling, PTEN loss or mRNA-based genomic signatures can be useful to help determine whether definitive therapy is required. In the setting of advanced disease, predictive biomarkers, such as the presence of DNA repair deficiency mediated by BRCA2 loss or mismatch repair gene defects, may suggest the utility of poly-ADP ribosylase inhibition or immune checkpoint blockade. Finally, androgen receptor-related biomarkers or diagnostic biomarkers indicating the presence of small cell neuroendocrine prostate cancer may help guide the use of androgen receptor signaling inhibitors and chemotherapy. In this review, we examine the current evidence for several prognostic, predictive and diagnostic tissue-based molecular biomarkers in prostate cancer management. For each assay, we summarize a recent survey of the International Society of Urology Pathology (ISUP) members on current testing practices and include recommendations for testing that emerged from the ISUP Working Group on Molecular Pathology of Prostate Cancer and the 2019 Consultation Conference on Molecular Pathology of Urogenital Cancers.
10.1097/PAS.0000000000001450
Exosomes are the Driving Force in Preparing the Soil for the Metastatic Seeds: Lessons from the Prostate Cancer.
Cells
Exosomes are nano-membrane vesicles that various cell types secrete during physiological and pathophysiological conditions. By shuttling bioactive molecules such as nucleic acids, proteins, and lipids to target cells, exosomes serve as key regulators for multiple cellular processes, including cancer metastasis. Recently, microvesicles have emerged as a challenge in the treatment of prostate cancer (PCa), encountered either when the number of vesicles increases or when the vesicles move into circulation, potentially with an ability to induce drug resistance, angiogenesis, and metastasis. Notably, the exosomal cargo can induce the desmoplastic response of PCa-associated cells in a tumor microenvironment (TME) to promote PCa metastasis. However, the crosstalk between PCa-derived exosomes and the TME remains only partially understood. In this review, we provide new insights into the metabolic and molecular signatures of PCa-associated exosomes in reprogramming the TME, and the subsequent promotion of aggressive phenotypes of PCa cells. Elucidating the molecular mechanisms of TME reprogramming by exosomes draws more practical and universal conclusions for the development of new therapeutic interventions when considering TME in the treatment of PCa patients.
10.3390/cells9030564
Epigenetic modulations and lineage plasticity in advanced prostate cancer.
Ge R,Wang Z,Montironi R,Jiang Z,Cheng M,Santoni M,Huang K,Massari F,Lu X,Cimadamore A,Lopez-Beltran A,Cheng L
Annals of oncology : official journal of the European Society for Medical Oncology
Prostate cancer is the most common cancer and second leading cause of cancer-related death in American men. Antiandrogen therapies are part of the standard of therapeutic regimen for advanced or metastatic prostate cancers; however, patients who receive these treatments are more likely to develop castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC). In the development of CRPC or NEPC, numerous genetic signaling pathways have been under preclinical investigations and in clinical trials. Accumulated evidence shows that DNA methylation, chromatin integrity, and accessibility for transcriptional regulation still play key roles in prostate cancer initiation and progression. Better understanding of how epigenetic change regulates the progression of prostate cancer and the interaction between epigenetic and genetic modulators driving NEPC may help develop a better risk stratification and more effective treatment regimens for prostate cancer patients.
10.1016/j.annonc.2020.02.002
Data-driven translational prostate cancer research: from biomarker discovery to clinical decision.
Lin Yuxin,Zhao Xiaojun,Miao Zhijun,Ling Zhixin,Wei Xuedong,Pu Jinxian,Hou Jianquan,Shen Bairong
Journal of translational medicine
Prostate cancer (PCa) is a common malignant tumor with increasing incidence and high heterogeneity among males worldwide. In the era of big data and artificial intelligence, the paradigm of biomarker discovery is shifting from traditional experimental and small data-based identification toward big data-driven and systems-level screening. Complex interactions between genetic factors and environmental effects provide opportunities for systems modeling of PCa genesis and evolution. We hereby review the current research frontiers in informatics for PCa clinical translation. First, the heterogeneity and complexity in PCa development and clinical theranostics are introduced to raise the concern for PCa systems biology studies. Then biomarkers and risk factors ranging from molecular alternations to clinical phenotype and lifestyle changes are explicated for PCa personalized management. Methodologies and applications for multi-dimensional data integration and computational modeling are discussed. The future perspectives and challenges for PCa systems medicine and holistic healthcare are finally provided.
10.1186/s12967-020-02281-4
NF-κB signaling promotes castration-resistant prostate cancer initiation and progression.
Thomas-Jardin Shayna E,Dahl Haley,Nawas Afshan F,Bautista Monica,Delk Nikki A
Pharmacology & therapeutics
Prostate Cancer (PCa) is the second leading cause of cancer-related death in men. Adenocarcinoma of the prostate is primarily composed of Androgen Receptor-positive (AR) luminal cells that require AR transcriptional activity for survival and proliferation. As a consequence, androgen deprivation and anti-androgens are used to treat PCa patients whose disease progresses following attempted surgical or radiation interventions. Unfortunately, patients with advanced PCa can develop incurable castration-resistant PCa (CRPCa) due to mutated, variant, or overexpressed AR. Conversely, low or no AR accumulation or activity can also underlie castration resistance. Whether CRPCa is due to aberrant AR activity or AR independence, NF-κB signaling is also implicated in the initiation and maintenance of CRPCa and, thus, the NF-κB pathway may be a promising alternative therapeutic target. In this review, we present evidence that NF-κB signaling promotes CRPCa initiation and progression, describe the dichotomic role of NF-κB in the regulation of AR expression and activity and outline studies that explore NF-κB inhibitors as PCa therapies.
10.1016/j.pharmthera.2020.107538
miRNA in prostate cancer: challenges toward translation.
Abramovic Irena,Ulamec Monika,Katusic Bojanac Ana,Bulic-Jakus Floriana,Jezek Davor,Sincic Nino
Epigenomics
Prostate cancer (PCa) represents the most commonly diagnosed neoplasm among men. miRNAs, as biomarkers, could further improve reliability in distinguishing malignant versus nonmalignant, and aggressive versus nonaggressive PCa. However, conflicting data was reported for certain miRNAs, and there was a lack of consistency and reproducibility, which has been attributed to diverse (pre)analytical factors. In order to address current challenges in miRNA clinical research on PCa, a PubMed-based literature search was conducted with the last update in May 2019. After identifying critical variations in designs and protocols that undermined clear-cut evidence acquisition, and reliable translation into clinical practice, we propose guidelines for most critical steps that should be considered in future research of miRNA as biomarkers, especially in PCa.
10.2217/epi-2019-0275
Caveola-forming proteins and prostate cancer.
Nassar Zeyad D,Parat Marie-Odile
Cancer metastasis reviews
Caveolae are specialised and dynamic plasma membrane subdomains, involved in many cellular functions including endocytosis, signal transduction, mechanosensing and lipid storage, trafficking, and metabolism. Two protein families are indispensable for caveola formation and function, namely caveolins and cavins. Mutations of genes encoding these caveolar proteins cause serious pathological conditions such as cardiomyopathies, skeletal muscle diseases, and lipodystrophies. Deregulation of caveola-forming protein expression is associated with many types of cancers including prostate cancer. The distinct function of secretion of the prostatic fluid, and the unique metabolic phenotype of prostate cells relying on lipid metabolism as a main bioenergetic pathway further suggest a significant role of caveolae and caveolar proteins in prostate malignancy. Accumulating in vitro, in vivo, and clinical evidence showed the association of caveolin-1 with prostate cancer grade, stage, metastasis, and drug resistance. In contrast, cavin-1 was found to exhibit tumour suppressive roles. Studies on prostate cancer were the first to show the distinct function of the caveolar proteins depending on their localisation within the caveolar compartment or as cytoplasmic or secreted proteins. In this review, we summarise the roles of caveola-forming proteins in prostate cancer and the potential of exploiting them as therapeutic targets or biological markers.
10.1007/s10555-020-09874-x
[Research Progress of the Roles of Ubiquitination/Deubiquitination in Androgen Receptor Abnormalities and Prostate Cancer].
Zhang Wei-Yu,Zhou Jian-Hua,Wang Huan-Rui,Mu Qing,Wang Qi,Xu Ke-Xin,Xu Tao,Hu Hao
Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae
Ubiquitin is a small molecule protein consisting of 76 amino acids,widely found in eukaryotic cells. The process by which ubiquitin binding to a specific protein is called ubiquitination. Deubiquitination is the reversed process of ubiquitination. Ubiquitination stimulates downstream signal,including complex assembly,protein conformation and activity changes,proteolysis,autophagy,guilt,chromatin remodeling,and DNA repair. More than 80% of eukaryotic protein degradation is mediated by the ubiquitination system,and ubiquitin-dependent proteolysis is an extremely complex process involving many biomolecular processes. By regulating protein homeostasis,ubiquitination can also regulate a variety of biological processes including cell cycle,cell proliferation,and apoptosis,which are closely related to tumorigenesis and progression. Many abnormalities of androgen receptor (AR) including AR gene amplification,mutation,shear mutation,and AR activity enhancement are closely related to prostate cancer progression. In particular,prostate cancer progression is regulated by the ubiquitination/deubiquitination processes. This article summarizes the recent research advances in the roles of ubiquitination/deubiquitination in AR abnormalities and prostate cancer.
10.3881/j.issn.1000-503X.11069
Effects of estrogen receptor signaling on prostate cancer carcinogenesis.
Qu Liang G,Wardan Hady,Davis Ian D,Pezaro Carmel,Sluka Pavel
Translational research : the journal of laboratory and clinical medicine
Management of advanced prostate cancer remains complex, with substantial changes in treatment options emerging in recent years having implications for treatment selection and sequencing. Recognition of the importance of androgen signaling has led to life-prolonging treatments, as well as "liquid biopsy" techniques to guide these treatments in some settings. Therapies that target estrogen receptor signaling are efficacious but infrequently used options for treatment of castration-resistant prostate cancer. It is possible that nuances of estrogen receptor (ER) signaling, or selective modulation of ER signaling, might favorably influence outcomes in castration-resistant prostate cancer. Expression of ERs and their variants has been investigated in other cancers such as breast. Constitutively activating gene alterations can potentially lead to ER activation and subsequently promote cancer progression. The identification of these aberrations may help identify cancer phenotypes that are susceptible or resistant to therapies involved in ER signaling. This review outlines the current literature regarding ER signaling in prostate cancer, and provides background for exploration of potentially useful ER signaling biomarkers in advanced prostate cancer.
10.1016/j.trsl.2020.04.003
Ras and Wnt Interaction Contribute in Prostate Cancer Bone Metastasis.
Molecules (Basel, Switzerland)
Prostate cancer (PCa) is one of the most prevalent and malignant cancer types in men, which causes more than three-hundred thousand cancer death each year. At late stage of PCa progression, bone marrow is the most often metastatic site that constitutes almost 70% of metastatic cases of the PCa population. However, the characteristic for the osteo-philic property of PCa is still puzzling. Recent studies reported that the Wnt and Ras signaling pathways are pivotal in bone metastasis and that take parts in different cytological changes, but their crosstalk is not well studied. In this review, we focused on interactions between the Wnt and Ras signaling pathways during each stage of bone metastasis and present the fate of those interactions. This review contributes insights that can guide other researchers by unveiling more details with regard to bone metastasis and might also help in finding potential therapeutic regimens for preventing PCa bone metastasis.
10.3390/molecules25102380
Comparison of diagnostic performance and inter-reader agreement between PI-RADS v2.1 and PI-RADS v2: systematic review and meta-analysis.
The British journal of radiology
OBJECTIVES:To perform a systematic review and meta-analysis comparing diagnostic performance and inter reader agreement between PI-RADS v. 2.1 and PI-RADS v. 2 in the detection of clinically significant prostate cancer (csPCa). METHODS:A systematic review was performed, searching the major biomedical databases (Medline, Embase, Scopus), using the keywords "PIRADS 2.1" or "PI RADS 2.1" or "PI-RADS 2.1". Studies reporting on head-to-head diagnostic comparison between PI-RADS v. 2.1 and v. 2 were included. Pooled sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were compared between PI-RADS v. 2.1 and v. 2. Summary receiver operator characteristic graphs were plotted. Analysis was performed for whole gland, and pre-planned subgroup analysis was performed by tumour location (whole gland transition zone (TZ)), high b-value DWI (b-value ≥1400 s/mm), and reader experience (<5 years vs ≥5 years with prostate MRI interpretation). Inter-reader agreement and pooled rates of csPCa for PI-RADS 1-3 lesions were compared between PI-RADS v. 2.1 and v. 2. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool v. 2 (QUADAS-2). RESULTS:Eight studies (1836 patients, 1921 lesions) were included. Pooled specificity for PI-RADS v. 2.1 was significantly lower than PI-RADS v. 2 for whole gland (0.62 0.66, = 0.02). Pooled sensitivities, PPVs and NPVs were not significantly different ( = 0.17, 0.31, 0.41). Pooled specificity for PI-RADS v. 2.1 was significantly lower than PI-RADS v. 2 for TZ only (0.67 0.72, = 0.01). Pooled sensitivities, PPVs and NPVs were not significantly different ( = 0.06, 0.36, 0.17). Amongst studies utilising diffusion-weighted imaging with highest b-value of ≥1400 s/mm, pooled sensitivities, specificities, PPVs and NPVs were not significantly different ( = 0.52, 0.4, 0.5, 0.47). There were no significant differences in pooled sensitivities, specificities, PPVs and NPVs between PI-RADS v. 2.1 and PI-RADS v. 2 for less-experienced readers ( = 0.65, 0.37, 0.65, 0.81) and for more experienced readers ( = 0.57, 0.90, 0.91, 0.65). For PI-RADS v. 2.1 alone, there were no significant differences in pooled sensitivity, specificity, PPV and NPV between less and more experienced readers ( = 0.38, 0.70, 1, 0.48). Inter-reader agreement was moderate to substantial for both PI-RADS v. 2.1 and v. 2. There were no significant differences between pooled csPCa rates between PI-RADS v. 2.1 and v. 2 for PI-RADS 1-2 lesions (6.6% vs 7.3%, = 0.53), or PI-RADS 3 lesions (24.1% vs 26.8%, = 0.28). CONCLUSIONS:Diagnostic performance and inter-reader agreement for PI-RADS v. 2.1 is comparable to PI-RADS v. 2, however the significantly lower specificity of PI-RADS v. 2.1 may result in increased number of unnecessary biopsies. ADVANCES IN KNOWLEDGE:1. Compared to PI-RADS v. 2, PI-RADS v. 2.1 has a non-significantly higher sensitivity but a significantly lower specificity for detection of clinically significant prostate cancer.2. PI-RADS v. 2.1 could potentially result in considerable increase in number of negative targeted biopsy rates for PI-RADS 3 lesions, which could have been potentially avoided.
10.1259/bjr.20210509
No association between three polymorphisms (rs1800629, rs361525 and rs1799724) in the tumor necrosis factor-α gene and susceptibility to prostate cancer: a comprehensive meta-analysis.
Yin Lei,Yue Chuang,Jing Hongwei,Yu Hongyuan,Zuo Li,Liu Tao
Hereditas
BACKGROUND:Inflammation is one of the factors associated with prostate cancer. The cytokine tumor necrosis factor-alpha (TNF-α) plays an important role in inflammation. Several studies have focused on the association between TNF-α polymorphisms and prostate cancer development. Our meta-analysis aimed to estimate the association between TNF-α rs1800629 (- 308 G/A), rs361525 (- 238 G/A) and rs1799724 polymorphisms and prostate cancer risk. METHODS:Eligible studies were identified from electronic databases (PubMed, Embase, Wanfang and CNKI) using keywords: TNF-α, polymorphism, prostate cancer, until Nov 15, 2019. Odds ratios (ORs) with 95% confidence intervals (CIs) were applied to determine the association from a quantitative point-of-view. Publication bias and sensitivity analysis were also applied to evaluate the power of current study. All statistical analyses were done with Stata 11.0 software. RESULTS:Twenty-two different articles were included (22 studies about rs1800629; 8 studies for rs361525 and 5 studies related to rs1799724). Overall, no significant association was found between rs1800629 and rs1799724 polymorphisms and the risk of prostate cancer in the whole (such as: OR = 1.03, 95% CI = 0.92-1.16, P = 0.580 in the allele for rs1800629; OR = 0.95, 95% CI = 0.84-1.07, P = 0.381 in the allele for rs1799724). The rs361525 polymorphism also had no association with prostate cancer in the cases (OR = 0.93, 95% CI = 0.66-1.32, P = 0.684 in the allele) and ethnicity subgroup. The stratified subgroup of genotype method, however, revealed that the rs361525 variant significantly decreased the risk of prostate cancer in the Others (OR = 0.65, 95% CI = 0.47-0.89, P = 0.008, A-allele vs G-allele) and PCR-RFLP (OR = 2.68, 95% CI = 1.00-7.20, P = 0.050, AG vs GG or AA+AG vs GG) methods. CONCLUSIONS:In summary, the findings of the current meta-analysis indicate that the TNF-α rs1800629, rs361525 and rs1799724 polymorphisms are not correlated with prostate cancer development, although there were some pooled positive results. Further well-designed studies are necessary to form more precise conclusions.
10.1186/s41065-020-00125-1
Integrin expression in correlation to clinicopathological features and prognosis of prostate cancer: A systematic review and meta-analysis.
Drivalos Alexandros,Emmanouil Georgios,Gavriatopoulou Maria,Terpos Evangelos,Sergentanis Theodoros N,Psaltopoulou Theodora
Urologic oncology
BACKGROUND:The prompt identification of patients with poor prognosis is essential in order to improve the treatment outcomes in prostate cancer (CaP); as a novel approach, several molecular markers, including integrins, have been discussed as prognostic biomarkers. Our aim was to comprehensively examine aberrant expression of integrins in correlation with clinicopathological features and prognosis in CaP by synthesizing all available evidence, in a systematic review and meta-analysis. METHODS:A systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. Scientific literature databases (Pubmed, Embase, and Scopus) were systematically searched until May 10, 2020. Random-effects (DerSimonian-Laird) models were used to estimate pooled odds ratios (ORs) for cross-sectional correlations with clinicopathological characteristics and relative risks for longitudinal associations with prognosis. RESULTS:Fourteen studies were included with a total number of 3,194 CaP cases examined (13 cross-sectional and four longitudinal cohort study arms). Correlation of low expression of α (pooled OR = 0.10, 95% confidence interval [CI]: 0.04-0.28, P < 0.001) and β (pooled OR = 0.45; 95% CI: 0.21-1.00, P = 0.049) integrin with high Gleason score was noted. A borderline trend between reduced expression of α integrin and an advanced clinical stage of CaP (pooled OR = 0.48; 95% CI: 0.22-1.03, P = 0.06) was observed. No associations with biochemical recurrence and survival were documented. CONCLUSIONS:Evidence on the association of low expression of integrins α and β and more advanced CaP exist, whereas significant results on survival were not documented; further studies are warranted.
10.1016/j.urolonc.2020.12.024
Diagnostic accuracy of prostate-specific antigen below 4 ng/mL as a cutoff for diagnosing prostate cancer in a hospital setting: A systematic review and meta-analysis.
Investigative and clinical urology
PURPOSE:A prostate-specific antigen (PSA) cutoff of 4 ng/mL has been widely used for prostate cancer screening in population-based settings. However, the accuracy of PSA below 4 ng/mL as a cutoff for diagnosing prostate cancer in a hospital setting is inconclusive. We systematically reviewed the accuracy of PSA below 4 ng/mL cutoff in a hospital setting. MATERIALS AND METHODS:We systematically reviewed the literature by searching major databases until March 2020, and a meta-analysis and quality assessment were performed. RESULTS:A total of 11 studies were included at the completion of the screening process. The meta-analysis showed a sensitivity of 0.92 and a specificity of 0.16 for a PSA cutoff below 4 ng/mL. The area under the hierarchical summary receiver operating characteristic curve was 0.87, the positive likelihood ratio was 1.23, the negative likelihood ratio was 0.46, and the diagnostic odds ratio was 2.64. PSA sensitivities and specificities varied according to the cutoff range: 0.94 and 0.17 for 2 to 2.99 ng/mL, and 0.92 and 0.16 for 3 to 3.99 ng/mL, respectively. No significant differences in the sensitivity and specificity of PSA cutoffs in the range of 2 to 2.99 ng/mL and 3 to 3.99 ng/mL were found. CONCLUSIONS:Although a PSA cutoff <3 ng/mL is relatively more sensitive and specific than PSA ≥3 ng/mL, no significant differences in sensitivity and specificity were found in the diagnosis of prostate cancer. Therefore, clinicians should choose an appropriate PSA cutoff on the basis of clinical circumstances and patients' characteristics.
10.4111/icu.20210429
Diagnosis accuracy of PCA3 level in patients with prostate cancer: a systematic review with meta-analysis.
International braz j urol : official journal of the Brazilian Society of Urology
BACKGROUND:The diagnostic value and suitability of prostate cancer antigen 3 (PCA3) for the detection of prostate cancer (PCa) have been inconsistent in previous studies. Thus, the aim of the present meta-analysis was performed to systematically evaluate the diagnostic value of PCA3 for PCa. MATERIALS AND METHODS:A meta-analysis was performed to search relevant studies using online databases EMBASE, PubMed and Web of Science published until February 1st, 2019. Ultimately, 65 studies met the inclusion criteria for this meta-analysis with 8.139 cases and 14.116 controls. The sensitivity, specificity, positive likelihood ratios (LR+), negative likelihood ratios (LR-), and other measures of PCA3 were pooled and determined to evaluate the diagnostic rate of PCa by the random-effect model. RESULTS:With PCA3, the pooled overall diagnostic sensitivity, specificity, LR+, LR-, and 95% confidence intervals (CIs) for predicting significant PCa were 0.68 (0.64-0.72), 0.72 (0.68-0.75), 2.41 (2.16-2.69), 0.44 (0.40-0.49), respectively. Besides, the summary diagnostic odds ratio (DOR) and 95% CIs for PCA3 was 5.44 (4.53-6.53). In addition, the area under summary receiver operating characteristic (sROC) curves and 95% CIs was 0.76 (0.72-0.79). The major design deficiencies of included studies were differential verification bias, and a lack of clear inclusion and exclusion criteria. CONCLUSIONS:The results of this meta-analysis suggested that PCA3 was a non-invasive method with the acceptable sensitivity and specificity in the diagnosis of PCa, to distinguish between patients and healthy individuals. To validate the potential applicability of PCA3 in the diagnosis of PCa, more rigorous studies were needed to confirm these conclusions.
10.1590/S1677-5538.IBJU.2019.0360
C-reactive protein levels could be a prognosis predictor of prostate cancer: A meta-analysis.
Frontiers in endocrinology
Background:The relationship between the C-reactive protein (CRP) and prognosis in prostate cancer (PCa) has been widely discussed over the past few years but remains controversial. Material and methods:In our meta-analysis, we searched 16 reliable studies in the PubMed, Embase, and Cochrane Library databases. Otherwise, we have successfully registered on the INPLASY. We also performed random- and fixed-effects models to evaluate the hazard ratio (HR) and 95% confidence interval (CI), respectively. Result:The result of our meta-analysis shows that elevated CRP levels were related to worse overall survival (OS) (HR = 1.752, 95% CI = 1.304-2.355, = 0.000), cancer-specific survival (CSS) (HR = 1.663, 95% CI = 1.064-2.6, = 0.026), and progression-free survival (PFS) (HR = 1.663, 95% CI = 1.064-2.6, = 0.026) of PCa patients. There was significant heterogeneity, so we performed a subgroup analysis according to the staging of the disease and found the same result. Furthermore, the heterogeneity was also reduced, and no statistical significance. Conclusion:Our study shows that the level of CRP could reflect the prognosis of prostate cancer patients. We find that PCa patients with high levels of CRP often have worse OS, CSS, and PFS, although the stages of the patients' disease are different. More studies are needed to verify this idea.
10.3389/fendo.2023.1111277
Association of glutathione-S-transferase p1 gene promoter methylation and the incidence of prostate cancer: a systematic review and meta-analysis.
Zhou Xueliang,Jiao Dechao,Dou Mengmeng,Chen Jianjian,Li Zhaonan,Li Yahua,Liu Juanfang,Han Xinwei
Journal of cancer research and clinical oncology
OBJECTIVE:Some studies have shown that the methylation status of the GSTP1 gene promoter is related to the incidence of prostate cancer, but this finding is still controversial. The aim of this study was to evaluate the association between glutathione-S-transferase p1 (GSTP1) promoter methylation and the incidence of prostate cancer. METHODS:The Medline, Embase, Web of Science, and Cochrane CENTRAL databases were searched from their inception to February 22, 2019. According to the inclusion criteria, studies of the association between the methylation status of the GSTP1 gene promoter and prostate cancer were included. The difference in the incidence of GSTP1 promoter methylation in tissues, blood, or urine between patients with prostate cancer and those without prostate cancer were compared, and the results were expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed-effects model or a random-effects model to generate forest plots. RESULTS:Ultimately, 15 studies (1540 samples) were included. The estimated effect from our meta-analysis showed that the incidence of GSTP1 promoter methylation was higher in patients with prostate cancer than in those without prostate cancer (OR 18.58, 95% CI 9.60-35.95, P = 0.000). GSTP1 promoter methylation was highly correlated with the incidence of prostate cancer. CONCLUSIONS:Methylation of the GSTP1 promoter may increase the risk of prostate cancer. This study may provide a strategic direction for prostate cancer research. Pending validation of these findings, the methylation of the GSTP1 promoter may be a potential biomarker to diagnose prostate cancer.
10.1007/s00432-019-02962-8
The Role of O-methylguanine-DNA Methyltransferase Polymorphisms in Prostate Cancer Susceptibility: a Meta-Analysis.
Zhang Wei,Liu Mingkai,Li Yue,Song Shichao,Li Kai,Ma Yongliang
Pathology oncology research : POR
To assess the associations between O-methylguanine-DNA methyltransferase(MGMT) polymorphisms and prostate cancer risk. We retrieved PubMed, Cochrane Library and Embase electronic database to search for all eligible studies published from Jan 1, 1970 to Sep 31, 2017 to conduct a Meta-analysis. we identified 11 independent studies in 5 eligible reports, including 5143 cases and 8118 controls. The data suggested that rs12917 was associated with higher PCa risk under the contrast of TT vs CC and recessive model in overall population (TT vs CC: OR = 1.599, 95%CI: 1.007-2.539, P = 0.047; TT vs CC + CT: OR = 1.627, 95%CI: 1.026-2.580, P = 0.038). In subgroup analyses stratified by ethnicity, the remarkable association with higher PCa risk was detected under allelic model, dominant model, the contrast of TC vs CC, and the contrast of TC vs CC + TT in Asian population. (T vs C: OR = 1.911, 95%CI: 1.182-3.090, P = 0.008; TC vs CC: OR = 1.948, 95%CI: 1.152-3.295, P = 0.013; TC + TT vs CC: OR = 1.994, 95%CI: 1.190-3.342, P = 0.009; TC vs CC + TT: OR = 1.926, 95%CI: 1.140-3.255, P = 0.014). However, the data suggest the rs2308327 and rs2308321 polymorphisms of the MGMT gene were nor associated with the susceptibility of prostate cancer. Based on the meta-analysis, MGMT rs12917 polymorphism increase the susceptibility to prostate cancer, which can be taken for a diagnosis and screening molecular biomarker for prostate cancer patients.
10.1007/s12253-019-00672-7
The association of BRCA1 and BRCA2 mutations with prostate cancer risk, frequency, and mortality: A meta-analysis.
Oh Mok,Alkhushaym Nasser,Fallatah Saad,Althagafi Abdulhamid,Aljadeed Rana,Alsowaida Yazed,Jeter Joanne,Martin Jennifer R,Babiker Hani M,McBride Ali,Abraham Ivo
The Prostate
BACKGROUND:A prior meta-analysis found no association between BRCA1 mutation and prostate cancer (PCa). Subsequent BRCA2 mutation studies have shown an association with PCa risk and mortality. We conducted a meta-analysis of overall BRCA mutation carriers and in subgroups to (1) estimate PCa risk in BRCA mutation carriers, (2) evaluate the frequency of BRCA mutation carriers in patients with PCa, and (3) compare cancer-specific survival (CSS) and overall survival (OS) among BRCA mutation carriers and noncarriers. METHODS:We searched the PubMed/MEDLINE, Embase, and Cochrane databases. Unadjusted odds ratio (OR), percentage (%), and hazard ratio (HR) were used to calculate pooled estimates for PCa risk, frequency, and survival, respectively. Subgroup analyses by mutation type ( BRCA1 or BRCA2) were conducted for the three objectives. Further subgroup analyses by study design (age-sex-adjusted or crude), ascertainment method (ascertained or inferred genotyping), population (Ashkenazi Jewish or general population), and survival outcomes (CSS or OS) were conducted. The associations were evaluated using random-effects models, in two-sided statistical tests. RESULTS:A total of 8 cohort, 7 case-control, 4 case-series, 28 frequency, and 11 survival studies were included. Being a BRCA mutation carrier ( BRCA1 and/or BRCA2) was associated with a significant increase in PCa risk (OR = 1.90, 95% CI = 1.58-2.29), with BRCA2 mutation being associated with a greater risk of PCa (OR = 2.64, 95% CI = 2.03-3.47) than BRCA1 (OR = 1.35, 95% CI = 1.03-1.76). The frequency of BRCA1 and BRCA2 carriers in patients with PCa was 0.9% and 2.2%, respectively. OS (HR = 2.21, 95% CI = 1.64-2.30) and CSS (HR = 2.63, 95% CI = 2.00-3.45) were significantly worse among BRCA2 carriers compared to noncarriers, whereas OS (HR = 0.47, 95% CI = 0.11-1.99) and CSS (HR = 1.07, 95% CI = 0.38-2.96) were statistically not significant when comparing BRCA1 carriers and noncarriers. CONCLUSIONS:There is a 1.90-fold greater risk of PCa in overall BRCA mutation carriers. This elevated PCa risk is attributable mainly to a 2.64-fold greater risk of PCa in BRCA2 carriers compared to a moderate 1.35-fold greater risk in BRCA1 carriers. The frequency of BRCA2 mutations was higher than BRCA1 mutations among patients with PCa. BRCA2 but not BRCA1 mutations were associated with higher PCa mortality. The BRCA mutation may be a clinical factor to stratify high-risk patients and guide clinical strategies for more effective treatments for patients with PCa.
10.1002/pros.23795
Evaluation of cell-free DNA accuracy as diagnostic biomarker for prostate cancer: A systematic review and meta-analysis.
Chen Caixia,Chen Chunfeng,Sadeghi Morteza
Biotechnology and applied biochemistry
PURPOSE:This updated meta-analysis aimed to assess the diagnostic performance of circulating cell-free DNA (cf-DNA) for prostate cancer (PCa). METHODS:A systematic search was conducted in PubMed, Scopus, Web of Science, and Embase databases to retrieve related studies. Several diagnostic estimates, including sensitivity (SE), specificity (SP), likelihood ratios (LRs), and diagnostic odds ratio (DOR) were also used to perform the meta-synthesis. Additionally, the area under hierarchical summary receiver operating characteristic curves (AU-HSROC) was used as a global measure of test accuracy. RESULTS:Twenty-nine unique articles were enrolled in the meta-analysis. Pooled SE and SP for overall accuracy of cf-DNA in PCa were obtained as 0.54 (95% CI: 0.47-0.61) and 0.92 (95% CI: 0.88-0.95), respectively. Positive LR (PLR) was 6.8 (95% CI: 4.9-9.5, I : 92.98%) and negative LR (NLR) was 0.5 (95% CI: 0.43-0.58). Pooled DOR was 13.56 (95% CI: 9.49-19.37) and the AU-HSROC was 0.83 (95% CI: 0.79-0.86). CONCLUSION:The present study suggested that cf-DNA assays have comparable SE as well as remarkably higher SP (qualitative assays) than common biomarkers in the detection of PCa like prostate-specific antigen (PSA). In addition, cf-DNA assays have better performance in PCa confirmation and almost similar performance to PSA in excluding PCa patients.
10.1002/bab.2149
Diagnostic Value of microRNA-375 as Future Biomarker for Prostate Cancer Detection: A Meta-Analysis.
Medicina (Kaunas, Lithuania)
Responding to the need for additional biomarkers for the diagnosis of prostate cancer (PCa), mounting studies show that microRNAs (miRNAs/miRs) possess great potential as future promising diagnostic tools. However, the usefulness of these miRNAs is still highly debated, as the degree of inconsistency between study designs and results is still elevated. Herein, we present a meta-analysis evaluating the diagnostic value and accuracy of circulating miR-375, as it is one of the most studied types of miRs in PCa. The diagnostic accuracy of miR-375 was evaluated using the QUADAS-2 tool, analyzing different statistical parameters. The seven studies (from six articles) that matched our selection included 422 PCa patients and 212 controls (70 healthy volunteers + 142 with benign prostate diseases). We obtained a -value of 0.76 for sensitivity, 0.83 for specificity, 16 for DOR, 4.6 for LR+, 0.29 for LR-, and 0.87 for AUC (95% CI 0.83-0.89). Our results confirm that miRNA-375 has high diagnostic potential for PCa, suggesting its usefulness as a powerful biomarker. More comprehensive studies are warranted to better assess its true value as a diagnostic biomarker for this urologic disease.
10.3390/medicina58040529
Prognostic Value of Lactate Dehydrogenase in Metastatic Prostate Cancer: A Systematic Review and Meta-analysis.
Mori Keiichiro,Kimura Shoji,Parizi Mehdi Kardoust,Enikeev Dmitry V,Glybochko Petr V,Seebacher Veronika,Fajkovic Harun,Mostafaei Hadi,Lysenko Ivan,Janisch Florian,Egawa Shin,Shariat Shahrokh F
Clinical genitourinary cancer
The purpose of this study was to assess the prognostic value of lactate dehydrogenase (LDH) in patients with metastatic prostate cancer (PC). A systematic review and meta-analysis was performed in March 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared patients with PC with high versus low LDH to determine the predictive value of LDH for overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS). We performed a formal meta-analysis for both OS and PFS. A total of 59 articles with 14,851 patients were included in the systematic review and 45 studies with 12,224 patients for the qualitative assessment. High LDH was associated with both worse OS (pooled hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.75-2.44) and PFS (pooled HR, 1.08; 95% CI, 1.01-1.16). In subgroup analyses of both patients with castration-resistant prostate cancer (CRPC) and those with hormone-sensitive prostate cancer (HSPC), LDH was associated with OS (pooled HR, 2.02; 95% CI, 1.69-2.42 and pooled HR, 2.25; 95% CI, 1.78-2.84, respectively). In patients with CRPC, LDH was associated with OS in those treated with docetaxel systemic chemotherapy and androgen receptor-axis-targeting agents (pooled HR, 2.03; 95% CI, 1.37-3.00 and pooled HR, 1.79; 95% CI, 1.25-2.57, respectively). Elevated serum levels of LDH were associated with an increased risk of mortality and progression in patients with metastatic PC. LDH was independently associated with OS in both patients with CRPC and HSPC. LDH could be integrated into prognostic tools that help guide treatment strategy, thereby facilitating the shared decision-making process.
10.1016/j.clgc.2019.07.009
Lower thiol, glutathione, and glutathione peroxidase levels in prostate cancer: a meta-analysis study.
Sajjaboontawee Nattanan,Supasitthumrong Thitiporn,Tunvirachaisakul Chavit,Nantachai Kanyapak,Snabboon Thiti,Reiche Edna Maria Vissoci,Simão Andréa Name Colado,Maes Michael
The aging male : the official journal of the International Society for the Study of the Aging Male
PURPOSE:Lowered thiol (-SH) groups and glutathione (GSH) metabolism may be associated with prostate cancer (PCa) and benign prostatic hyperplasia (BPH). The objectives of this study were to systematically review and meta-analyze the associations among -SH groups, GSH, GSH peroxidase (GPx), GSH reductase (GR), and GSH transferase (GST) and PCa/BPH. METHODS:Four electronic databases were searched for studies that reported -SH and GSH variables in PCa/BPH and healthy controls (HC) and the data were meta-analyzed by calculating Hedges's with 95% confidence intervals. RESULTS:Twenty studies were included in this meta-analysis. Total -SH ( = -1.750, -2.341/-1.159), GPx ( = -0.789, -1.234/-0.344), GSH ( = -2.219, -4.132/-0.305), and the combination of -SH, GPx, and GSH ( = -1.271, -1.271/-0.800) were significantly lower in PCa patients than in HC. -SH ( = -1.752, -3.123/-0.381) and the combination of -SH, GPx, and GSH ( = -0.813, -1.298/-0.327) were significantly lower in BPH patients than in HC. GPx was significantly lower in PCa than in BPH patients ( = -0.455, -0.896/-0.014). Heterogeneity levels were very high, but Egger's test showed that none of the biomarkers showed significant publication bias. CONCLUSION:Thiol/GPx antioxidant defenses are significantly attenuated in patients with PCa while patients with BPH occupy an intermediate risk group position between PCa patients and HC.
10.1080/13685538.2020.1858048
Prognostic and clinicopathological value of CDK12 mutation in prostate cancer: a meta-analysis.
Expert review of anticancer therapy
BACKGROUND:Cyclin-dependent kinase 12 (CDK12) mutation has been shown to be associated with the prognosis and clinicopathological characteristics of various tumors. The aim of this meta-analysis was to investigate the role of mutations in prostate cancer (PCa). RESEARCH DESIGN AND METHODS:PubMed/Medline, EMBASE, Cochrane Library, and Web of Science database were searched for relevant articles. Meta-analysis was performed by using RevMan5.3 software, and the quality of the included literature was evaluated according to the Newcastle-Ottawa scale (NOS). RESULTS:A total of 13 studies comprising 5182 participants were enrolled in this meta-analysis. The frequency of CDK12 mutation in PCa was 7.26%. CDK12 mutation was significantly correlated with poor OS/PFS and had a shorter time to progress to CRPC. CDK12 mutant was associated with high-grade Gleason scores, while no relationships were found among CDK12 mutant, age, and the PSA level at diagnosis. CONCLUSION:This meta-analysis indicates that patients with CDK12 mutation have poor prognosis in PCa. CDK12 may be used as a biomarker for molecular subtype and a potential therapeutic target of PCa.
10.1080/14737140.2023.2168647
Prognostic value of miR-21 for prostate cancer: a systematic review and meta-analysis.
Stafford M Y Cynthia,Willoughby Colin E,Walsh Colum P,McKenna Declan J
Bioscience reports
Elevated levels of miR-21 expression are associated with many cancers, suggesting it may be a promising clinical biomarker. In prostate cancer (PCa), however, there is still no consensus about the usefulness of miR-21 as an indicator of disease progression. This systematic review and meta-analysis was conducted to investigate the value of miR-21 expression as a prognostic measurement in PCa patients. Medline (Ovid), EMBASE, Web of Science, Scopus and Cochrane Library databases were systematically searched for relevant publications between 2010 to 2021. Studies exploring the relationship between miR-21 expression, PCa prognosis and clinicopathological factors were selected for review. Those reporting hazard ratio (HR) and 95% confidence intervals (CIs) were subject to meta-analyses. Fixed-effect models were employed to calculated pooled HRs and 95% CIs. Risk of bias in each study was assessed using QUIPS tool. Certainty of evidence in each meta-analysis was assessed using GRADE guidelines. A total of 64 studies were included in the systematic review. Of these, 11 were eligible for inclusion in meta-analysis. Meta-analyses revealed that high miR-21 expression was associated with poor prognosis: HR = 1.58 (95% CI = 1.19-2.09) for biochemical recurrence, MODERATE certainty; HR = 1.46 (95% CI = 1.06-2.01) for death, VERY LOW certainty; and HR = 1.26 (95% CI = 0.70-2.27) for disease progression, VERY LOW certainty. Qualitative summary revealed elevated miR-21 expression was significantly positively associated with PCa stage, Gleason score and risk groups. This systematic review and meta-analysis suggests that elevated levels of miR-21 are associated with poor prognosis in PCa patients. miR-21 expression may therefore be a useful prognostic biomarker in this disease.
10.1042/BSR20211972
Interplay Among PI3K/AKT, PTEN/FOXO and AR Signaling in Prostate Cancer.
Yan Yuqian,Huang Haojie
Advances in experimental medicine and biology
The PI3K signaling pathway is activated in a majority of cancer types. It promotes tumorigenesis by regulating nutrient metabolism, cell proliferation, survival, migration, and angiogenesis. The underlying mechanisms of PI3K/AKT activation are mainly due to deletions or mutations in its key negative regulator gene-PTEN. However, mutations in other pathway genes, such as the tumor suppressor gene SPOP, may contribute indirectly to the activation of this pathway. Interestingly, a mutually exclusive relationship exists between genomic alterations in PTEN and mutations in SPOP in prostate cancer patients, suggesting that altered functions of these two tumor suppressors might share similar or at least partially overlapping mechanisms in tumorigenesis. Activated AKT can phosphorylate directly a number of downstream effectors and thereby inhibit or activate their functions. An important target of PI3K/AKT signaling is FOXO1 protein that can be phosphorylated directly by AKT leading to translocation of FOXO1 from the cytoplasm to the nucleus. This not only impairs FOXO1 activities on transactivation of downstream target genes, but also abolishes its transcriptional activity-independent inhibitory effect on other targets such as AR, ERG and RUNX2. Interestingly, heterozygous deletion of Pten, or mutation of Spop alone has minimal effects on tumorigenesis in the mouse prostate, suggesting that PI3K/AKT pathway interacts with other pathways to drive prostate cancer progression. Indeed, the cross talk between PI3K/AKT and other pathways, such as AR, WNT, and ERK signaling pathways is known to play essential roles in disease progression and drug resistance in prostate cancer. Therefore, co-targeting the PI3K/AKT signaling pathway and its cooperating pathways may be critical for improving the anti-cancer efficacy of PI3K/AKT inhibitors in the clinic.
10.1007/978-3-030-32656-2_14
Wnt/Beta-Catenin Signaling and Prostate Cancer Therapy Resistance.
Yeh Yunshin,Guo Qiaozhi,Connelly Zachary,Cheng Siyuan,Yang Shu,Prieto-Dominguez Nestor,Yu Xiuping
Advances in experimental medicine and biology
Metastatic or locally advanced prostate cancer (PCa) is typically treated with androgen deprivation therapy (ADT). Initially, PCa responds to the treatment and regresses. However, PCa almost always develops resistance to androgen deprivation and progresses to castrate-resistant prostate cancer (CRPCa), a currently incurable form of PCa. Wnt/β-Catenin signaling is frequently activated in late stage PCa and contributes to the development of therapy resistance. Although activating mutations in the Wnt/β-Catenin pathway are not common in primary PCa, this signaling cascade can be activated through other mechanisms in late stage PCa, including cross talk with other signaling pathways, growth factors and cytokines produced by the damaged tumor microenvironment, release of the co-activator β-Catenin from sequestration after inhibition of androgen receptor (AR) signaling, altered expression of Wnt ligands and factors that modulate the Wnt signaling, and therapy-induced cellular senescence. Research from genetically engineered mouse models indicates that activation of Wnt/β-Catenin signaling in the prostate is oncogenic, enables castrate-resistant PCa growth, induces an epithelial-to-mesenchymal transition (EMT), promotes neuroendocrine (NE) differentiation, and confers stem cell-like features to PCa cells. These important roles of Wnt/β-Catenin signaling in PCa progression underscore the need for the development of drugs targeting this pathway to treat therapy-resistant PCa.
10.1007/978-3-030-32656-2_16
DNA Methylation-Based Testing in Liquid Biopsies as Detection and Prognostic Biomarkers for the Four Major Cancer Types.
Cells
Lung, breast, colorectal, and prostate cancers are the most incident worldwide. Optimal population-based cancer screening methods remain an unmet need, since cancer detection at early stages increases the prospects of successful and curative treatment, leading to a lower incidence of recurrences. Moreover, the current parameters for cancer patients' stratification have been associated with divergent outcomes. Therefore, new biomarkers that could aid in cancer detection and prognosis, preferably detected by minimally invasive methods are of major importance. Aberrant DNA methylation is an early event in cancer development and may be detected in circulating cell-free DNA (ccfDNA), constituting a valuable cancer biomarker. Furthermore, DNA methylation is a stable alteration that can be easily and rapidly quantified by methylation-specific PCR methods. Thus, the main goal of this review is to provide an overview of the most important studies that report methylation biomarkers for the detection and prognosis of the four major cancers after a critical analysis of the available literature. DNA methylation-based biomarkers show promise for cancer detection and management, with some studies describing a "PanCancer" detection approach for the simultaneous detection of several cancer types. Nonetheless, DNA methylation biomarkers still lack large-scale validation, precluding implementation in clinical practice.
10.3390/cells9030624
Serum and urine biomarkers for detecting clinically significant prostate cancer.
Becerra Maria F,Atluri Venkatasai S,Bhattu Amit S,Punnen Sanoj
Urologic oncology
Since the "prostate-specific antigen (PSA) era," we have seen an increase in unnecessary biopsies, which has ultimately lead to an overtreatment of low-risk cancers. Given the limitations of prostate-specific antigen and the invasive nature of prostate biopsy several serum and urinary biomarkers have been developed. In this paper, we provide a comprehensive review of the available biomarkers for the detection clinically significant prostate cancer namely PHI, 4Kscore, PCA3, MiPS, SelectMDx, ExosomeDX. Current literature suggests that these biomarkers can improve detection of clinically significant prostate cancer reducing overtreatment and making treatment strategies more cost-effective. Nevertheless, large prospective studies with head-to-head-comparisons of the available biomarkers are necessary to fully assess the potential of incorporating biomarkers in routine clinical practice.
10.1016/j.urolonc.2020.02.018
Detection and Prognosis of Prostate Cancer Using Blood-Based Biomarkers.
Mediators of inflammation
Prostate cancer (PCa) is second only to lung cancer as a cause of death. Clinical assessment of patients and treatment efficiency therefore depend on the disease being diagnosed as early as possible. However, due to issues regarding the use of prostate-specific antigen (PSA) for screening purposes, PCa management is among the most contentious of healthcare matters. PSA screening is problematic primarily because of diagnosis difficulties and the high rate of false-positive biopsies. Novel PCa biomarkers, such as the Prostate Health Index (PHI) and the 4Kscore, have been proposed in recent times to improve PSA prediction accuracy and have shown higher performance by preventing redundant biopsies. The 4Kscore also shows high precision in determining the risk of developing high-grade PCa, whereas elevated PHI levels suggest that the tumor is aggressive. Some evidence also supports the effectiveness of miRNAs as biomarkers for distinguishing PCa from benign prostatic hyperplasia and for assessing the aggressiveness of the disease. A number of miRNAs that possibly act as tumor inhibitors or oncogenes are impaired in PCa. These new biomarkers are comprehensively reviewed in the present study in terms of their potential use in diagnosing and treating PCa.
10.1155/2020/8730608
CCL2/CCR2 signaling in cancer pathogenesis.
Hao Qiongyu,Vadgama Jaydutt V,Wang Piwen
Cell communication and signaling : CCS
Chemokines are a family of small cytokines, which guide a variety of immune/inflammatory cells to the site of tumor in tumorigenesis. A dysregulated expression of chemokines is implicated in different types of cancer including prostate cancer. The progression and metastasis of prostate cancer involve a complex network of chemokines that regulate the recruitment and trafficking of immune cells. The chemokine CCL2 and its main receptor CCR2 have been receiving particular interest on their roles in cancer pathogenesis. The up-regulation of CCL2/CCR2 and varied immune conditions in prostate cancer, are associated with cancer advancement, metastasis, and relapse. Here we reviewed recent findings, which link CCL2/CCR2 to the inflammation and cancer pathogenesis, and discussed the therapeutic potential of CCL2/CCR2 axis in cancer treatment based on results from our group and other investigators, with a major focus on prostate cancer. Video Abstract.
10.1186/s12964-020-00589-8
The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling.
International journal of molecular sciences
Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.
10.3390/ijms21124507
Biomarkers That Differentiate Benign Prostatic Hyperplasia from Prostate Cancer: A Literature Review.
McNally Christopher J,Ruddock Mark W,Moore Tara,McKenna Declan J
Cancer management and research
Prediction of prostate cancer in primary care is typically based upon serum total prostate-specific antigen (tPSA) and digital rectal examination results. However, these tests lack sensitivity and specificity, leading to over-diagnosis of disease and unnecessary, invasive biopsies. Therefore, there is a clinical need for diagnostic tests that can differentiate between benign conditions and early-stage malignant disease in the prostate. In this review, we evaluate research papers published from 2009 to 2019 reporting biomarkers that identified or differentiated benign prostatic hyperplasia (BPH) from prostate cancer. Our review identifies hundreds of potential biomarkers in urine, serum, tissue, and semen proposed as useful targets for differentiating between prostate cancer and BPH patients. However, it is still not apparent which of these candidate biomarkers are most useful, and many will not progress beyond the discovery stage unless they are properly validated for clinical practice. We conclude that this validation will come through the use of multivariate panels which can assess the value of biomarker candidates in combination with clinical parameters as part of a risk prediction calculator. Implementation of such a model will help clinicians stratify patients with prostate cancer symptoms in primary care, with tangible benefits for both the patient and the health service.
10.2147/CMAR.S250829
Targeting defective DNA repair in prostate cancer.
Carmichael Juliet,Maza Maria de Los Dolores Fenor de la,Rescigno Pasquale,Chandran Khobe,de Bono Johann
Current opinion in oncology
PURPOSE OF REVIEW:Prostate cancer is the second leading cause of cancer death in men. Characterization of the genomic landscape of prostate cancer has demonstrated frequent aberrations in DNA repair pathways, identifiable in up to 25% patients with metastatic disease, which may sensitize to novel therapies, including PARP inhibitors and immunotherapy. Here, we summarize the current clinical landscape and future horizons for targeting defective DNA repair pathways in PC. RECENT FINDINGS:Several clinical trials have demonstrated efficacy of different PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC), most pronounced in those with BRCA mutations. The PROfound trial is the first positive phase 3 biomarker-selected trial to demonstrate improved outcomes with a targeted treatment, Olaparib, in mCRPC. Whilst the Keynote-199 trial failed to demonstrate efficacy of immune-checkpoint inhibitor pembrolizumab in unselected mCRPC patients, there was evidence of response in those harbouring DNA repair defects. SUMMARY:These landmark trials represent a significant advance towards personalization of PC therapy. However, resistance remains inevitable and there is a lack of reliable predictive biomarkers to select patients for treatment. Characterization of resistance mechanisms, and validation of novel biomarkers is critical to maximize clinical benefit and inform novel treatment combinations to improve outcomes.
10.1097/CCO.0000000000000654
Altered expression of cytochrome P450 enzymes involved in metabolism of androgens and vitamin D in the prostate as a risk factor for prostate cancer.
Maksymchuk Oksana V,Kashuba Vladimir I
Pharmacological reports : PR
Prostate cancer is the most common malignant disease among men. The signaling pathways, regulated by the androgen and vitamin D receptors, play a key role in prostate cancer. The intracellular level of androgens and vitamin D determines not only receptor functionality, but also the efficacy of cellular processes regulated by them (cell proliferation, apoptosis, differentiation etc.). It is known that several androgen-metabolizing P450s (CYP3A4/5/43 and CYP2B6) and P450 enzymes (CYP2R1, CYP27A1, CYP27B1, CYP24A1, CYP3A4, CYP2J2), which are necessary for vitamin D metabolism, are expressed in the prostate. It was shown that alterations in an expression pattern of the certain cytochrome P450s might lead to the development of castration-resistant cancer (CYP3A4, CYP2J2, CYP24A1), and to chemo-resistance (CYP3A4, CYP3A5, CYP2B6) and early mortality (CYP2B6, CYP27A1, CYP24A1). Moreover, steroidogenic CYPs (CYP17A1, CYP11A1) are not expressed in normal prostate tissue. Alterations in their expression levels in steroidogenic tissues are closely associated with carcinogenesis, and, most importantly, with the development of aggressive forms of prostate cancer. Hence, it is important, to study how expression of CYPs in the prostate might be regulated, to understand the mechanisms of disease development and to improve the effectiveness of therapy. Several CYPs (CYP3A43, CYP2B6, CYP27A1, CYP24A1) can be considered as prognostic and diagnostic markers of prostate cancer. To propose personalized treatment, individual differences in CYP expression should be taken into account.
10.1007/s43440-020-00133-y
Genetic testing for the clinician in prostate cancer.
López-Campos Fernando,Linares-Espinós Estefanía,Maldonado Pijoan Xavier,Sancho Pardo Gemma,Morgan Todd Mathew,Martínez-Ballesteros Claudio,Martínez-Salamanca Juan,Couñago Felipe
Expert review of molecular diagnostics
INTRODUCTION:Prostate cancer (PCa) is one of the most common cancers worldwide and a leading cause of cancer-related mortality. Although the diagnosis and treatment of prostate cancer has improved substantially in recent years, new molecular biomarkers are needed to further prolong survival and improve the quality of life in these patients. AREAS COVERED:This review analyzes the current evidence for prognostic and predictive molecular biomarkers that can be applied across different clinical scenarios, ranging from localized disease to metastatic castration-resistant PCa, with a particular emphasis on the biomarkers likely to become available in routine clinical practice in the near future. EXPERT OPINION:There is a growing need for molecular testing to identify the most indolent types of prostate cancer to help optimize treatment strategies and spare treatment in these patients when possible. Current trends in the treatment of prostate cancer underscore the unmet clinical need for biomarkers to improve decision-making in a challenging clinical setting.
10.1080/14737159.2020.1816170
The auxiliary diagnostic value of prostate-specific antigen and α-methylacyl-CoA racemase in prostate cancer.
Yang Daijun,Shi Xiang,Lei Yu,Zhou Xianrong,Chen Qiuxiang
Oncology letters
Prostate cancer (PCa) is one of the most common types of malignant tumor, which places a major burden on the health of men, worldwide. A prerequisite to ensure good treatment outcomes for patients with PCa is an accurate diagnosis. The present study aimed to investigate the diagnostic value of prostate-specific antigen (PSA) and α-methylacyl-CoA racemase (P504S) in PCa, using the tumor-associated immunolabels. In total, clinical data was collected from 125 patients undergoing prostate biopsy or surgery between January 2015 and September 2019, and stratified into: PCa (45), benign prostatic hyperplasia (BPH) (60) and unconfirmed diagnosis (20). Immunohistochemistry analysis was performed to assess PSA and P504S expression levels in each group compared with that in the controls (the normal tissue in each group was the internal control). The results demonstrated that the expression level of P504S was significantly higher in the PCa group compared with that in the BPH group. Furthermore, no significant association was observed in the PCa group between PSA and P504S expression levels, and the Gleason grading groups. A total of 20 unconfirmed diagnoses was verified via PSA/P504S. Taken together, the results suggest that combination PSA and P504S have a positive effect in identifying prostate cancer. However, PSA and P504S still have limitations in their diagnosis and the final results need to be carefully and comprehensively analyzed, thus further studies are required to determine their diagnostic values.
10.3892/ol.2020.11658
Detection of rare prostate cancer cells in human urine offers prospect of non-invasive diagnosis.
Scientific reports
Two molecular cytology approaches, (i) time-gated immunoluminescence assay (TGiA) and (ii) Raman-active immunolabeling assay (RiA), have been developed to detect prostate cancer (PCa) cells in urine from five prostate cancer patients. For TGiA, PCa cells stained by a biocompatible europium chelate antibody-conjugated probe were quantitated by automated time-gated microscopy (OSAM). For RiA, PCa cells labeled by antibody-conjugated Raman probe were detected by Raman spectrometer. TGiA and RiA were first optimized by the detection of PCa cultured cells (DU145) spiked into control urine, with TGiA-OSAM showing single-cell PCa detection sensitivity, while RiA had a limit of detection of 4-10 cells/mL. Blinded analysis of each patient urine sample, using MIL-38 antibody specific for PCa cells, was performed using both assays in parallel with control urine. Both assays detected very low abundance PCa cells in patient urine (3-20 PCa cells per mL by TGiA, 4-13 cells/mL by RiA). The normalized mean of the detected PCa cells per 1 ml of urine was plotted against the clinical data including prostate specific antigen (PSA) level and Clinical Risk Assessment for each patient. Both cell detection assays showed correlation with PSA in the high risk patients but aligned with the Clinical Assessment rather than with PSA levels of the low/intermediate risk patients. Despite the limited available urine samples of PCa patients, the data presented in this proof-of-principle work is promising for the development of highly sensitive diagnostic urine tests for PCa.
10.1038/s41598-022-21656-9
The Genetic Complexity of Prostate Cancer.
Genes
Prostate cancer (PCa) is a major concern in public health, with many genetically distinct subsets. Genomic alterations in PCa are extraordinarily complex, and both germline and somatic mutations are of great importance in the development of this tumor. The aim of this review is to provide an overview of genetic changes that can occur in the development of PCa and their role in potential therapeutic approaches. Various pathways and mechanisms proposed to play major roles in PCa are described in detail to provide an overview of current knowledge.
10.3390/genes11121396
The crossroads of adenosinergic pathway and epithelial-mesenchymal plasticity in cancer.
Seminars in cancer biology
Epithelial-mesenchymal transition (EMT) is a key mechanism related to tumor progression, invasion, metastasis, resistance to therapy and poor prognosis in several types of cancer. However, targeting EMT or partial-EMT, as well as the molecules involved in this process, has remained a challenge. Recently, the CD73 enzyme, which hydrolyzes AMP to produce adenosine (ADO), has been linked to the EMT process. This relationship is not only due to the production of the immunosuppressant ADO but also to its role as a receptor for extracellular matrix proteins, being involved in cell adhesion and migration. This article reviews the crosstalk between the adenosinergic pathway and the EMT program and the impact of this interrelation on cancer development and progression. An in silico analysis of RNAseq datasets showed that several tumor types have a significant correlation between an EMT score and NT5E (CD73) and ENTPD1 (CD39) expressions, with the strongest correlations being in prostate adenocarcinoma. Furthermore, it is evident that the cooperation between EMT and the adenosinergic pathway in tumor progression is context and tumor-dependent. The increased knowledge about this topic will help broaden the view to explore new treatments and therapies for different types of cancer.
10.1016/j.semcancer.2022.06.012
Liquid Biopsy for Prostate and Bladder Cancer: Progress and Pitfalls.
European urology focus
Urinary liquid biopsy (LB) tests have contributed to reducing overtreatment and improving the detection of bladder and prostate cancer. Circulating tumor cells, DNA, and RNA are the focus of next-generation blood-based LB tests. These tests aim to stratify risk according to the detection of resistance and recurrence markers in patients with metastatic disease. The costs, lack of standardization, reimbursement challenges, and specialized workflows associated with characterization of blood-derived biomarkers are the primary barriers to their clinical implementation. This review provides an overview of the successes and pitfalls of LB-based tests for bladder and prostate cancer. PATIENT SUMMARY: Urinary and blood-based liquid biopsy tests are minimally invasive and highly efficacious in detecting clinically significant cancer.
10.1016/j.euf.2022.08.013
P2Y purinergic signaling in prostate cancer: Emerging insights into pathophysiology and therapy.
Biochimica et biophysica acta. Reviews on cancer
Despite recent advances in the treatment landscape for prostate cancer, many challenges still remain. A more profound understanding of prostate cancer pathogenesis and the underlying mechanisms is critical to developing novel therapeutics strategies. Extracellular nucleotides play a central role in the growth and progression of a variety of cancer types - almost all tumor cells and immune cells express purinergic membrane receptors for extracellular nucleotides (ATP, ADP, UTP, UDP, UDP-sugar) and their metabolic nucleoside products (e.g., adenosine). Herein we review the pathological and immunomodulatory roles of P2Y purinergic nucleotide receptors in prostate cancer and their potential as therapeutic targets to address some of the clinical limitations in prostate cancer treatment.
10.1016/j.bbcan.2022.188732
Role of bromodomain and extraterminal (BET) proteins in prostate cancer.
Expert opinion on investigational drugs
INTRODUCTION:The bromodomain and extraterminal (BET) family of proteins are epigenetic readers of acetylated histones and are critical activators of oncogenic networks across many cancers. Therapeutic targeting of BET proteins has been an attractive area of clinical development for metastatic castration-resistant prostate cancer. In recent years, many structurally diverse BET inhibitors have been discovered and tested. Preclinical studies have demonstrated significant antiproliferative activity of BET inhibitors against prostate cancer. However, their clinical success as monotherapies has been limited by treatment-associated toxicities, primary and acquired drug resistance, and a lack of predictive biomarkers of benefit. AREAS COVERED:This review provides an overview of advancements in BET inhibitor design, preclinical research, and conclusions from clinical trials in prostate cancer. We speculate on incorporating BET inhibitors into combination regimens with other agents to improve the therapeutic index of BET inhibition in treating prostate cancer. EXPERT OPINION:The therapeutic potential of BET inhibitors for prostate cancer has been demonstrated in preclinical studies. However, further research is needed to identify biomarkers that can predict sensitivity to BET inhibitors and to develop novel, highly selective inhibitors to reduce toxicities. Finally, BET inhibitors are likely to hold the most clinical potential in combination with other agents.
10.1080/13543784.2023.2186851
Diagnosing and Prognosing Bone Metastasis in Prostate Cancer: Clinical Utility of Blood Biomarkers.
Anticancer research
Bone metastasis (BM) may occur in any type of cancer. The diagnosis of patients with BM has increased due to improved imaging technologies and advances in cancer drug therapy that have prolonged the survival time of cancer patients. BM may be asymptomatic in the early stages; however, as the disease progresses, it causes pain, fracture, neurological symptoms associated with spinal cord compression, hypercalcemia, and other specific symptoms that significantly impair the patient's quality of life (QOL). Imaging modalities have disadvantages, such as high cost, radiation exposure, and bone pain associated with holding posture for imaging test; further, they are time-consuming. Hence, patients with BM require convenient and useful biomarkers. However, no blood biomarkers generally useful for diagnosis and therapeutic monitoring of BM are established. Prostate cancer (PC) and breast cancer, in particular, are among the most prone to BM because BM occurs in approximately 70% of patients with advanced disease. Herein, we reviewed various potential bone turnover markers and liquid biopsy for diagnosis and prognosis prediction in patients with BM of PC based on PubMed literature search. The usefulness of conventional bone turnover markers of BM in PC is limited, and cut-off values vary. In the future, the creation of algorithms using these conventional markers and multiple tests, such as liquid biopsy and imaging tests, will help to develop highly accurate techniques for the diagnosis of BM.
10.21873/anticanres.16161
Circulating myeloid-derived suppressor cells and survival in prostate cancer patients: systematic review and meta-analysis.
Prostate cancer and prostatic diseases
BACKGROUND:Immunotherapy has not achieved improvement of survival in prostate cancer patients. Myeloid-derived suppressor cells (MDSCs) in tumor microenvironment can hamper its efficacy. Some preclinical studies explored the role of MDSCs in prostate cancer development. We aimed to verify the availability of studies exploring the prognostic effect of circulating MDSCs in prostate cancer patients. METHODS:We systematically selected studies for a meta-analysis, which compares survival between prostate cancer patients with high vs low circulating MDSC levels. We extracted or calculated hazard ratios (HRs) and relative 95% confidence intervals (CIs) in terms of overall survival (OS) from selected studies. We calculated the pooled HR and relative 95% CIs and estimated publication bias. RESULTS:Among 133 studies retrieved from search on Pubmed, 5 eligible studies (236 prostate cancer patients) met inclusion criteria. High circulating MDSC levels are associated with a worse OS (HR = 2.19; 95%CI = 1.51-3.17). Heterogeneity was not significant (I = 0%; p = 0.64). Publication bias was also not significant (Egger's test, p = 0.09). CONCLUSIONS:High levels of circulating MDSCs induce a worse OS in prostate cancer patients than in those with low levels. This finding supports the importance of MDSC detection and targeting also in prostate cancer patients.
10.1038/s41391-022-00615-5
Crucial Roles of microRNA-Mediated Autophagy in Urologic Malignancies.
International journal of biological sciences
Urologic oncologies are major public health problems worldwide. Both microRNA and autophagy, separately or concurrently, are involved in a variety of the cellular and molecular processes of multiple cancers, including urologic malignancies. In this review, we have summarized the related studies and found that microRNA-mediated autophagy acted as carcinogenic factors or suppressors in prostate cancer, kidney cancer, and bladder cancer. MiRNAs, targeted genes, and the different signaling pathways constitute a complex network that orchestrates autophagy regulation, militating the oncogenic and tumor-suppressive effects in urologic malignancies. Aberrant expression of miRNAs may induce the dysregulation of the autophagy process, resulting in tumorigenesis, progression, and resistance to anticancer therapies. Targeting specific miRNAs for autophagy modulation may present as reliable diagnostic and prognostic biomarkers or promising therapeutic strategies for urologic oncologies.
10.7150/ijbs.61175
BRCA2 gene mutation and prostate cancer risk. Comprehensive review and update.
Saudi medical journal
The second most common type of tumor worldwide is prostate cancer (PCa). Certain genetic factors contribute to a risk of developing PCa of as much as 40%. BRCA1 and BRCA2 mutations have linked with an increased risk for breast, ovarian, and PCa. However, BRCA2 is the most common gene found altered in early-onset of PCa in males younger than 65. BRCA2 mutation has a higher chance of developing an advanced stage of the disease, resulting in short survival time. This review aimed to describe the genetic changes in BRCA2 that contribute to the risk of PCa, to define its role in the early diagnosis in a man with a strong family history, and to outline the purpose of genetic testing and counseling. Also, the review summarizes the impact of BRCA2 gene mutation in localized PCa, and the treatment strategies have used for PCa patients with a BRCA2 modification.
10.15537/smj.2020.1.24759
The emerging landscape of tumor marker panels for the identification of aggressive prostate cancer: the perspective through bibliometric analysis of an Italian translational working group in uro-oncology.
Ferro Matteo,Lucarelli Giuseppe,de Cobelli Ottavio,Del Giudice Francesco,Musi Gennaro,Mistretta Francesco A,Luzzago Stefano,Busetto Gian M,Buonerba Carlo,Sciarra Alessandro,Conti Simon,Porreca Angelo,Battaglia Michele,Ditonno Pasquale,Manfredi Matteo,Fiori Cristian,Porpiglia Francesco,Terracciano Daniela
Minerva urology and nephrology
Molecular heterogeneity and availability of different therapeutic strategies are relevant clinical features of prostate cancer. On this basis, there is an urgent need to identify prognostic and predictive biomarkers for an individualized therapeutic approach. In this context, researchers focused their attention on biomarkers able to discriminate potential life-threatening from organ-confined disease. Such biomarker could provide aid in clinical decision making, helping to choose the treatment which ensures the best results in terms of patient survival and quality of life. To address this need, many new laboratory tests have been proposed, with a clear tendency to use panels of combined biomarkers. In this review we evaluate current data on the application in clinical practice of the most promising laboratory tests: Phi, 4K score and Stockholm 3 as circulating biomarkers, Mi-prostate score, Exo DX Prostate and Select MD-X as urinary biomarkers, Confirm MDx, Oncotype Dx, Prolaris and Decipher as tissue biomarkers. In particular, the ability of these tests in the identification of clinically significant PCa and their potential use for precision medicine have been explored in this review.
10.23736/S2724-6051.21.04098-4
Prostate cancer-specific hallmarks of amino acids metabolism: Towards a paradigm of precision medicine.
Strmiska Vladislav,Michalek Petr,Eckschlager Tomas,Stiborova Marie,Adam Vojtech,Krizkova Sona,Heger Zbynek
Biochimica et biophysica acta. Reviews on cancer
So far multiple differences in prostate cancer-specific amino acids metabolism have been discovered. Moreover, attempts to utilize these alterations for prostate cancer diagnosis and treatment have been made. The prostate cancer metabolism and biosynthesis of amino acids are particularly focused on anaplerosis more than on energy production. Other crucial requirements on amino acids pool come from the serine, one‑carbon cycle, glycine synthesis pathway and folate metabolism forming major sources of interproducts for synthesis of nucleobases necessary for rapidly proliferating cells. Considering the lack of some amino acids biosynthetic pathways and/or their extraordinary importance for prostate cancer cells, there is a widespread potential for targeted therapeutic applications with no effect on non-malignant cells. This review summarizes the up-to-date knowledge of the importance of amino acids for prostate cancer pathogenesis with a special emphasis on potential applications of metabolic variabilities in the new oncologic paradigm of precision medicine.
10.1016/j.bbcan.2019.01.001
Genetic biomarkers to guide poly(ADP-ribose) polymerase inhibitor precision treatment of prostate cancer.
Varnai Reka,Sipeky Csilla
Pharmacogenomics
Precision therapy for a subgroup of genetically defined metastatic castration-resistant prostate cancer patients may become a reality in the near future. DNA damage repair gene mutated prostate cancer might be vulnerable to treatment with PARP inhibitors (PARPi). PARPi clinical trials for prostate cancer investigate both germline and somatic genomic alterations of 43 genes for the applicability as genomic biomarker of PARPi sensitivity. Clinical trials with preliminary results show that and , but also , additionally , and may affect clinical end points, and may be potential candidates for genome-guided patient selection in PARPi treatment of prostate cancer.
10.2217/pgs-2020-0019
Molecular tracing of prostate cancer lethality.
Wang Yuanshuo Alice,Sfakianos John,Tewari Ashutosh K,Cordon-Cardo Carlos,Kyprianou Natasha
Oncogene
Prostate cancer is diagnosed mostly in men over the age of 50 years, and has favorable 5-year survival rates due to early cancer detection and availability of curative surgical management. However, progression to metastasis and emergence of therapeutic resistance are responsible for the majority of prostate cancer mortalities. Recent advancement in sequencing technologies and computational capabilities have improved the ability to organize and analyze large data, thus enabling the identification of novel biomarkers for survival, metastatic progression and patient prognosis. Large-scale sequencing studies have also uncovered genetic and epigenetic signatures associated with prostate cancer molecular subtypes, supporting the development of personalized targeted-therapies. However, the current state of mainstream prostate cancer management does not take full advantage of the personalized diagnostic and treatment modalities available. This review focuses on interrogating biomarkers of prostate cancer progression, including gene signatures that correspond to the acquisition of tumor lethality and those of predictive and prognostic value in progression to advanced disease, and suggest how we can use our knowledge of biomarkers and molecular subtypes to improve patient treatment and survival outcomes.
10.1038/s41388-020-01496-5
Intraductal Carcinoma of the Prostate: Pathogenesis and Molecular Perspectives.
European urology focus
Intraductal carcinoma of the prostate (IDC-P), a clinicopathological entity characterized by malignant prostatic epithelial cells growing within ducts and/or acini, has a distinct architectural pattern, cytological features, and biological behavior. Whereas most IDC-P tumors could be derived from adjacent high-grade invasive cancer via retrograde spreading of cancer cells along benign ducts and acini, a small subset of IDC-P may arise from the transformation and intraductal proliferation of precancerous cells induced by various oncogenic events. These isolated IDC-P tumors possess a distinct mutational profile and may function as a carcinoma in situ lesion with de novo intraductal outgrowth of malignant cells. Further molecular characterization of these two types of IDC-P and better understanding of the mechanisms underlying IDC-P formation and progression could be translated into valuable biomarkers for differential diagnosis and actionable targets for therapeutic interventions. PATIENT SUMMARY: Intraductal carcinoma of the prostate is an aggressive type of prostate cancer associated with high risk for local recurrence and distant metastasis. In this review, we discussed pathogenesis, biomarkers, differential diagnoses, and therapeutic strategies for this tumor.
10.1016/j.euf.2020.10.007
Molecular pathology of prostate cancer: a practical approach.
Vlajnic Tatjana,Bubendorf Lukas
Pathology
While localised prostate cancer can be cured by local treatment, 'high-risk' prostate cancer often progresses to castration resistant disease and remains incurable with a dismal prognosis. In recent years, technical advances and development of novel methodologies have largely contributed to a better understanding of underlying molecular mechanisms that promote tumour growth and progression. Consecutively, novel therapeutic strategies for treatment of prostate cancer have emerged during the last decade, calling for the identification of predictive biomarkers. The concept of personalised medicine is to tailor treatment according to the specific tumour profile of an individual patient. Moreover, acquired molecular changes during tumour evolution and in response to therapy selection pressure require adapted predictive marker testing at different time points during the disease. In this setting, the pathologist plays a critical role in patient management and treatment selection. In this review, we provide a comprehensive overview of the current knowledge of molecular aspects of prostate cancer and their potential utility in the context of different therapeutic approaches. Furthermore, we discuss methods for molecular marker testing in routine clinical practice, with a focus on castration resistant prostate cancer.
10.1016/j.pathol.2020.10.003
Prostate Cancer Biomarker Development: National Cancer Institute's Early Detection Research Network Prostate Cancer Collaborative Group Review.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Prostate cancer remains the most common non-skin cancer and second leading cause of death among men in the United States. Although progress has been made in diagnosis and risk assessment, many clinical questions remain regarding early identification of prostate cancer and management. The early detection of aggressive disease continues to provide high curative rates if diagnosed in a localized state. Unfortunately, prostate cancer displays significant heterogeneity within the prostate organ and between individual patients making detection and treatment strategies complex. Although prostate cancer is common among men, the majority will not die from prostate cancer, introducing the issue of overtreatment as a major concern in clinical management of the disease. The focus of the future is to identify those at highest risk for aggressive prostate cancer and to develop prevention and screening strategies, as well as discerning the difference in malignant potential of diagnosed tumors. The Prostate Cancer Research Group of the National Cancer Institute's Early Detection Research Network has contributed to the progress in addressing these concerns. This summary is an overview of the activities of the group.
10.1158/1055-9965.EPI-20-1104
The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer.
Cells
Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K-AKT-mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K-AKT-mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.
10.3390/cells9112342
A Quest for New Cancer Diagnosis, Prognosis and Prediction Biomarkers and Their Use in Biosensors Development.
Ramirez-Valles Eda G,Rodríguez-Pulido Alicia,Barraza-Salas Marcelo,Martínez-Velis Isaac,Meneses-Morales Iván,Ayala-García Víctor M,Alba-Fierro Carlos A
Technology in cancer research & treatment
Traditional techniques for cancer diagnosis, such as nuclear magnetic resonance, ultrasound and tissue analysis, require sophisticated devices and highly trained personnel, which are characterized by elevated operation costs. The use of biomarkers has emerged as an alternative for cancer diagnosis, prognosis and prediction because their measurement in tissues or fluids, such as blood, urine or saliva, is characterized by shorter processing times. However, the biomarkers used currently, and the techniques used for their measurement, including ELISA, western-blot, polymerase chain reaction (PCR) or immunohistochemistry, possess low sensitivity and specificity. Therefore, the search for new proteomic, genomic or immunological biomarkers and the development of new noninvasive, easier and cheaper techniques that meet the sensitivity and specificity criteria for the diagnosis, prognosis and prediction of this disease has become a relevant topic. The purpose of this review is to provide an overview about the search for new cancer biomarkers, including the strategies that must be followed to identify them, as well as presenting the latest advances in the development of biosensors that possess a high potential for cancer diagnosis, prognosis and prediction, mainly focusing on their relevance in lung, prostate and breast cancers.
10.1177/1533033820957033
Proteomic discovery of non-invasive biomarkers of localized prostate cancer using mass spectrometry.
Nature reviews. Urology
Prostate cancer is the second most frequently diagnosed non-skin cancer in men worldwide. Patient outcomes are remarkably heterogeneous and the best existing clinical prognostic tools such as International Society of Urological Pathology Grade Group, pretreatment serum PSA concentration and T-category, do not accurately predict disease outcome for individual patients. Thus, patients newly diagnosed with prostate cancer are often overtreated or undertreated, reducing quality of life and increasing disease-specific mortality. Biomarkers that can improve the risk stratification of these patients are, therefore, urgently needed. The ideal biomarker in this setting will be non-invasive and affordable, enabling longitudinal evaluation of disease status. Prostatic secretions, urine and blood can be sources of biomarker discovery, validation and clinical implementation, and mass spectrometry can be used to detect and quantify proteins in these fluids. Protein biomarkers currently in use for diagnosis, prognosis and relapse-monitoring of localized prostate cancer in fluids remain centred around PSA and its variants, and opportunities exist for clinically validating novel and complimentary candidate protein biomarkers and deploying them into the clinic.
10.1038/s41585-021-00500-1
Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment.
International journal of molecular sciences
The reduction in androgen synthesis and the blockade of the androgen receptor (AR) function by chemical castration and AR signaling inhibitors represent the main treatment lines for the initial stages of prostate cancer. Unfortunately, resistance mechanisms ultimately develop due to alterations in the AR pathway, such as gene amplification or mutations, and also the emergence of alternative pathways that render the tumor less or, more rarely, completely independent of androgen activation. An essential oncogenic axis activated in prostate cancer is the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, as evidenced by the frequent alterations of the negative regulator phosphatase and tensin homolog (PTEN) and by the activating mutations in PI3K subunits. Additionally, crosstalk and reciprocal feedback loops between androgen signaling and the PI3K/AKT/mTOR signaling cascade that activate pro-survival signals and play an essential role in disease recurrence and progression have been evidenced. Inhibitors addressing different players of the PI3K/AKT/mTOR pathway have been evaluated in the clinic. Only a limited benefit has been reported in prostate cancer up to now due to the associated side effects, so novel combination approaches and biomarkers predictive of patient response are urgently needed. Here, we reviewed recent data on the crosstalk between AR signaling and the PI3K/AKT/mTOR pathway, the selective inhibitors identified, and the most advanced clinical studies, with a focus on combination treatments. A deeper understanding of the complex molecular mechanisms involved in disease progression and treatment resistance is essential to further guide therapeutic approaches with improved outcomes.
10.3390/ijms24032289
Biomarkers of Aggressive Prostate Cancer at Diagnosis.
International journal of molecular sciences
In the United States, prostate cancer (CaP) remains the second leading cause of cancer deaths in men. CaP is predominantly indolent at diagnosis, with a small fraction (25-30%) representing an aggressive subtype (Gleason score 7-10) that is prone to metastatic progression. This fact, coupled with the criticism surrounding the role of prostate specific antigen in prostate cancer screening, demonstrates the current need for a biomarker(s) that can identify clinically significant CaP and avoid unnecessary biopsy procedures and psychological implications of being diagnosed with low-risk prostate cancer. Although several diagnostic biomarkers are available to clinicians, very few comparative trials have been performed to assess the clinical effectiveness of these biomarkers. It is of note, however, that a majority of these clinical trials have been over-represented by men of Caucasian origin, despite the fact that African American men have a 1.7 times higher incidence and 2.1 times higher rate of mortality from prostate cancer. Biomarkers for CaP diagnosis based on the tissue of origin include urine-based gene expression assays (PCA3, Select MDx, ExoDx Prostate IntelliScore, Mi-Prostate Score, PCA3-PCGEM1 gene panel), blood-based protein biomarkers (4K, PHI), and tissue-based DNA biomarker (Confirm MDx). Another potential direction that has emerged to aid in the CaP diagnosis include multi-parametric magnetic resonance imaging (mpMRI) and bi-parametric magnetic resonance imaging (bpMRI), which in conjunction with clinically validated biomarkers may provide a better approach to predict clinically significant CaP at diagnosis. In this review, we discuss some of the adjunctive biomarker tests along with newer imaging modalities that are currently available to help clinicians decide which patients are at risk of having high-grade CaP on prostate biopsy with the emphasis on clinical utility of the tests across African American (AA) and Caucasian (CA) men.
10.3390/ijms24032185
Pseudouridine as a novel biomarker in prostate cancer.
Urologic oncology
Epitranscriptomic analysis has recently led to the profiling of modified nucleosides in cancer cell biological matrices, helping to elucidate their functional roles in cancer and reigniting interest in exploring their use as potential markers of cancer development and progression. Pseudouridine, one of the most well-known and the most abundant of the RNA nucleotide modifications, is the C5-glycoside isomer of uridine and its distinctive physiochemical properties allows it to perform many essential functions. Pseudouridine functionally (a) confers rigidity to local RNA structure by enhancing RNA stacking, engaging in a cooperative effect on neighboring nucleosides that overall contributes to RNA stabilization (b) refines the structure of tRNAs, which influences their decoding activity (c) facilitates the accuracy of decoding and proofreading during translation and efficiency of peptide bond formation, thus collectively improving the fidelity of protein biosynthesis and (e) dynamically regulates mRNA coding and translation. Biochemical synthesis of pseudouridine is carried out by pseudouridine synthases. In this review we discuss the evidence supporting an association between elevated pseudouridine levels with the incidence and progression of human prostate cancer and the translational significance of the value of this modified nucleotide as a novel biomarker in prostate cancer progression to advanced disease.
10.1016/j.urolonc.2020.06.026
Extracellular Vesicle Proteome in Prostate Cancer: A Comparative Analysis of Mass Spectrometry Studies.
Bernardino Rui Miguel Marques,Leão Ricardo,Henrique Rui,Pinheiro Luis Campos,Kumar Prashant,Suravajhala Prashanth,Beck Hans Christian,Carvalho Ana Sofia,Matthiesen Rune
International journal of molecular sciences
Molecular diagnostics based on discovery research holds the promise of improving screening methods for prostate cancer (PCa). Furthermore, the congregated information prompts the question whether the urinary extracellular vesicles (uEV) proteome has been thoroughly explored, especially at the proteome level. In fact, most extracellular vesicles (EV) based biomarker studies have mainly targeted plasma or serum. Therefore, in this study, we aim to inquire about possible strategies for urinary biomarker discovery particularly focused on the proteome of urine EVs. Proteomics data deposited in the PRIDE archive were reanalyzed to target identifications of potential PCa markers. Network analysis of the markers proposed by different prostate cancer studies revealed moderate overlap. The recent throughput improvements in mass spectrometry together with the network analysis performed in this study, suggest that a larger standardized cohort may provide potential biomarkers that are able to fully characterize the heterogeneity of PCa. According to our analysis PCa studies based on urinary EV proteome presents higher protein coverage compared to plasma, plasma EV, and voided urine proteome. This together with a direct interaction of the prostate gland and urethra makes uEVs an attractive option for protein biomarker studies. In addition, urinary proteome based PCa studies must also evaluate samples from bladder and renal cancers to assess specificity for PCa.
10.3390/ijms222413605
New markers in prostate cancer: Genomics.
Fuessel Susanne,Wirth Manfred P
Archivos espanoles de urologia
Prostate cancer (PCa) is a very heterogeneous disease with unknown outcome at the time of first diagnosis. Multiple clinicopathological parameters andmodern imaging approaches are currently used to detect PCa and to assess the necessity of early or delayed treatment according to the predicted aggressiveness of the tumor. Despite regular adjustments of predictive systems based on histopathological factors such as the Gleason grading system or based on prostate MRI such as the Prostate Imaging Reporting and Data System (PIRADS) these tools for risk stratification of PCa patients still harbor significant limitations with regard to the accuracy of PCa outcome prediction. Therefore, great hopes have been placed on the use of biomolecular markers which might be more closely associated with the underlying biological characteristics of this tumor entity and able to predict the course of the disease better than clinical parameters. Such biomarkers are expected to serve as valuable tools not only to improve PCa diagnostics but also to enhance pre- and posttreatment risk stratification which could finally facilitate therapeutic decisions.In this review, current literature on genomic biomarkers used for PCa detection and early prediction of the tumor aggressiveness is examined. First, germline mutations and single nucleotide polymorphisms which might influence PCa onset are discussed in relation to the usefulness of targeted PCa screening approaches.Moreover, different urine- and tissue-based diagnostic tests assessing PCa-associated alterations on genetic, epigenetic and transcriptional level are reviewed. Most of these genomic biomarker assays were validated in large patient cohorts and their potential clinical usability could be proven. They provide useful diagnostic information to facilitate decisions with regard to screen men at risk to develop PCa or to repeat diagnostics in men with negative biopsy results, but persistent suspicion of cancer.Several assays can assist the early identification of patients with high-risk PCa, who potentially would need treatment, and may facilitate the selection of patients suitable for active surveillance. More evidence of the clinicalusability of such genomic PCa detection assays has to be provided by further prospective studies to support the transferability of these new diagnostic approaches to daily clinical practice.
Prostate Cancer Epigenetics: From Basic Mechanisms to Clinical Implications.
Yegnasubramanian Srinivasan,De Marzo Angelo M,Nelson William G
Cold Spring Harbor perspectives in medicine
A level of epigenetic programming, encoded by complex sets of chemical marks on DNA and histones, and by context-specific DNA, RNA, protein interactions, that all regulate the structure, organization, and function of the genome, is critical to establish both normal and neoplastic cell identities and functions. This structure-function relationship of the genome encoded by the epigenetic programming can be thought of as an epigenetic cityscape that is built on the underlying genetic landscape. Alterations in the epigenetic cityscape of prostate cancer cells compared with normal prostate tissues have a complex interplay with genetic alterations to drive prostate cancer initiation and progression. Indeed, mutations in genes encoding epigenetic enzymes are often observed in human cancers including prostate cancer. Interestingly, alterations in the prostate cancer epigenetic cityscape can be highly recurrent, a facet that can be exploited for development of biomarkers and potentially as therapeutic targets.
10.1101/cshperspect.a030445
A 25-year perspective on evaluation and understanding of biomarkers in urologic cancers.
Feldman Adam S,Lokeshwar Vinata,Lin Daniel W
Urologic oncology
The past 25 years have witnessed an explosion of investigative attempts to identify clinically useful biomarkers which can have meaningful impacts for patients with urologic cancers. However, in spite of the enormous amount of research aiming to identify markers with the hope of impacting patient care, only a handful have proven to have true clinical utility. Improvements in targeted imaging, pan-omics evaluation, and genetic sequencing at the tissue and single-cell levels have yielded many potential targets for continued biomarker investigation. This article, as one in this series for the 25th Anniversary Issue of Urologic Oncology: Seminars and Original Investigations, serves to give a perspective on our progress and failures over the past quarter-century in our highest volume urologic cancers: prostate, bladder, and kidney cancers.
10.1016/j.urolonc.2021.06.010
Divergent Modulation of Proteostasis in Prostate Cancer.
Ballar Kirmizibayrak Petek,Erbaykent-Tepedelen Burcu,Gozen Oguz,Erzurumlu Yalcin
Advances in experimental medicine and biology
Proteostasis regulates key cellular processes such as cell proliferation, differentiation, transcription, and apoptosis. The mechanisms by which proteostasis is regulated are crucial and the deterioration of cellular proteostasis has been significantly associated with tumorigenesis since it specifically targets key oncoproteins and tumor suppressors. Prostate cancer (PCa) is the second most common cause of cancer death in men worldwide. Androgens mediate one of the most central signaling pathways in all stages of PCa via the androgen receptor (AR). In addition to their regulation by hormones, PCa cells are also known to be highly secretory and are particularly prone to ER stress as proper ER function is essential. Alterations in various complex signaling pathways and cellular processes including cell cycle control, transcription, DNA repair, apoptosis, cell adhesion, epithelial-mesenchymal transition (EMT), and angiogenesis are critical factors influencing PCa development through key molecular changes mainly by posttranslational modifications in PCa-related proteins, including AR, NKX3.1, PTEN, p53, cyclin D1, and p27. Several ubiquitin ligases like MDM2, Siah2, RNF6, CHIP, and substrate-binding adaptor SPOP; deubiquitinases such as USP7, USP10, USP26, and USP12 are just some of the modifiers involved in the regulation of these key proteins via ubiquitin-proteasome system (UPS). Some ubiquitin-like modifiers, especially SUMOs, have been also closely associated with PCa. On the other hand, the proteotoxicity resulting from misfolded proteins and failure of ER adaptive capacity induce unfolded protein response (UPR) that is an indispensable signaling mechanism for PCa development. Lastly, ER-associated degradation (ERAD) also plays a crucial role in prostate tumorigenesis. In this section, the relationship between prostate cancer and proteostasis will be discussed in terms of UPS, UPR, SUMOylation, ERAD, and autophagy.
10.1007/978-3-030-38266-7_5
Metabolomic profiling for the identification of novel diagnostic markers and therapeutic targets in prostate cancer: an update.
Lucarelli Giuseppe,Loizzo Davide,Ferro Matteo,Rutigliano Monica,Vartolomei Mihai Dorin,Cantiello Francesco,Buonerba Carlo,Di Lorenzo Giuseppe,Terracciano Daniela,De Cobelli Ottavio,Bettocchi Carlo,Ditonno Pasquale,Battaglia Michele
Expert review of molecular diagnostics
INTRODUCTION:An altered metabolic regulation is involved in the development and progression of different cancer types. As well as this, many genes associated with tumors are shown to have an important role in control of the metabolism. The incidence of prostate cancer (PCa) is increased in men with metabolic disorders. In particular, obesity is an established risk factor for PCa. An increased body mass index correlates with aggressive disease, and a higher risk of biochemical recurrence and prostate cancer-specific mortality. Increased lipogenesis is also one of the most significant events in PCa metabolism reprogramming. Areas covered: In this article, we provide an updated review of the current understanding of the PCa metabolome and evaluate the possibility of unveiling novel therapeutic targets. Expert opinion: Obesity is an established risk factor for PCa, and an increased BMI correlates with aggressive disease, and a higher risk of biochemical recurrence and prostate cancer-specific mortality. PCa metabolome is characterized by the accumulation of metabolic intermediates and an increased expression of genes in the tricarboxylic acid cycle, the induction of de novo lipogenesis and cholesterogenesis. PCa cells can induce different alterations in their microenvironment by modulating the crosstalk between cancer and stromal cells.
10.1080/14737159.2019.1604223
Liquid biomarkers in active surveillance.
Dall'Era Marc
World journal of urology
PURPOSE:In the past two decades, new biomarkers for prostate cancer detection and risk prediction have become available for clinical use. While tissue-based gene expression assays offer molecular risk assessment after diagnoses, several serum- and urine-based 'liquid' biomarkers are available for the pre-biopsy setting which may also play a role for active surveillance (AS). METHODS:The medical literature was queried utilizing PubMed (pubmed.ncbi.nlm.nih.gov) for all relevant original publications describing prostate cancer biomarkers that can be identified in the blood, urine, or semen. Referenced studies must have defined patient inclusion criteria and descriptions of the biomarkers. Included studies investigated the utility of liquid biomarkers for selection or monitoring of men with prostate cancer for active surveillance. RESULTS:PSA is the most common and readily available biomarker for prostate cancer diagnosis and treatment. Contemporary AS guidelines consider diagnostic PSA level in addition to other clinical factors when selecting men for this approach, with most recommending that initial PSA should be under 10 ng/ml. Serum PSA changes are associated with outcomes on AS but are not adequately sensitive so drive men to secondary treatment in isolation. PSA derivates including the Prostate Health Index (phi) and the 4K Score can predict higher grade cancer and may help tailor repeat prostate biopsy strategies, but further data are needed prior to routine clinic use. Several urine-based biomarkers including PCA3 and TMPRSS2:ERG levels have also been studied in the AS setting. CONCLUSIONS:Multiple serum- and urine-based liquid biomarkers are available for use in men with prostate cancer. For AS, serum PSA is utilized in part for patient selection as well as to monitor disease over time. Models that incorporate PSA kinetics with other clinical characteristics may help tailor surveillance strategies to reduce disease burden and health care costs over time. Several novel liquid biomarkers demonstrate promise and may eventually have applications for prostate cancer surveillance as well.
10.1007/s00345-021-03609-5
microRNA-205 in prostate cancer: Overview to clinical translation.
Biochimica et biophysica acta. Reviews on cancer
Prostate cancer (PrCa) is the most common type of cancer among men in the United States. The metastatic and advanced PrCa develops drug resistance to current regimens which accounts for the poor management. microRNAs (miRNAs) have been well-documented for their diagnostic, prognostic, and therapeutic roles in various human cancers. Recent literature confirmed that microRNA-205 (miR-205) has been established as one of the tumor suppressors in PrCa. miR-205 regulates number of cellular functions, such as proliferation, invasion, migration/metastasis, and apoptosis. It is also evident that miR-205 can serve as a key biomarker in diagnostic, prognostic, and therapy of PrCa. Therefore, in this review, we will provide an overview of tumor suppressive role of miR-205 in PrCa. This work also outlines miR-205's specific role in targeted mechanisms for chemosensitization and radiosensitization in PrCa. A facile approach of delivery paths for successful clinical translation is documented. Together, all these studies provide a novel insight of miR-205 as an adjuvant agent for reducing the widening gaps in clinical outcome of PrCa patients.
10.1016/j.bbcan.2022.188809
Urinary exosomal shuttle RNA: Promising cancer diagnosis biomarkers of lower urinary tract.
The International journal of biological markers
BACKGROUND:Prostate and bladder cancers continue to be the first and fourth most common cancers in men worldwide; thus there is an urgent need for more accurate biomarkers that can detect these types of cancer in a non-invasive way. Liquid biopsy is a new non-invasive tool for diagnosis and with a virtually unlimited supply urine is even more attractive resource since urinary exosomes have been discovered to contain RNAs that are hallmarks of cancer. It is challenging to assay those secreting lower amounts of molecules. METHODS:This review, based on articles identified through a PubMed/MEDLINE search, comprehensively summarizes state of the art approaches used in the discovery and validation of exosomal RNA biomarkers purified from the urine for lower urinary tract cancer. RESULTS:The combination of and has shown a relatively good improvement in diagnostic performance; examples of other potential biomarkers and the methods utilized in their discovery are also discussed in this review. CONCLUSIONS:Of these last markers, to date there are still few data to implement these for routine diagnosis.
10.1177/1724600819827023
Emerging Biomarker-Guided Therapies in Prostate Cancer.
Current oncology (Toronto, Ont.)
Prostate cancer remains one of the leading causes of cancer death in men worldwide. In the past decade, several new treatments for advanced prostate cancer have been approved. With a wide variety of available drugs, including cytotoxic agents, androgen receptor axis-targeted therapies, and alpha-emitting radiation therapy, identifying their optimal sequencing remains a challenge. Progress in the understanding of the biology of prostate cancer has provided an opportunity for a more refined and personalized treatment selection process. With the advancement of molecular sequencing techniques, genomic precision through the identification of potential treatment targets and predictive biomarkers has been rapidly evolving. In this review, we discussed biomarker-driven treatments for advanced prostate cancer. First, we presented predictive biomarkers for established, global standard treatments for advanced diseases, such as chemotherapy and androgen receptor axis-targeted agents. We also discussed targeted agents with recent approval for special populations, such as poly ADP ribose polymerase (PARP) inhibitors in patients with metastatic castrate-resistant prostate cancer with homologous recombination repair-deficient tumors, pembrolizumab in patients with high levels of microsatellite instability or high tumor mutational burden, and prostate-specific membrane antigen (PSMA) directed radioligand theragnostic treatment for PSMA expressing tumors. Additionally, we discussed evolving treatments, such as cancer vaccines, chimeric antigen receptor T-cells (CAR-T), Bispecific T-cell engagers (BiTEs), other targeted agents such as AKT inhibitors, and various combination treatments. In summary, advances in molecular genetics have begun to propel personalized medicine forward in the management of advanced prostate cancer, allowing for a more precise, biomarker-driven treatment selection with the goal of improving overall efficacy.
10.3390/curroncol29070400
Cancer metabolomic markers in urine: evidence, techniques and recommendations.
Dinges Sarah S,Hohm Annika,Vandergrift Lindsey A,Nowak Johannes,Habbel Piet,Kaltashov Igor A,Cheng Leo L
Nature reviews. Urology
Urinary tests have been used as noninvasive, cost-effective tools for screening, diagnosis and monitoring of diseases since ancient times. As we progress through the 21st century, modern analytical platforms have enabled effective measurement of metabolites, with promising results for both a deeper understanding of cancer pathophysiology and, ultimately, clinical translation. The first study to measure metabolomic urinary cancer biomarkers using NMR and mass spectrometry (MS) was published in 2006 and, since then, these techniques have been used to detect cancers of the urological system (kidney, prostate and bladder) and nonurological tumours including those of the breast, ovary, lung, liver, gastrointestinal tract, pancreas, bone and blood. This growing field warrants an assessment of the current status of research developments and recommendations to help systematize future research.
10.1038/s41585-019-0185-3
Clinical application of immune checkpoints in targeted immunotherapy of prostate cancer.
Cellular and molecular life sciences : CMLS
Immunotherapy is considered as an effective method for cancer treatment owing to the induction of specific and long-lasting anti-cancer effects. Immunotherapeutic strategies have shown significant success in human malignancies, particularly in prostate cancer (PCa), a major global health issue regarding its high metastatic rates. In fact, the first cancer vaccine approved by FDA was Provenge, which has been successfully used for treatment of PCa. Despite the remarkable success of cancer immunotherapy in PCa, many of the developed immunotherapy methods show poor therapeutic outcomes. Immunosuppression in tumor microenvironment (TME) induced by non-functional T cells (CD4 and CD8), tolerogenic dendritic cells (DCs), and regulatory T cells, has been reported to be the main obstacle to the effectiveness of anti-tumor immune responses induced by an immunotherapy method. The present review particularly focuses on the latest findings of the immune checkpoints (ICPs), including CTLA-4, PD-1, PD-L1, LAG-3, OX40, B7-H3, 4-1BB, VISTA, TIM-3, and ICOS; these checkpoints are able to have immune modulatory effects on the TME of PCa. This paper further discusses different approaches in ICPs targeting therapy and summarizes the latest advances in the clinical application of ICP-targeted therapy as monotherapy or in combination with other cancer therapy modalities in PCa.
10.1007/s00018-020-03459-1
Extracellular vesicles as a source of prostate cancer biomarkers in liquid biopsies: a decade of research.
British journal of cancer
Prostate cancer is a global cancer burden and considerable effort has been made through the years to identify biomarkers for the disease. Approximately a decade ago, the potential of analysing extracellular vesicles in liquid biopsies started to be envisaged. This was the beginning of a new exciting area of research investigating the rich molecular treasure found in extracellular vesicles to identify biomarkers for a variety of diseases. Vesicles released from prostate cancer cells and cells of the tumour microenvironment carry molecular information about the disease that can be analysed in several biological fluids. Numerous studies document the interest of researchers in this field of research. However, methodological issues such as the isolation of vesicles have been challenging. Remarkably, novel technologies, including those based on nanotechnology, show promise for the further development and clinical use of extracellular vesicles as liquid biomarkers. Development of biomarkers is a long and complicated process, and there are still not many biomarkers based on extracellular vesicles in clinical use. However, the knowledge acquired during the last decade constitutes a solid basis for the future development of liquid biopsy tests for prostate cancer. These are urgently needed to bring prostate cancer treatment to the next level in precision medicine.
10.1038/s41416-021-01610-8
Prognostic Role of RNA Expression Molecular Biomarkers in Prostate and Bladder Cancers.
European urology focus
Prostate cancer and bladder cancer are two of the most common urologic cancers. Cancer risk stratification and prediction of prognosis have always been challenging. Following recent advances in genomic and proteomic technologies, several genomic biomarkers have been developed and proposed as a noninvasive and nonexpansive approach that can supplement our current data to improve prediction and accuracy. Several biomarkers have shown efficacy in patient risk stratification and in predicting prognosis. Here we provide a mini-review of current RNA biomarkers approved by the US Food and Drug Administration, including the Decipher, Oncotype DX Prostate, and Prolaris tests. We also provide a summary of their approved clinical utility in prostate cancer and bladder cancer management. PATIENT SUMMARY: A number of tests are available for measuring expression levels of genes related to prostate or bladder cancer. We review the usefulness of these tests in stratifying risk for patients and predicting their prognosis.
10.1016/j.euf.2022.06.009
Race and prostate cancer: genomic landscape.
Nature reviews. Urology
In the past 20 years, new insights into the genomic pathogenesis of prostate cancer have been provided. Large-scale integrative genomics approaches enabled researchers to characterize the genetic and epigenetic landscape of prostate cancer and to define different molecular subclasses based on the combination of genetic alterations, gene expression patterns and methylation profiles. Several molecular drivers of prostate cancer have been identified, some of which are different in men of different races. However, the extent to which genomics can explain racial disparities in prostate cancer outcomes is unclear. Future collaborative genomic studies overcoming the underrepresentation of non-white patients and other minority populations are essential.
10.1038/s41585-022-00622-0
FOXO3a and Its Regulators in Prostate Cancer.
Habrowska-Górczyńska Dominika Ewa,Kozieł Marta Justyna,Kowalska Karolina,Piastowska-Ciesielska Agnieszka Wanda
International journal of molecular sciences
Forkhead box O3 (FOXO3a) is a member of a subfamily of forkhead transcription factors involved in the basic processes within a cell, including proliferation, apoptosis, cell cycle regulation, and DNA damage. As a transcription factor, FOXO3a is involved in the response to cellular stress, UV radiation, or oxidative stress. Its regulation is based on the modification of proteins as well as regulation by other proteins, e.g., growth factors. FOXO3a is commonly deregulated in cancer cells, and its inactivation is associated with initiation and progression of tumorigenesis, suggesting its role as a tumor suppressor; however, its role is still disputed and seems to be dependent on upstream signaling. Nevertheless, FOXO3a serves as an interesting potential target in therapies as it is regulated during treatment with very common anti-cancer drugs such as paclitaxel, cisplatin, docetaxel, and doxorubicin. This review aims to update the reported role of FOXO3a in prostate cancer (PCa), with a focus on its regulators that might serve as potential therapeutic agents in PCa therapy.
10.3390/ijms222212530
Landscape of Noncoding RNA in Prostate Cancer.
Hua Junjie T,Chen Sujun,He Housheng H
Trends in genetics : TIG
The transcriptome of prostate cancer is highly heterogeneous, with noncoding transcripts being essential players. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are two unique classes of noncoding RNA drawing increasing attention. Biologically, they have intriguing properties with important regulatory functions. Clinically, they present as promising biomarkers and therapeutic targets. Recent advancements in technologies have opened up new directions for noncoding RNA research, which include RNA-protein interaction, RNA secondary structure, and spatial transcriptomics. Furthermore, recent work has also evaluated the clinical applications of these noncoding RNAs in noninvasive liquid biopsy and RNA-based therapies. In this review, we summarize recent findings on lncRNAs and circRNAs in prostate cancer, discuss their clinical utilities, and highlight these exciting areas of research.
10.1016/j.tig.2019.08.004
Prostate Cancer: The Role of Inflammation and Chemokines.
Rani Aradhana,Dasgupta Prokar,Murphy John J
The American journal of pathology
Prostate cancer (PC) is a leading cause of death in men. Inflammation is one of the initiating processes whereby cells are trafficked into the tumor microenvironment by specific cytokines termed chemokines. This recruitment is complex and involves diverse leukocyte subsets with procancer and anticancer functions. Chemokines promote/abrogate proliferation of cancerous cells, block/aid apoptosis, and are instrumental/detrimental in cancer cell migration required for metastasis. Chemokines guide the release/transport of immune cells that serve as chaperones at sites of inflammation, and after subsequent activation, they lead to an immune response. The variety of immune cells recruited at the site of tumor initiation possess unique functions, and the plethora of chemokines released by each cell derived from a progenitor cell activated under a defined set of conditions dictates its specific role in cancer progression/regression. Geographic consequences that govern the climate and endemic diseases, along with the associated evolutionary effects that at times protect populations from one disease, could lead to genetic variations that determine a role for ethnicity and race in PC risk and susceptibility. Dysregulated expression or an imbalance in the homeostatic mechanisms associated with chemokines is implicated in PC. This review discusses the role of inflammation and chemokines in PC.
10.1016/j.ajpath.2019.07.007
Prostate cancer research in the 21st century; report from the 2021 Coffey-Holden prostate cancer academy meeting.
The Prostate
INTRODUCTION:The 2021 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Prostate Cancer Research in the 21st Century," was held virtually, from June 24-25, 2021. METHODS:The CHPCA Meeting is organized by the Prostate Cancer Foundation as a unique discussion-oriented meeting focusing on critical topics in prostate cancer research envisioned to bridge the next major advances in prostate cancer biology and treatment. The 2021 CHPCA Meeting was virtually attended by 89 investigators and included 31 talks over nine sessions. RESULTS:Major topic areas discussed at the meeting included: cancer genomics and sequencing, functional genomic approaches to studying mediators of plasticity, emerging signaling pathways in metastatic castration resistant prostate cancer, Wnt signaling biology and the challenges of targeted therapy, clonal hematopoiesis, neuroendocrine cell plasticity and antitumor immunity, cancer immunotherapy and its synergizers, and imaging the tumor microenvironment and metabolism. DISCUSSION:This meeting report summarizes the research presented at the 2021 CHPCA Meeting. We hope that publication of this knowledge will accelerate new understandings and the development of new biomarkers and treatments for prostate cancer.
10.1002/pros.24262
De novo neuroendocrine features in prostate cancer.
Human pathology
Neuroendocrine tumors of the prostate are rare and encompass a group of entities that are classified based on a combination of morphological and immunohistochemical features. Despite the 2016 World Health Organization classification of prostatic neuroendocrine tumors, variants have been reported that do not fit well in the categorization scheme. While the majority of these tumors arise in the setting of castration-resistant prostate cancer (postandrogen deprivation therapy), de novo cases may occur. In this review, we highlight the most significant pathological and immunohistochemical features, emerging biomarkers, and molecular features of such tumors.
10.1016/j.humpath.2022.07.002
The cyclin-dependent kinases pathway as a target for prostate cancer treatment: rationale and future perspectives.
Brighi Nicole,Conteduca Vincenza,Lolli Cristian,Gurioli Giorgia,Schepisi Giuseppe,Palleschi Michela,Mariotti Marita,Casadei Chiara,De Giorgi Ugo
Critical reviews in oncology/hematology
The rapidly expanding scenario of treatment options for patients affected by prostate cancer (PC) is leading to improved outcomes; however, PC still represents one of the most frequent causes of male mortality. Thus, while translational research is trying to unravel the molecular landscape underlying carcinogenesis, disease progression and treatment resistance, several clinical trials are evaluating novel options to further expand therapeutic options. The cyclin-dependent kinases (CDK)-pathway represents a promising therapeutic target for different cancer types; due to the pivotal role of this pathway in the regulation of PC cell cycle, three CDK4/6-inhibitors (abemaciclib, palbociclib and ribociclib) are currently being investigated in several clinical trials. In this paper, we review the current knowledge on CDK-pathway and the mechanism of action of CDK-inhibitors; we discuss the biological rationale for their use in PC and the state of the art of clinical trials focused on the demonstration of their potential role in early or advanced stage, in hormone-sensitive and castration-resistant state. Finally, the potential application of precision oncology for treatment selection in PC is discussed.
10.1016/j.critrevonc.2020.103199
DNA Damage Repair Deficiency in Prostate Cancer.
Burdak-Rothkamm Susanne,Mansour Wael Y,Rothkamm Kai
Trends in cancer
Molecular-targeted therapies and treatment stratification based on molecular biomarkers have rapidly gained momentum in the therapeutic spectrum for patients with prostate cancer, particularly those with aggressive disease. DNA damage repair (DDR) pathways are commonly impaired in prostate cancer. Recent studies have detailed mechanisms interconnecting the DDR with the androgen receptor (AR) signaling pathway as well as its interplay with the immune response. The prominent role of DDR deficiency in prostate cancer development and treatment response encourages innovative strategies for the detection of DDR deficiency in individual tumors. In this review, we describe recent preclinical and early clinical data on the exploitation of DDR defects as predictive biomarkers and also as molecular therapeutic targets.
10.1016/j.trecan.2020.05.011
Molecular Mechanisms of Castrate-Resistant Prostate Cancer.
The Urologic clinics of North America
Despite newer therapies for castrate-resistant prostate cancer (CRPC), many patients do not experience a treatment response, and most eventually experience secondary resistance. Various androgen-receptor-related and alternative mechanisms of resistance in CRPC have been identified. This focus on understanding the molecular basis of therapeutic resistance, including lineage plasticity, neuroendocrine transformation, and a range of other implicated genomic alterations will hopefully inform decision-making in the care of this lethal cancer.
10.1016/j.ucl.2022.07.005
Targeting LIN28: a new hope in prostate cancer theranostics.
Shrivastava Garima,Aljabali Alaa Aa,Shahcheraghi Seyed Hossein,Lotfi Marzieh,Shastri Madhur D,Shukla Shakti D,Chellappan Dinesh K,Jha Niraj Kumar,Anand Krishnan,Dureja Harish,Pabari Ritesh M,Mishra Vijay,Almutary Abdulmajeed G,Alnuqaydan Abdullah M,Charbe Nitin,Prasher Parteek,Negi Poonam,Goyal Rohit,Dua Kamal,Gupta Gaurav,Serrano-Aroca Ángel,Bahar Bojlul,Barh Debmalya,Panda Pritam Kumar,Takayama Kazuo,Lundstorm Kenneth,McCarron Paul,Bakshi Hamid,Tambuwala Murtaza M
Future oncology (London, England)
The mortality and morbidity rates for prostate cancer have recently increased to alarming levels, rising higher than lung cancer. Due to a lack of drug targets and molecular probes, existing theranostic techniques are limited. Human LIN28A and its paralog LIN28B overexpression are associated with a number of tumors resulting in a remarkable increase in cancer aggression and poor prognoses. The current review aims to highlight recent work identifying the key roles of LIN28A and LIN28B in prostate cancer, and to instigate further preclinical and clinical research in this important area.
10.2217/fon-2021-0247
Biomarkers in Prostate Cancer Diagnosis: From Current Knowledge to the Role of Metabolomics and Exosomes.
Salciccia Stefano,Capriotti Anna Laura,Laganà Aldo,Fais Stefano,Logozzi Mariantonia,De Berardinis Ettore,Busetto Gian Maria,Di Pierro Giovanni Battista,Ricciuti Gian Piero,Del Giudice Francesco,Sciarra Alessandro,Carroll Peter R,Cooperberg Matthew R,Sciarra Beatrice,Maggi Martina
International journal of molecular sciences
Early detection of prostate cancer (PC) is largely carried out using assessment of prostate-specific antigen (PSA) level; yet it cannot reliably discriminate between benign pathologies and clinically significant forms of PC. To overcome the current limitations of PSA, new urinary and serum biomarkers have been developed in recent years. Although several biomarkers have been explored in various scenarios and patient settings, to date, specific guidelines with a high level of evidence on the use of these markers are lacking. Recent advances in metabolomic, genomics, and proteomics have made new potential biomarkers available. A number of studies focused on the characterization of the specific PC metabolic phenotype using different experimental approaches has been recently reported; yet, to date, research on metabolomic application for PC has focused on a small group of metabolites that have been known to be related to the prostate gland. Exosomes are extracellular vesicles that are secreted from all mammalian cells and virtually detected in all bio-fluids, thus allowing their use as tumor biomarkers. Thanks to a general improvement of the technical equipment to analyze exosomes, we are able to obtain reliable quantitative and qualitative information useful for clinical application. Although some pilot clinical investigations have proposed potential PC biomarkers, data are still preliminary and non-conclusive.
10.3390/ijms22094367
The roles of proteases in prostate cancer.
IUBMB life
Since the proposition of the pro-invasive activity of proteolytic enzymes over 70 years ago, several roles for proteases in cancer progression have been established. About half of the 473 active human proteases are expressed in the prostate and many of the most well-characterized members of this enzyme family are regulated by androgens, hormones essential for development of prostate cancer. Most notably, several kallikrein-related peptidases, including KLK3 (prostate-specific antigen, PSA), the most well-known prostate cancer marker, and type II transmembrane serine proteases, such as TMPRSS2 and matriptase, have been extensively studied and found to promote prostate cancer progression. Recent findings also suggest a critical role for proteases in the development of advanced and aggressive castration-resistant prostate cancer (CRPC). Perhaps the most intriguing evidence for this role comes from studies showing that the protease-activated transmembrane proteins, Notch and CDCP1, are associated with the development of CRPC. Here, we review the roles of proteases in prostate cancer, with a special focus on their regulation by androgens.
10.1002/iub.2700
Metabolic changes during prostate cancer development and progression.
Journal of cancer research and clinical oncology
Metabolic reprogramming has been recognised as a hallmark in solid tumours. Malignant modification of the tumour's bioenergetics provides energy for tumour growth and progression. Otto Warburg first reported these metabolic and biochemical changes in 1927. In prostate cancer (PCa) epithelial cells, the tumour metabolism also changes during development and progress. These alterations are partly driven by the androgen receptor, the key regulator in PCa development, progress, and survival. In contrast to other epithelial cells of different entities, glycolytic metabolism in prostate cells sustains physiological citrate secretion in the normal prostatic epithelium. In the early stages of PCa, citrate is utilised to power oxidative phosphorylation and fuel lipogenesis, enabling tumour growth and progression. In advanced and incurable castration-resistant PCa, a metabolic shift towards choline, amino acid, and glycolytic metabolism fueling tumour growth and progression has been described. Therefore, even if the metabolic changes are not fully understood, the altered metabolism during tumour progression may provide opportunities for novel therapeutic strategies, especially in advanced PCa stages. This review focuses on the main differences in PCa's metabolism during tumourigenesis and progression highlighting glutamine's role in PCa.
10.1007/s00432-022-04371-w
MicroRNAs as Diagnostic, Prognostic, and Therapeutic Biomarkers in Prostate Cancer.
Aghdam Arad Mobasher,Amiri Atefeh,Salarinia Reza,Masoudifar Aria,Ghasemi Faezeh,Mirzaei Hamed
Critical reviews in eukaryotic gene expression
Prostate cancer is the most prevalent nonskin cancer and a major cause of cancer-related deaths worldwide. Prostate-specific antigen (PSA) testing is routinely used for screening and early detection of prostate cancer; however, it does not reduce death from prostate cancer. Moreover, PSA is not specific for prostate cancer and results in high false-positive rates, and it is poorly correlated with cancer stage. Therefore, the need for another diagnostic and prognostic factor in prostate cancer is apparent. MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs which are involved in modulation of gene expression posttranscriptionally. Multiple lines of evidence indicate that miRNAs play key roles in various physiological events. Deregulation of miRNAs is related to initiation and development of various diseases such as prostate cancer. It has been shown that various miRNAs (miR-34, miR-21, miR-155, miR-221, miR-222, and let-7) exert their effects by targeting a variety of cellular and molecular pathways (c-Myc, EZH2, c-RSC, BCL2L2, E2F6, ZEB, HMGA251, and CCND2) involved in prostate cancer pathogenesis. Hence, it seems that miRNA expression profiles can be seen as potential candidates for prognosis, diagnosis, and treatment of prostate cancer. Here, we summarize various miRNAs as prognostic, diagnostic, and therapeutic biomarkers for prostate cancer therapy.
10.1615/CritRevEukaryotGeneExpr.2019025273
The promising role of new molecular biomarkers in prostate cancer: from coding and non-coding genes to artificial intelligence approaches.
Prostate cancer and prostatic diseases
BACKGROUND:Risk stratification or progression in prostate cancer is performed with the support of clinical-pathological data such as the sum of the Gleason score and serum levels PSA. For several decades, methods aimed at the early detection of prostate cancer have included the determination of PSA serum levels. The aim of this systematic review is to provide an overview about recent advances in the discovery of new molecular biomarkers through transcriptomics, genomics and artificial intelligence that are expected to improve clinical management of the prostate cancer patient. METHODS:An exhaustive search was conducted by Pubmed, Google Scholar and Connected Papers using keywords relating to the genetics, genomics and artificial intelligence in prostate cancer, it includes "biomarkers", "non-coding RNAs", "lncRNAs", "microRNAs", "repetitive sequence", "prognosis", "prediction", "whole-genome sequencing", "RNA-Seq", "transcriptome", "machine learning", and "deep learning". RESULTS:New advances, including the search for changes in novel biomarkers such as mRNAs, microRNAs, lncRNAs, and repetitive sequences, are expected to contribute to an earlier and accurate diagnosis for each patient in the context of precision medicine, thus improving the prognosis and quality of life of patients. We analyze several aspects that are relevant for prostate cancer including its new molecular markers associated with diagnosis, prognosis, and prediction to therapy and how bioinformatic approaches such as machine learning and deep learning can contribute to clinic. Furthermore, we also include current techniques that will allow an earlier diagnosis, such as Spatial Transcriptomics, Exome Sequencing, and Whole-Genome Sequencing. CONCLUSION:Transcriptomic and genomic analysis have contributed to generate knowledge in the field of prostate carcinogenesis, new information about coding and non-coding genes as biomarkers has emerged. Synergies created by the implementation of artificial intelligence to analyze and understand sequencing data have allowed the development of clinical strategies that facilitate decision-making and improve personalized management in prostate cancer.
10.1038/s41391-022-00537-2
Long Noncoding RNAs as Innovative Urinary Diagnostic Biomarkers.
Brisotto Giulia,Guerrieri Roberto,Colizzi Francesca,Steffan Agostino,Montico Barbara,Fratta Elisabetta
Methods in molecular biology (Clifton, N.J.)
The characterization of circulating tumor cells (CTCs) is now widely studied as a promising source of cancer-derived biomarkers because of their role in tumor formation and progression. However, CTCs analysis presents some limitations and no standardized method for CTCs isolation from urine has been defined so far. In fact, besides blood, urine represents an ideal source of noninvasive biomarkers, especially for the early detection of genitourinary tumors. Besides CTCs, long noncoding RNAs (lncRNAs) have also been proposed as potential noninvasive biomarkers, and the evaluation of the diagnostic accuracy of urinary lncRNAs has dramatically increased over the last years, with many studies being published. Therefore, this review provides an update on the clinical utility of urinary lncRNAs as novel biomarkers for the diagnosis of bladder and prostate cancers.
10.1007/978-1-0716-1354-2_7
Molecular mechanisms underlying the development of neuroendocrine prostate cancer.
Seminars in cancer biology
Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer-associated deaths among men in the United States. Androgen deprivation therapy (ADT) is the standard of care for advanced prostate cancer. While patients with advanced prostate cancer initially respond to ADT, the disease frequently progresses to a lethal metastatic form, defined as castration-resistant prostate cancer (CRPC). After multiple rounds of anti-androgen therapies, 20-25% of metastatic CRPCs develop a neuroendocrine (NE) phenotype. These tumors are classified as neuroendocrine prostate cancer (NEPC). De novo NEPC is rare and accounts for less than 2% of all prostate cancers at diagnosis. NEPC is commonly characterized by the expression of NE markers and the absence of androgen receptor (AR) expression. NEPC is usually associated with tumor aggressiveness, hormone therapy resistance, and poor clinical outcome. Here, we review the molecular mechanisms underlying the emergence of NEPC and provide insights into the future perspectives on potential therapeutic strategies for NEPC.
10.1016/j.semcancer.2022.05.007
Molecular Genetics of Prostate Cancer and Role of Genomic Testing.
Surgical pathology clinics
Prostate cancer (PCa) is characterized by profound genomic heterogeneity. Recent advances in personalized treatment entail an increasing need of genomic profiling. For localized PCa, gene expression assays can support clinical decisions regarding active surveillance and adjuvant treatment. In metastatic PCa, homologous recombination deficiency, microsatellite instability-high (MSI-H), and CDK12 deficiency constitute main actionable alterations. Alterations in DNA repair genes confer variable sensitivities to poly(ADP-ribose)polymerase inhibitors, and the use of genomic instability assays as predictive biomarker is still incipient. MSI can be assessed by immunohistochemistry To date there is a lack of consensus as to testing standards.
10.1016/j.path.2022.08.002
Prostate Cancer Transcriptomic Subtypes.
Spratt Daniel E
Advances in experimental medicine and biology
While the DNA of a tumor is often equated to a fingerprint or its unique genetic identify, a tumor's RNA profile represents a complex dynamic state more akin to a tumors personality or distinct behavior. Of the 11 types of RNA, the translational and clinical focus in prostate cancer has been primarily on mRNA and lncRNA. The most common use of RNA-based biomarkers is to assess a tumor's aggressiveness or treatment sensitivity. However, multiple gene expression signatures have been developed to capture the functional state that results from canonical DNA alterations, including ERG fusions, SPOP mutations, and Rb loss. More commonly, these biomarkers have been used to develop over 30 prognostic gene expression signatures, three of which are now commercially available and being increasingly incorporated into clinical trials. In parallel, the ability to use microarray and RNAseq technologies have allowed high throughput methods of performing whole transcriptomic analyses. This has enabled the discovery and training of numerous predictive biomarker signatures rooted in biologically informed pathways to determine which tumors are more sensitive or resistant to various treatments, including androgen-deprivation therapy, radiotherapy, chemotherapy, and PARP inhibition. This chapter will review the various types of RNA, technologies available to assess gene expression, and describe the available gene expression signatures for prostate cancer.
10.1007/978-3-030-32656-2_6
Chromogranin A: a useful biomarker in castration-resistant prostate cancer.
World journal of urology
PURPOSE:The natural history of prostate cancer (PC) almost always evolves to castration-resistant prostate cancer (CRPC) status, sometimes comprising pure or mixed neuroendocrine prostate cancers (NEPC) differentiation. In CRPC, monitoring using only prostate-specific antigen (PSA) is not optimal since neuroendocrine differentiated cells do not secrete PSA. Thus, monitoring with PSA and chromogranin A (CgA) may be useful. This review aims to evaluate evidence for the usefulness of CgA assessments during the monitoring of prostate cancer. METHOD:This review was based on three recent meta-analysis concerning CgA and prostate cancer. Further data were obtained from PubMed and Embase databases by searches using keywords, including chromogranin A and prostate cancer. RESULTS:CgA levels remain largely unchanged during the early PC evolution. The development of NEPC is characterised by lower PSA secretion and increased CgA secretion. Data supporting the prognostic value of high CgA baseline levels for survival are contrasting and scarce. However, increasing CgA levels early during treatment of metastatic (m)CRPC suggests resistance to treatment and predicts shorter survival, particularly in men with high baseline levels of CgA levels. In men with mCRPC, the first-line chemotherapy may be more appropriate than other agents when baseline CgA levels are high. Also, increasing CgA levels during treatment may indicate disease progression and may warrant a change of therapy. CONCLUSION:CgA monitoring at baseline and regularly during mCRPC management may be useful for monitoring disease evolution. An increased CgA baseline levels and increasing CgA levels may assist physicians with choosing and modifying therapy.
10.1007/s00345-022-04248-0
The potential of cell-free and exosomal microRNAs as biomarkers in liquid biopsy in patients with prostate cancer.
Journal of cancer research and clinical oncology
PURPOSE:Prostate cancer (PCa) is the 4th most diagnosed cancer and the 8th leading cause of cancer-related death worldwide. Currently, clinical risk stratification models including factors like PSA levels, Gleason score, and digital rectal examination are used for this purpose. There is a need for novel biomarkers that can distinguish between indolent and aggressive pathology and reduce the risk of overdiagnosis/overtreatment. Liquid biopsy has a non-invasive character, can lead to less morbidity and provide new biomarkers, such as miRNAs, that regulate diverse important cellular processes. Here, we report an extended revision about the role of cell-free and exosomal miRNAs (exomiRNAs) as biomarkers for screening, diagnosis, prognosis, or treatment of PCa. METHODS:A comprehensive review of the published literature was conducted focusing on the usefulness, advantages, and clinical applications of cell-free and exomiRNAs in serum and plasma. Using PubMed database 53 articles published between 2012 and 2021 were selected and discussed from the perspective of their use as diagnostic, prognostic and therapeutic biomarkers for PCa. RESULTS:We identify 119 miRNAs associated with PCa development and the cell-free and exosomal miR-21, miR-141, miR-200c, and miR-375 were consistently associated with progression in multiple cohorts/studies. However, standardized experimental procedures, and well-defined and clinically relevant cohort studies are urgently needed to confirm the biomarker potential of cell-free and exomiRNAs in serum or plasma. CONCLUSION:Cell-free and exomiRNAs in serum or plasma are promising tools for be used as non-invasive biomarkers for diagnostic, prognosis, therapy improvement and clinical outcome prediction in PCa patients.
10.1007/s00432-022-04213-9
Contribution of the L-Type Amino Acid Transporter Family in the Diagnosis and Treatment of Prostate Cancer.
International journal of molecular sciences
The L-type amino acid transporter (LAT) family contains four members, LAT1~4, which are important amino acid transporters. They mainly transport specific amino acids through cell membranes, provide nutrients to cells, and are involved in a variety of metabolic pathways. They regulate the mTOR signaling pathway which has been found to be strongly linked to cancer in recent years. However, in the field of prostate cancer (PCa), the LAT family is still in the nascent stage of research, and the importance of LATs in the diagnosis and treatment of prostate cancer is still unknown. Therefore, this article aims to report the role of LATs in prostate cancer and their clinical significance and application. LATs promote the progression of prostate cancer by increasing amino acid uptake, activating the mammalian target of rapamycin (mTOR) pathway and downstream signals, mediating castration-resistance, promoting tumor angiogenesis, and enhancing chemotherapy resistance. The importance of LATs as diagnostic and therapeutic targets for prostate cancer was emphasized and the latest research results were introduced. In addition, we introduced selective LAT1 inhibitors, including JPH203 and OKY034, which showed excellent inhibitory effects on the proliferation of various tumor cells. This is the future direction of amino acid transporter targeting therapy drugs.
10.3390/ijms24076178
The role of JNK in prostate cancer progression and therapeutic strategies.
Xu Ruiyuan,Hu Jieping
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Prostate cancer (PC), which has high morbidity and mortality among elderly men, is becoming the most common malignancy in men. The progression of PC is associated with several aspects including apoptosis, proliferation and metastasis. C-Jun N-terminal kinase (JNK) is a member of mitogen-activated protein kinases (MAPKs), which play vital roles in regulating diverse cell processes. JNK has been shown to activate multiple substrates to modulate apoptosis, proliferation, tumorigenesis and inflammation in response to various stimuli including cytokines, pathogens, growth factors, oxidative stress, ultraviolet radiation, toxins and drugs. In addition, emerging evidence has indicated the significant roles of androgen receptor in prostate cancer development. In this review, we will summarize our current knowledge on the roles of JNK in the apoptosis, proliferation, migration and DNA repair as well as dissect the relationships between JNK and androgen receptor in prostate cancer. Chemotherapeutic drugs targeting JNK will also be discussed, possibly providing an overview on the development of therapeutic strategies.
10.1016/j.biopha.2019.109679
Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach.
International journal of molecular sciences
Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.
10.3390/ijms22084109
Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: Still a potential druggable target?
Braglia Luca,Zavatti Manuela,Vinceti Marco,Martelli Alberto M,Marmiroli Sandra
Biochimica et biophysica acta. Molecular cell research
Although the prognosis of patients with localized prostate cancer is good after surgery, with a favorable response to androgen deprivation therapy, about one third of them invariably relapse, and progress to castration-resistant prostate cancer. Overall, prostate cancer therapies remain scarcely effective, thus it is mandatory to devise alternative treatments enhancing the efficacy of surgical castration and hormone administration. Dysregulation of the phosphoinositide 3-kinase pathway has attracted growing attention in prostate cancer due to the highly frequent association of epigenetic and post-translational modifications as well as to genetic alterations of both phosphoinositide 3-kinase and PTEN to onset and/or progression of this malignancy, and to resistance to canonical androgen-deprivation therapy. Here we provide a summary of the biological functions of the major players of this cascade and their deregulation in prostate cancer, summarizing the results of preclinical and clinical studies with PI3K signaling inhibitors and the reasons of failure independent from genomic changes.
10.1016/j.bbamcr.2020.118731
Selenoproteins of the Human Prostate: Unusual Properties and Role in Cancer Etiology.
Biological trace element research
The prostate is an important organ for the maintenance of sperm health with prostate cancer being a common disease for which there is a critical need to distinguish indolent from aggressive disease. Several selenium-containing proteins have been implicated in prostate cancer risk or outcome due to either enzyme function, the reduced levels of these proteins being associated with cancer recurrence after prostatectomy or their corresponding genes containing single-nucleotide polymorphisms associated with increased risk. Moreover, experimental data obtained from the manipulation of either cultured cells or animal models have indicated that some of these proteins are contributing mechanistically to prostate cancer incidence or progression. Among these are selenocysteine-containing proteins selenoprotein P (SELENOP), glutathione peroxidase (GPX1), and selenoprotein 15 (SELENOF); and the selenium-associated protein selenium-binding protein 1 (SBP1). Genotyping of some of the genes for these proteins has identified functional single-nucleotide polymorphisms that are associated with prostate cancer risk and the direct quantification of these proteins in human prostate tissues has not only revealed associations to clinical outcomes but have also identified unique properties that are different from what is observed in other tissue types. The location of GPX1 in the nucleus and SELENOF in the plasma membrane of prostate epithelial cells indicates that these proteins may have functions in normal prostate tissue that are distinct from that of the other tissue types.
10.1007/s12011-019-01809-0
Extracellular vesicles: the next generation of biomarkers for liquid biopsy-based prostate cancer diagnosis.
Theranostics
Prostate cancer (PCa) is a leading cause of cancer death for males in western countries. The current gold standard for PCa diagnosis - template needle biopsies - often does not convey a true representation of the molecular profile given sampling error and complex tumour heterogeneity. Presently available biomarker blood tests have limited accuracy. There is a growing demand for novel diagnostic approaches to reduce both the number of men with an abnormal PSA/ DRE who undergo invasive biopsy and the number of cores collected per biopsy. 'Liquid biopsy' is a minimally invasive biofluid-based approach that has the potential to provide information and improve the accuracy of diagnosis for patients' treatment selection, prognostic counselling and development of risk-adjusted follow-up protocols. Extracellular vesicles (EVs) are lipid bilayer-delimited particles released by tumour cells which may provide a real-time snapshot of the entire tumour in a non-invasive way. EVs can regulate physiological processes and mediate systemic dissemination of various types of cancers. Emerging evidence suggests that EVs have crucial roles in PCa development and metastasis. Most importantly, EVs are directly derived from their parent cells with their information. EVs contain components including proteins, mRNAs, DNA fragments, non-coding RNAs and lipids, and play a critical role in intercellular communication. Therefore, EVs hold promise for the discovery of liquid biopsy-based biomarkers for PCa diagnosis. Here, we review the current approaches for EV isolation and analysis, summarise the recent advances in EV protein biomarkers in PCa and focus on liquid biopsy-based EV biomarkers in PCa diagnosis for personalised medicine.
10.7150/thno.39486
Recent scenario of long non-coding RNAs as a diagnostic and prognostic biomarkers of prostate cancer.
Shukla Kamla Kant,Misra Sanjeev,Sankanagoudar Shrimanjunath,Sharma Himanshu,Choudhary Gautam Ram,Pareek Puneet,Vishnoi Jeevan Ram,Sharma Praveen
Urologic oncology
Prostate cancer (CaP) is a leading cause of cancer deaths in the worldwide with broad range of clinical manifestations ranging from relatively indolent to aggressive metastasis. Altered expression of many circulating long non-coding RNAs (lncRNAs), known to have role in tumorigenesis and metastasis, have already been reported in CaP patients. These lncRNAs modulate CaP pathogenesis by modulating multiple genes and thus altering metabolic pathways. Sustained androgen receptor (AR) signaling is one such key feature of castration-resistant prostate cancer, a CaP stage that has unmet need of accurate diagnostic and prognostic tools, that is affected by lncRNAs. In this review, we have discussed the emerging functions and associations of AR lncRNAs in CaP and highlighted their potential implications in cancer diagnostics and therapeutics. Further, extensive literature analysis in this article indicates that there is an immediate unmet need in the translational approach toward the hitherto identified AR lncRNAs. The characterization of AR lncRNAs involved in CaP is not exhaustive and adequate validation studies are still required to corroborate the present results that would be the impending future of basic research setting into clinical practice.
10.1016/j.urolonc.2020.06.003
Genetic Testing in Prostate Cancer.
Current oncology reports
PURPOSE OF REVIEW:This review summarizes recent advances in prostate cancer (PCa) genetics. RECENT FINDINGS:Upwards of 20% of metastatic castration-resistant prostate tumors (mCRPC) carry homologous recombination (HR) repair gene mutations, of which ~ 10% are germline (inherited). Another ~ 5% exhibit microsatellite instability (MSI-H) and/or mismatch repair deficiency (MMRd). Pembrolizumab is approved for tumors with MMRd, thus patients with mCRPC and MMRd are candidates for pembrolizumab. Emerging data indicate that platinum chemotherapy and poly ADP-ribose polymerase inhibitors (PARPi) are effective in PCa exhibiting HR deficiency. NCCN guidelines now recommend germline and somatic tumor testing in specific clinical scenarios due to treatment and family implications. Genetic testing in PCa patients may inform prognosis, treatment options, and have implications for family counseling. PARPi, platinum chemotherapy, and immune checkpoint inhibitors are promising targeted therapies for PCa with specific molecular features. Therapeutic advances, along with importance to relatives, are driving genetic testing in prostate cancer.
10.1007/s11912-020-0863-6
PRMT5: a putative oncogene and therapeutic target in prostate cancer.
Cancer gene therapy
Protein arginine methyltransferase 5 (PRMT5) was discovered two decades ago. The first decade focused on the biochemical characterization of PRMT5 as a regulator of many cellular processes in a healthy organism. However, over the past decade, evidence has accumulated to suggest that PRMT5 may function as an oncogene in multiple cancers via both epigenetic and non-epigenetic mechanisms. In this review, we focus on recent progress made in prostate cancer, including the role of PRMT5 in the androgen receptor (AR) expression and signaling and DNA damage response, particularly DNA double-strand break repair. We also discuss how PRMT5-interacting proteins that are considered PRMT5 cofactors may cooperate with PRMT5 to regulate PRMT5 activity and target gene expression, and how PRMT5 can interact with other epigenetic regulators implicated in prostate cancer development and progression. Finally, we suggest that targeting PRMT5 may be employed to develop multiple therapeutic approaches to enhance the treatment of prostate cancer.
10.1038/s41417-021-00327-3
Active Surveillance in Prostate Cancer: Role of Available Biomarkers in Daily Practice.
International journal of molecular sciences
Prostate cancer (PCa) is the most commonly diagnosed cancer in men. The diagnosis is currently based on PSA levels, which are associated with overdiagnosis and overtreatment. Moreover, most PCas are localized tumours; hence, many patients with low-/very low-risk PCa could benefit from active surveillance (AS) programs instead of more aggressive, active treatments. Heterogeneity within inclusion criteria and follow-up strategies are the main controversial issues that AS presently faces. Many biomarkers are currently under investigation in this setting; however, none has yet demonstrated enough diagnostic ability as an independent predictor of pathological or clinical progression. This work aims to review the currently available literature on tissue, blood and urine biomarkers validated in clinical practice for the management of AS patients.
10.3390/ijms22126266
Exosomal microRNAs as liquid biopsy biomarkers in prostate cancer.
Wang Jingpu,Ni Jie,Beretov Julia,Thompson James,Graham Peter,Li Yong
Critical reviews in oncology/hematology
Prostate cancer (PCa) is the most commonly diagnosed solid-organ cancer in males. The PSA testing may cause overdiagnosis and overtreatment for PCa patients. There is an urgent need for new biomarkers with greater discriminative precision for diagnosis and risk-stratification, to select for prostate biopsy and treatment of PCa. Liquid biopsy is a promising field with the potential to provide comprehensive information on the genetic landscape at diagnosis and to track genomic evolution over time in order to tailor the therapeutic choices at all stages of PCa. Exosomes, containing RNAs, DNAs and proteins, have been shown to be involved in tumour progression and a rich potential source of tumour biomarkers, especially for profiling analysis of their miRNAs content. In this review, we summarise the exosomal miRNAs in PCa diagnosis, prognosis and management, and further discuss their possible technical challenges associated with isolating PCa-specific exosomes.
10.1016/j.critrevonc.2019.102860
Germline Testing for Prostate Cancer Prognosis: Implications for Active Surveillance.
Helfand Brian T,Xu Jianfeng
The Urologic clinics of North America
Available evidence supports routine implementation of germline genetic testing for many aspects of prostate cancer (PCa) decision making. The purpose of obtaining genetic testing for newly diagnosed men would be focused on identifying mutations that predispose to aggressive PCa. Based on an evidence-based review, the authors review germline rare pathogenic mutations in several genes that are significantly associated with aggressiveness, metastases, and mortality. Then recent studies of these germline mutations in predicting tumor grade reclassification among patients undergoing active surveillance are discussed. Single nucleotide polymorphisms-based polygenic risk scores in differentiating PCa aggressiveness and prognosis are reviewed.
10.1016/j.ucl.2021.04.003
TGF-BETA IN THE NATURAL HISTORY OF PROSTATE CANCER.
Ahel Jamal,Hudorović Narcis,Vičić-Hudorović Višnja,Nikles Hrvoje
Acta clinica Croatica
All transforming growth factors beta (TGFß) are cytokines that regulate several cellular functions such as cell growth, differentiation and motility. They may also have a role in immunosuppression. Their role is important for normal prostate development. TGFß is active in the regulation of balance between epithelial cell proliferation and apoptosis through stromal epithelia the androgen receptor action. TGFß protects and maintains prostate stem cells, an important population necessary for prostate tissue regeneration. However, TGFß is shown to have a contrasting role in prostate tumor genesis. In the early stages of tumor development, TGFß acts as a tumor suppressor, whereas in the later stages, TGFß becomes a tumor promoter by inducing proliferation, invasion and metastasis. In this review, we outline complex interactions that TGFß-mediated signaling has on prostate tumor genesis, focusing on the role of these interactions during the course of prostate cancer and, in particular, during disease progression.
10.20471/acc.2019.58.01.17
Gene Isoforms: A Potential Biomarker and Therapeutic Target in Prostate Cancer.
Sharad Shashwat,Dobi Albert,Srivastava Shiv,Srinivasan Alagarsamy,Li Hua
Biomolecules
The identification of prostate transmembrane protein androgen induced 1 (), an androgen responsive gene, came initially from the studies of androgen regulatory gene networks in prostate cancer. It was soon followed by the documentation of the expression and functional analysis of transmembrane prostate androgen-induced protein ()/ in other solid tumors including renal, colon, breast, lung, and ovarian cancers. Further elucidation of gene expression and sequence analysis revealed the presence of five isoforms with distinct extracellular domains (isoforms , , , , and ). Notably, the predicted amino acid sequences of PMEPA1 isoforms show differences at the N-termini, a conserved membrane spanning and cytoplasmic domains. serves as an essential regulator of multiple signaling pathways including androgen and TGF-β signaling in solid tumors. Structure-function studies indicate that specific motifs present in the cytoplasmic domain (PY, SIM, SH3, and WW binding domains) are utilized to mediate isoform-specific functions through interactions with other proteins. The understanding of the "division of labor" paradigm exhibited by isoforms further expands our knowledge of gene's multiple functions in tumorigenesis. In this review, we aim to summarize the most recent advances in understanding of isoform-specific functions and their associations with prostate cancer progression, highlighting the potentials as biomarker and therapeutic target in prostate cancer.
10.3390/biom10091221
An overview of current and emerging diagnostic, staging and prognostic markers for prostate cancer.
Brönimann Stephan,Pradere Benjamin,Karakiewicz Pierre,Abufaraj Mohammad,Briganti Alberto,Shariat Shahrokh F
Expert review of molecular diagnostics
INTRODUCTION:This manuscript aims to give an overview of current diagnostic, staging, and prognostic markers for prostate cancer (PCa) and discuss emerging approaches. The widespread use of PSA for early detection led to improved survival but at the cost of over-diagnosis, often associated with over-treatment and its adverse events. There is thus an unmet need for new markers to sustainably improve the diagnosis and risk assessment, thereby providing a more accurate treatment decision for each individual patient. AREAS COVERED:Promising new molecular serum (PSA, PHI, 4Kscore®), urine (Progensa®, SelectMDx®, MiPS) and tissue-based markers (Ki-67, Prolaris®, ConfirmMDx®, Oncotype Dx®, Decipher®, Promark®) will be discussed in this review. EXPERT OPINION:Over-diagnosis and difficulties in prognosticating clinical outcome among patients with similar histological and clinical parameters often lead to over- or under-treatment. New markers will probably be used with clinical and histopathological features as well as imaging diagnostics to capture the comprehensive biology and clinical behavior of PCa. New biomarkers open the avenue to avoid mpMRI with targeted biopsy in the future, thereby sparing risks and pitfalls associated with this approach. Before this utopia becomes reality, the panel of technologically complementary markers need to prove that they are better, cheaper, and faster than current strategies.
10.1080/14737159.2020.1785288
Long non-coding RNAs and their potential impact on diagnosis, prognosis, and therapy in prostate cancer: racial, ethnic, and geographical considerations.
Expert review of molecular diagnostics
INTRODUCTION:Advances in high-throughput sequencing have greatly advanced our understanding of long non-coding RNAs (lncRNAs) in a relatively short period of time. This has expanded our knowledge of cancer, particularly how lncRNAs drive many important cancer phenotypes via their regulation of gene expression. AREAS COVERED:Men of African descent are disproportionately affected by PC in terms of incidence, morbidity, and mortality. LncRNAs could serve as biomarkers to differentiate low-risk from high-risk diseases. Additionally, they may represent therapeutic targets for advanced and castrate-resistant cancer. We review current research surrounding lncRNAs and their association with PC. We discuss how lncRNAs can provide new insights and diagnostic biomarkers for African American men. Finally, we review advances in computational approaches that predict the regulatory effects of lncRNAs in cancer. EXPERT OPINION:PC diagnostic biomarkers that offer high specificity and sensitivity are urgently needed. PC specific lncRNAs are compelling as diagnostic biomarkers owing to their high tissue and tumor specificity and presence in bodily fluids. Recent studies indicate that clinical utility might be restricted to men of European descent. Further work is required to develop lncRNA biomarkers tailored for men of African descent.
10.1080/14737159.2021.1996227
Prostate-specific markers to identify rare prostate cancer cells in liquid biopsies.
van der Toom Emma E,Axelrod Haley D,de la Rosette Jean J,de Reijke Theo M,Pienta Kenneth J,Valkenburg Kenneth C
Nature reviews. Urology
Despite improvements in early detection and advances in treatment, patients with prostate cancer continue to die from their disease. Minimal residual disease after primary definitive treatment can lead to relapse and distant metastases, and increasing evidence suggests that circulating tumour cells (CTCs) and bone marrow-derived disseminated tumour cells (BM-DTCs) can offer clinically relevant biological insights into prostate cancer dissemination and metastasis. Using epithelial markers to accurately detect CTCs and BM-DTCs is associated with difficulties, and prostate-specific markers are needed for the detection of these cells using rare cell assays. Putative prostate-specific markers have been identified, and an optimized strategy for staining rare cancer cells from liquid biopsies using these markers is required. The ideal prostate-specific marker will be expressed on every CTC or BM-DTC throughout disease progression (giving high sensitivity) and will not be expressed on non-prostate-cancer cells in the sample (giving high specificity). Some markers might not be specific enough to the prostate to be used as individual markers of prostate cancer cells, whereas others could be truly prostate-specific and would make ideal markers for use in rare cell assays. The goal of future studies is to use sensitive and specific prostate markers to consistently and reliably identify rare cancer cells.
10.1038/s41585-018-0119-5
Galectin-3 in prostate cancer and heart diseases: a biomarker for these two frightening pathologies?
Molecular biology reports
Galectin-3 (Gal-3) belongs to galectin protein family, a type of β-galactose-binding lectin having more than one evolutionarily conserved domain of carbohydrate recognition. Gal-3 is mainly located in the cytoplasm, but it also enters the nucleus and is secreted into the extracellular environment and biological fluids such as urine, saliva, and serum. It plays an important role in many biological functions, such as angiogenesis, apoptosis, cell differentiation, cell growth, fibrosis, inflammation, host defense, cellular modification, splicing of pre-mRNA, and transformation. Many previous studies have shown that Gal-3 can be used as a diagnostic or prognostic biomarker for heart ailments, kidney diseases, and other major illnesses including cancer. Moreover, it may also play a major role in risk stratification in different diseases, and in this review, we have summarized the potential roles and application of Gal-3 as diagnostic, prognostic, and risk stratifying biomarker from previously reported studies in heart diseases and cancer, with special emphasis on prostate cancer.
10.1007/s11033-022-08207-1
Mass Spectrometry-Based Glycoproteomics and Prostate Cancer.
Gabriele Caterina,Prestagiacomo Licia E,Cuda Giovanni,Gaspari Marco
International journal of molecular sciences
Aberrant glycosylation has long been known to be associated with cancer, since it is involved in key mechanisms such as tumour onset, development and progression. This review will focus on protein glycosylation studies in cells, tissue, urine and serum in the context of prostate cancer. A dedicated section will cover the glycoforms of prostate specific antigen, the molecule that, despite some important limitations, is routinely tested for helping prostate cancer diagnosis. Our aim is to provide readers with an overview of mass spectrometry-based glycoproteomics of prostate cancer. From this perspective, the first part of this review will illustrate the main strategies for glycopeptide enrichment and mass spectrometric analysis. The molecular information obtained by glycoproteomic analysis performed by mass spectrometry has led to new insights into the mechanism linking aberrant glycosylation to cancer cell proliferation, migration and immunoescape.
10.3390/ijms22105222
Clinical utility of emerging biomarkers in prostate cancer liquid biopsies.
Boerrigter Emmy,Groen Levi N,Van Erp Nielka P,Verhaegh Gerald W,Schalken Jack A
Expert review of molecular diagnostics
: Prostate cancer (PCa) is one of the most common malignancies in men and a major cause of cancer deaths among men worldwide. Prostate specific antigen (PSA) monitoring and histopathological examination of tumor biopsies remain gold standards in PCa diagnostics. These clinical parameters are not well suited for patient stratification, predicting and monitoring treatment response. On the other hand, liquid biopsies offer a unique opportunity to easily isolate tumor-derived material for longitudinal clinical assessment.: In this review we focus on the clinical application of novel liquid biomarkers that have the potential to monitor and stratify patients in order to achieve better therapeutic effects and improve clinical outcomes. Enumeration and characterization of circulating tumor cells (CTCs), tumor-educated platelets, exosomes, and cell-free nucleic acids have been studied for their clinical utility in PCa diagnostics, prognostics, monitoring treatment response and guiding treatment choice.: Liquid biomarkers have high potential to be used for prognosis, monitoring treatment response and guiding treatment selection. Although there is a remarkable progress in PCa biomarker discovery, their clinical validation is very limited. Research should be focused on biomarker validation and the incorporation of these biomarkers in clinical practice.
10.1080/14737159.2019.1675515
Molecular mechanisms of neuroendocrine differentiation in prostate cancer progression.
Journal of cancer research and clinical oncology
BACKGROUND:Rapid evolution of the therapeutic management of prostate cancer, especially in in second-generation androgen inhibitors, has increased the opportunity of transformation from prostate cancer (PCa) to neuroendocrine prostate cancer (NEPC). NEPC still lacks effective diagnostic and therapeutic interventions. Researches into the molecular characteristics of neuroendocrine differentiation is undoubtedly crucial to the discovery of new target genes for accurate diagnostic and therapeutic targets. PURPOSE:In this review, we focus on the relevant genes and molecular mechanisms that have contributed to the transformation in the progression of PCa and discuss the potential targeted molecule that might improve diagnostic accuracy and therapeutic effectiveness. METHODS:The relevant literatures from PubMed have been reviewed for this article. CONCLUSION:Several molecular characteristics influence the progression of neuroendocrine differentiation of prostate cancer which will provide a novel sight for accurate diagnosis and target therapeutic intervention for patients with NEPC.
10.1007/s00432-022-04061-7
[FOXO3a signaling pathway in prostate cancer: Progress in studies].
Tao Yan,Li Lan-Lan,Liu Shan-Hui,Hong Mei
Zhonghua nan ke xue = National journal of andrology
FOXO3a is an important member of the FOXO subfamily of Forkhead transcription factors, which plays an important role in promoting cell apoptosis, inducing cell cycle arrest, inhibiting cell proliferation and suppressing tumor metastasis through phosphorylation, ubiquitination-mediated degradation and microRNA. Studies show that upregulated expression of FOXO3a can inhibit the growth of PCa cells. This review summarizes the advances in the studies of the FOXO3a signaling pathway in PCa, aiming to provide some new ideas on the clinical diagnosis and targeted therapy of the malignancy.
Association between lactate dehydrogenase levels and oncologic outcomes in metastatic prostate cancer: A meta-analysis.
Li Fan,Xiang Hui,Pang Zisen,Chen Zejia,Dai Jinlong,Chen Shu,Xu Bin,Zhang Tianyu
Cancer medicine
PURPOSE:Previous studies have provided evidence of the high expression of lactate dehydrogenase (LDH) in multiple solid tumors; however, its prognostic relationship with metastatic prostate cancer (mPCa) remains controversial. We performed a meta-analysis to better understand the prognostic potential of LDH in mPCa. METHODS:In our investigation, we included PubMed, Embase, Web of Science, and Cochrane Library as web-based resources, as well as studies published before January 2020 on the predictive value of LDH in mPCa. We independently screened the studies according to the inclusion and exclusion criteria, evaluated the quality of the literature, extracted the data, and used RevMan 5.3 and STATA12.0 software for analysis. RESULT:From the 38 published studies, the records of 9813 patients with mPCa were included in this meta-analysis. We observed that higher levels of LDH in patients with mPCa were significantly associated with poorer overall survival (OS) (HR = 2.17, 95% CI: 1.91-2.47, P < .00001) and progression-free survival (PFS) (HR = 1.60, 95% CI: 1.20-2.13, P = .001). The subgroup analyses indicated that the negative prognostic impact of higher levels of LDH on the oncologic outcomes of mPCa was significant regardless of ethnicity, publication year, sample size, analysis type, treatment type, age, and disease state. CONCLUSION:Our analysis suggested the association between a higher level of LDH and poorer OS and PFS in patients with mPCa. As a parameter that can be conveniently evaluated, the LDH levels should be included as a valuable biomarker in the management of mPCa.
10.1002/cam4.3108
Emerging promising biomarkers for treatment decision in metastatic castration-resistant prostate cancer.
Kafka Mona,Eder Iris E,Klocker Helmut,Heidegger Isabel
Urologic oncology
Prostate cancer is one of the most common causes of death in males. Even if treatment is often of curative intent in early stages of the disease, up to 50% of patients relapse after primary therapy. Moreover, 10% to 15% of patients present in a primary metastatic stage of disease. In the past years the treatment landscape of metastatic castration-resistant prostate cancer expanded due to the development of second-generation antiandrogens (abiraterone acetate, enzalutamide), chemotherapeutic agents and radium-223. With the availability of several therapeutic lines, we are now confronted with the problem of choosing the most suitable therapy in each state of disease. As often observed in clinical routine, prostate specific antigen is not sufficient for early prediction of a therapy response. Furthermore, biomarkers for prediction of the optimal first-line therapy are badly needed in order to avoid primary resistance. Therefore, the present short review article gives an overview of currently available clinical and preclinical biomarkers for treatment response to metastatic castration-resistant prostate cancer therapeutic agents with the aim of providing support for a personalized decision-making process in everyday use.
10.1016/j.urolonc.2020.05.025
Role of the runt-related transcription factor (RUNX) family in prostate cancer.
Ashe Hannah,Krakowiak Patryk,Hasterok Sylwia,Sleppy Rosalie,Roller Devin G,Gioeli Daniel
The FEBS journal
Prostate cancer (PCa) is a very complex disease that is a major cause of death in men worldwide. Currently, PCa dependence on the androgen receptor (AR) has resulted in use of AR antagonists and antiandrogen therapies that reduce endogenous steroid hormone production. However, within two to three years of receiving first-line androgen deprivation therapy, the majority of patients diagnosed with PCa progress to castration-resistant prostate cancer (CRPC). There is an urgent need for therapies that are more durable than antagonism of the AR axis. Studies of runt-related transcription factors (RUNX) and their heterodimerization partner, core-binding factor subunit b (CBFβ), are revealing that the RUNX family are drivers of CRPC. In this review, we describe what is presently understood about RUNX members in PCa, including what regulates and is regulated by RUNX proteins, and the role of RUNX proteins in the tumor microenvironment and AR signaling. We discuss the implications for therapeutically targeting RUNX, the potential for RUNX as PCa biomarkers, and the current pressing questions in the field.
10.1111/febs.15804
RNA-based biomarkers for the diagnosis, prognosis, and therapeutic response monitoring of prostate cancer.
Bae Juhyeon,Yang Seung-Hoon,Kim Aram,Kim Hyeong Gon
Urologic oncology
Prostate cancer (CaP) is the most common malignant neoplasm of the urinary tract. The current recommendations for CaP diagnosis rely on the prostate-specific antigen levels and a digital rectal examination for anatomical abnormalities. However, these diagnostic tools are not highly sensitive. In particular, prostate-specific antigen has a low positive predictive value (approximately 30%). Thus, there is a need to develop biomarkers to improve the early clinical detection of CaP. Several novel technologies enable the identification of biomarkers from diverse sources, including the urine, serum, and prostate tissues. Furthermore, advances in genomic techniques have enabled the analysis of novel biomarkers, such as deoxyribonucleic acids (DNAs), ribonucleic acids (RNAs), proteins, and circulating tumor cells. Previous studies have demonstrated that RNAs are potential diagnostic biomarkers for various cancers using high-throughput sequencing analysis. The sensitivity and specificity of RNA biomarkers are higher than those of protein biomarkers. Polymerase chain reaction enables the amplification of trace levels of RNAs with high sensitivity and specificity. RNA biomarkers provide dynamic insights into cellular states and regulatory processes when compared with DNA biomarkers. Additionally, multiple copies of various RNAs in a cell provide more information than DNA. The levels of specific RNAs in CaP tissues are upregulated when compared with those in non-cancerous tissues. Additionally, RNAs can be easily isolated from various body fluids. Thus, RNAs are potential non-invasive biomarkers for CaP. Moreover, the analysis of RNA levels adjusted for each stage of CaP enables the determination of prognostic individualized therapy for aggressive or progressive CaP. This review focused on the diagnostic and prognostic values of RNAs for CaP.
10.1016/j.urolonc.2021.11.012
Prostate-Specific Membrane Antigen-Based PET Brings New Insights into the Management of Prostate Cancer.
PET clinics
Prostate cancer (PCa) is the third most common cancer diagnosed in the world. Since its first identification in 1987 and its first molecular cloning in 1993, prostate-specific membrane antigen (PSMA) has been developed as a theragnostic imaging biomarker and therapeutic agent for PCa. For metastatic castration-resistant PCa, PSMA-based PET imaging can be applied to the monitoring of disease and response assessment with PSMA-based therapeutics. This novel imaging modality is bringing new insights into diagnosis, stratification, and clinical decision-making and treatment.
10.1016/j.cpet.2022.07.001
Role of tumor-associated immune cells in prostate cancer: angel or devil?
Wu Shui-Qing,Su Hao,Wang Yin-Huai,Zhao Xiao-Kun
Asian journal of andrology
Prostate cancer is the most common malignancy in the reproductive system of older males. Androgen deprivation therapy (ADT) is an important treatment for prostate cancer patients. However, almost all prostate cancer patients unavoidably progress to the castration-resistant stage after ADT treatment. Recent studies have shown that tumor-associated immune cells play major roles in the initiation, progression, and metastasis of prostate cancer. Various phenotypes of tumor-associated immune cells have tumor-promoting or antitumor functions mediated by interacting with tumor cells. Here, we review the current knowledge of tumor-associated immune cells in prostate cancer.
10.4103/aja.aja_47_19
Liquid biomarkers for early detection of prostate cancer and summary of available data for their use in African-American men.
Prostate cancer and prostatic diseases
BACKGROUND:Several liquid biomarker tests have been developed to account for the limitations of prostate specific antigen (PSA) screening prior to prostate biopsy. African ancestry is an established risk factor for prostate cancer (PCa) and must be particularly considered when evaluating patients with liquid biomarkers. While multiple tests have been developed over decades of exploration, recent advances can help patients and physicians incorporate data into a broader clinical context. METHODS:We sought to review currently available liquid biomarker tests in a practical, clinically directed fashion with particular focus on performance in men with African ancestry. We reviewed discovery and validation studies and highlight important considerations for each test. RESULTS:We discuss the advantages and limitations of percent free PSA, Prostate Health Index, Progensa® PCA3, ExoDx® Prostate Test, SelectMDx®, 4Kscore® Test, and Mi-Prostate Score and summarize salient studies on their use. A literature review of evidence specifically for men with African ancestry was conducted and available studies were summarized. CONCLUSIONS:Liquid biomarkers can be useful tools for aiding in risk stratification prior to prostate biopsy. Use of such tests should be individualized based on a thorough knowledge of supporting evidence and the goals of the patient and physician. Further study should prioritize evaluation of such biomarkers in men with African ancestry.
10.1038/s41391-022-00507-8
Clinical implications of genomic alterations in metastatic prostate cancer.
Prostate cancer and prostatic diseases
There has been a rapid expansion in treatment options for the management of metastatic prostate cancer, but individual patient outcomes can be variable due to inter-patient tumor heterogeneity. Fortunately, the disease can be stratified on the basis of common somatic features, providing potential for the development of clinically useful prognostic and predictive biomarkers. Tissue biopsy programs and studies leveraging circulating tumor DNA (ctDNA) have revealed specific genomic alterations that are associated with aggressive disease biology. In this review, we discuss the potential for genomic subtyping to improve prognostication and to help guide treatment selection. We summarize data on associations between AR pathway alterations and patient response to AR signaling inhibitors and other standards of care. We describe the links between detection of different types of DNA damage repair defects and clinical outcomes with targeted therapies such as poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors or immune checkpoint inhibitors. PI3K signaling pathway inhibitors are also in advanced clinical development and we report upon the potential for these and other novel targeted therapies to have impact in specific molecular subsets of metastatic prostate cancer. Finally, we discuss the growing use of blood-based analytes for prognostic and predictive biomarker development, and summarize ongoing prospective biomarker-driven clinical trials.
10.1038/s41391-020-00308-x
Complexity of Neural Component of Tumor Microenvironment in Prostate Cancer.
Sejda Aleksandra,Sigorski Dawid,Gulczyński Jacek,Wesołowski Wojciech,Kitlińska Joanna,Iżycka-Świeszewska Ewa
Pathobiology : journal of immunopathology, molecular and cellular biology
The tumor microenvironment (TME) plays an essential role in the development and progression of neoplasms. TME consists of the extracellular matrix and numerous specialized cells interacting with cancer cells by paracrine and autocrine mechanisms. Tumor axonogenesis and neoneurogenesis constitute a developing area of investigation. Prostate cancer (PC) is one of the most common malignancies in men worldwide. During the past years, more and more studies have shown that mechanisms leading to the development of PC are not confined only to the epithelial cancer cell, but also involve the tumor stroma. Different nerve types and neurotransmitters present within the TME are thought to be important factors in PC biology. Moreover, perineural invasion, which is a common way of PC spreading, in parallel creates the neural niche for malignant cells. Cancer neurobiology seems to have become a new discipline to explore the contribution of neoplastic cell interactions with the nervous system and the neural TME component, also to search for potential therapeutic targets in malignant tumors such as PC.
10.1159/000505437
From Research to the Real World: Moving Prostate Cancer Biomarkers into the Clinic.
Critical reviews in oncogenesis
Effective biomarkers provide the potential to significantly improve treatment decisions and outcomes in prostate cancer patients. While the literature is inundated with prostate cancer biomarkers in the early phases of testing, very few reach the clinic. Research should be focused on progressing effective biomarkers from discovery to clinical utility and implementation. Presented here is an overview of the biomarker development pathway and a discussion of the current issues impeding our efforts to deliver biomarkers that improve clinical outcomes in men with prostate cancer.
10.1615/CritRevOncog.2022043394
Prospective role of 3βHSD1 in prostate cancer precision medicine.
The Prostate
BACKGROUND:Prostate cancer is addicted to androgens. The steroidogenic enzyme 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) recognizes pregnenolone, dehydroepiandrosterone (DHEA), and steroidal medicine abiraterone as substrates to accelerate disease progression. METHODS:References for this review were identified through searches of PubMed with the search terms "prostate cancer", "HSD3B1", and "3bHSD1" from 1990 until June, 2022. RESULTS:Genotype of 3βHSD1 has been reported to correlate with tumor aggressiveness of advanced prostate cancer in multiple clinical scenarios. The ethnic differences and limitations of using 3βHSD1 genotype as a prognostic biomarker have been discussed here. The activity of 3βHSD1 increases in patients treated with abiraterone and enzalutamide, giving rise to treatment resistance. Further elucidation of 3βHSD1 regulatory mechanisms will shed light on more approaches for disease intervention. We also review the recent advance on 3βHSD1 inhibitors and targeting 3βHSD1 for prostate cancer management. Novel 3βHSD1 inhibitors will be needed to provide additional options for prostate cancer management. CONCLUSION:3βHSD1 is both a predictive biomarker and a promising therapeutic target for prostate cancer.
10.1002/pros.24504
Semen as a rich source of diagnostic biomarkers for prostate cancer: latest evidence and implications.
Mao Chenyu,Ding Yongfeng,Xu Nong
Molecular and cellular biochemistry
Prostate cancer (PCa) is one of the most common cancers in men and the cause of numerous cancer deaths in the world. Nowadays, based on diagnostic criteria, prostate-specific antigen (PSA) evaluation and rectal examination are used to diagnose prostate-related malignancies. However, due to the different types of PCa, there are several doubts about the diagnostic value of PSA. On the other hand, semen is considered an appropriate source and contains various biomarkers in non-invasive diagnosing several autoimmune disorders and malignancies. Evidence suggests that analysis of semen biomarkers could be helpful in PCa diagnosis. Therefore, due to the invasiveness of most diagnostic methods in PCa, the use of semen as a biologic sample containing various biomarkers can lead to the emergence of novel and non-invasive diagnostic approaches. This review summarized recent studies on the use of various seminal biomarkers for diagnosis, prognosis and prediction of PCa.
10.1007/s11010-021-04273-4
Exosomal miRNAs-a diagnostic biomarker acting as a guiding light in the diagnosis of prostate cancer.
Functional & integrative genomics
Prostate cancer, one of the major causes of mortality globally is regarded as the second leading cause of mortality among men. It is known to affect the stromal cells surrounding it. Through the use of exosomes, the affected stromal cells can promote the growth and spread of the cancer. Exosomes are known to play a role not only in the development and progression of cancer but also contribute to the drug-resistance character of cancer cells. Recently, the discovery of the small non-coding RNAs or miRNA has attracted attention of cancer researchers as they can regulate the expression of different genes. Therefore, exosomal miRNA can be used as a novel and reliable biomarker for the diagnosis and treatment of prostate cancer. In addition, exosomal miRNAs can also be used as a potential treatment for prostate cancer. The goal of this review is to provide a comprehensive analysis of the current knowledge about the role of exosomal miRNAs in the treatment of patients with prostate cancer and their potential role in monitoring the disease.
10.1007/s10142-022-00951-8
Current state of biomarkers for the diagnosis and assessment of treatment efficacy of prostate cancer.
Liu Jihai,Li Yirui,Yang Dongliang,Yang Chunhua,Mao Lijun
Discovery medicine
In recent years, with the westernization of lifestyle, reduced physical activity and increased prostate-specific antigen (PSA) testing, the incidence of prostate cancer (PCa) has risen significantly in developing countries. Currently, PSA is the only PCa biomarker applied clinically, but it does not perform well in the early diagnosis and distinguishing between benign prostatic hyperplasia and prostate cancer. With the advances in deep sequencing technology, a series of new PCa biomarkers have been recently proposed to improve the diagnostic value of PSA, such as prostate cancer antigen 3 (PCA3), TMPRSS2-ETS fusion gene, microRNA, and other regulatory non-coding RNAs. In addition, the prostate health index (PHI) has been approved by the U.S. Food and Drug Administration (FDA) for clinical use in the detection of PCa. The prostate-specific membrane antigen (PSMA) has been confirmed to be specifically expressed on the surface of PCa cells. In this review, we provide an updated summary of the value and features of these novel biomarkers in the diagnosis and treatment of PCa.
Research Progress for the Clinical Application of Circulating Tumor Cells in Prostate Cancer Diagnosis and Treatment.
Yang Mei,Zhang Xiaotian,Guo Lixia,Liu Xiumin,Wu Jing,Zhu Hongquan
BioMed research international
Prostate cancer is a life-threatening and highly heterogeneous malignancy. In the past decade, circulating tumor cells (CTCs) have been suggested to play a critical role in the occurrence and progression of prostate cancer. In particular, as the "seed" of the cancer metastasis cascade, CTCs determine numerous biological behaviors, such as tumor invasion into adjacent tissues and migration to distant organs. Many studies have shown that CTCs are necessary in the processes of tumor progression, including tumorigenesis, invasion, metastasis, and colonization. Furthermore, CTCs express various biomarkers relevant to prostate cancer and thus can be applied clinically in noninvasive tests. Moreover, CTCs can serve as potential prognostic targets in prostate cancer due to their roles in regulating many processes associated with cancer metastasis. In this review, we discuss the isolation and detection of CTCs as predictive markers of prostate cancer, and we discuss their clinical application in the diagnosis and prognosis of prostate cancer and in monitoring the response to treatment and the prediction of metastasis.
10.1155/2021/6230826
Relevance of emerging metabolomics-based biomarkers of prostate cancer: a systematic review.
Expert reviews in molecular medicine
Prostate cancer (PC) presents great challenges in early diagnosis and often leads to unnecessary invasive procedures as well as over diagnosis and treatment, thus highlighting the need for promising early diagnostic biomarkers. The aim of this review is to provide an up-to-date summary of chronologically existing metabolomics PC biomarkers, their potential to improve clinical PC diagnosis and to reduce the proliferation and monitoring of PC. The systematic research was conducted on PubMed in accordance with PRISMA guidelines to report PC biomarkers. The majority of the studies distinguished malignant from benign prostate and few explored the biomarkers associated with the progression of PC. The present review summarises the primary outcomes of most significant studies to extend our knowledge of PC metabolomics biomarkers. We observed divergent inter-laboratory technical procedures employing different statistical approaches produced abundant information regarding PC metabolites perturbation. Since PC metabolomics is still in its early phase, it is vital that we dig out the most specific, sensitive and accurate metabolic signatures and conduct more studies with milestone findings with comparable sample sizes to validate and corroborate the findings.
10.1017/erm.2022.20
Optimal Use of Tumor-Based Molecular Assays for Localized Prostate Cancer.
Current oncology reports
PURPOSEOF REVIEW:The use of genomic testing for prostate cancer continues to grow; however, utilization remains institutionally dependent. Herein, we review current tissue-based markers and comment on current use with active surveillance and prostate MRI. RECENT FINDINGS:While data continues to emerge, several studies have shown a role for genomic testing for treatment selection. Novel testing options include ConfirmMDx, ProMark, Prolaris, and Decipher, which have shown utility in select patients. The current body of literature on this specific topic remains very limited; prospective trials with long-term follow-up are needed to improve our understanding on how these genomic tests fit when combined with our current clinical tools. As the literature matures, it is likely that newer risk calculators that combine our classic clinical variables with genomic and imaging data will be developed to bring about standard protocols for prostate cancer decision-making.
10.1007/s11912-021-01180-1
Targeting the BAF complex in advanced prostate cancer.
Expert opinion on drug discovery
INTRODUCTION:The BRG1/BRM associated factors (BAF) complex is a chromatin remodeling SWI/SNF which is mutated in 20% of cancers. This complex has many interchangeable subunits which may have oncogenic or tumor suppressor activity in a context-dependent manner. The BAF complex is mutated in 35-50% of metastatic prostate cancer (PC); however, its role in advanced disease is unclear. This review attempts to consolidate current knowledge of the BAF complex in PC and explore potential therapeutic approaches. AREAS COVERED:This review covers the known roles of some BAF subunits, their alterations, and the models which best explain their mechanisms in driving PC. Following this, the authors provide their expert perspective on how this complex could be targeted in the future with a personalized medicine approach. EXPERT OPINION:Personalized medicine would allow for patient stratification to exploit synthetic lethal strategies in targeting a mutated BAF complex as shown experimentally in other cancers. BAF dependency can also be targeted in patients stratified for other molecular markers such as BRG1 targeting in phosphatase and tensin homolog (PTEN) deficient PC.
10.1080/17460441.2020.1821644
Known epigenetic biomarkers for prostate cancer detection and management: exploring the potential of blood-based liquid biopsies.
Constâncio Vera,Barros-Silva Daniela,Jerónimo Carmen,Henrique Rui
Expert review of molecular diagnostics
INTRODUCTION:Although prostate cancer (PCa) stands as an important cause of cancer-related deaths, a sizeable proportion of diagnosed cases are clinically insignificant. Hence, novel and more specific biomarkers to identify clinically significant PCa are needed. Liquid biopsies offer the potential to accurately identify cancer markers, including PCa. Epigenetic biomarkers such as cell-free DNA and circulating RNAs have emerged as minimally invasive cancer markers. Areas covered: Herein, we provide an overview of epigenetic biomarkers current state based on a comprehensive review of the relevant literature in blood-based liquid biopsies and challenges/limitations of this new and growing field of cancer biomarkers. Expert opinion: The epigenetic-based biomarkers characteristics make them attractive to the clinics and their minimally invasive assessment are a promising opportunity for PCa detection/management. The main limitations are the lack of robust validation studies and integrated approaches. Future studies would benefit from a change in focus to a 'selected PCa detection'.
10.1080/14737159.2019.1604224
Crosstalk between myeloid-derived suppressor cells and the immune system in prostate cancer: MDSCs and immune system in Prostate cancer.
Sanaei Mohammad-Javad,Salimzadeh Loghman,Bagheri Nader
Journal of leukocyte biology
Prostate cancer is the second most common cancer and the fifth leading cause of cancer-associated death in men. Previous studies have revealed a surprising ability for an immature population of myeloid cells called myeloid-derived suppressor cells (MDSCs) in the commencement and development of many tumors, including those of prostate cancer. Herein, the molecular and cellular changes of MDSCs in prostate cancer in both human and nonhuman models are reviewed. The suppressive function of MDSCs are also discussed with a particular focus on the role of IL-6 and JAK/STAT3 signaling pathways in the induction of their suppressive activity. Ultimately, a brief review of MDSC-targeting approaches for potential cancer therapy is presented.
10.1002/JLB.4RU0819-150RR
Genomic Features and Clinical Implications of Intraductal Carcinoma of the Prostate.
Kang Minyong,Lee Hyunwoo,Byeon Sun-Ju,Kwon Ghee Young,Jeon Seong Soo
International journal of molecular sciences
Intraductal carcinoma of the prostate (IDC-P) is a rare and unique form of aggressive prostate carcinoma, which is characterized by an expansile proliferation of malignant prostatic epithelial cells within prostatic ducts or acini and the preservation of basal cell layers around the involved glands. The vast majority of IDC-P tumors result from adjacent high-grade invasive cancer via the retrograde spreading of tumor cells into normal prostatic ducts or acini. A subset of IDC-P tumors is rarely derived from the de novo intraductal proliferation of premalignant cells. The presence of IDC-P in biopsy or surgical specimens is significantly associated with aggressive pathologic features, such as high Gleason grade, large tumor volume, and advanced tumor stage, and with poor clinical courses, including earlier biochemical recurrence, distant metastasis, and worse survival outcomes. These architectural and behavioral features of IDC-P may be driven by specific molecular properties. Notably, IDC-P possesses distinct genomic profiles, including higher rates of gene fusions and loss, increased percentage of genomic instability, and higher prevalence of germline mutations. Considering that IDC-P tumors are usually resistant to conventional therapies for prostate cancer, further studies should be performed to develop optimal therapeutic strategies based on distinct genomic features, such as treatment with immune checkpoint blockades or poly (adenosine diphosphate-ribose) polymerase inhibitors for patients harboring increased genomic instability or mutations, as well as genetic counseling with genetic testing. Patient-derived xenografts and tumor organoid models can be the promising in vitro platforms for investigating the molecular features of IDC-P tumor.
10.3390/ijms222313125
A review on the role of tissue-based molecular biomarkers for active surveillance.
Banerjee ,Punnen Sanoj
World journal of urology
PURPOSE:Over the last decade, we have seen the emergence of tissue-based genomic prognostic markers that can be used for decision-making regarding the need for treatment. This review provides an up-to-date summary of the relevant literature surrounding these markers with a discussion of the relevant strength and limitations. METHODS:We performed a literature search of tissue-based genomic prognostic markers and selected those that were currently available for clinical use. We selected the following markers for further review: Decipher (Decipher Bioscience), Polaris (Myriad), Genome Prostate Score (Oncotype Dx), and Promark. We selected the initial validation study for each marker along with other validation studies in independent cohorts. Furthermore, we selected available clinical utility studies or studies combining multi parametric MRI. RESULTS:In this article, we provide an in-depth review of four commercially available biomarkers and discuss the current literature surrounding these markers, including the benefits and limitations of their use. We found that each of these markers has evidence supporting their role as an independent predictor of relevant prostate cancer endpoints, which can be helpful for clinical decision-making. However, issues related to heterogeneity and a lack of prospective randomized studies supporting their utility are limitations. Evidence appears to suggest that MRI and genomic risk assessment maybe complementary. CONCLUSION:Although these markers can help in improved risk stratification of patients eligible for AS, more prospective studies with head to head comparison between markers are needed to elucidate the true potential of these markers in AS.
10.1007/s00345-021-03610-y
Molecular mechanisms and genetic alterations in prostate cancer: From diagnosis to targeted therapy.
Fontana Fabrizio,Anselmi Martina,Limonta Patrizia
Cancer letters
Prostate cancer remains one of the most lethal malignancies among men worldwide. Although the primary tumor can be successfully managed by surgery and radiotherapy, advanced metastatic carcinoma requires better therapeutic approaches. In this context, a deeper understanding of the molecular mechanisms that underlie the initiation and progression of this disease is urgently needed, leading to the identification of new diagnostic/prognostic markers and the development of more effective treatments. Herein, the current state of knowledge of prostate cancer genetic alterations is discussed, with a focus on their potential in tumor detection and staging as well as in the screening of novel therapeutics.
10.1016/j.canlet.2022.215619
On the Road to Accurate Protein Biomarkers in Prostate Cancer Diagnosis and Prognosis: Current Status and Future Advances.
International journal of molecular sciences
Prostate cancer (PC) is a leading cause of morbidity and mortality among men worldwide. Molecular biomarkers work in conjunction with existing clinicopathologic tools to help physicians decide who to biopsy, re-biopsy, treat, or re-treat. The past decade has witnessed the commercialization of multiple PC protein biomarkers with improved performance, remarkable progress in proteomic technologies for global discovery and targeted validation of novel protein biomarkers from clinical specimens, and the emergence of novel, promising PC protein biomarkers. In this review, we summarize these advances and discuss the challenges and potential solutions for identifying and validating clinically useful protein biomarkers in PC diagnosis and prognosis. The identification of multi-protein biomarkers with high sensitivity and specificity, as well as their integration with clinicopathologic parameters, imaging, and other molecular biomarkers, bodes well for optimal personalized management of PC patients.
10.3390/ijms222413537
Flavonoids as Epigenetic Modulators for Prostate Cancer Prevention.
Nutrients
Prostate cancer (PCa) is a multifactorial disease with an unclear etiology. Due to its high prevalence, long latency, and slow progression, PCa is an ideal target for chemoprevention strategies. Many research studies have highlighted the positive effects of natural flavonoids on chronic diseases, including PCa. Different classes of dietary flavonoids exhibit anti-oxidative, anti-inflammatory, anti-mutagenic, anti-aging, cardioprotective, anti-viral/bacterial and anti-carcinogenic properties. We overviewed the most recent evidence of the antitumoral effects exerted by dietary flavonoids, with a special focus on their epigenetic action in PCa. Epigenetic alterations have been identified as key initiating events in several kinds of cancer. Many dietary flavonoids have been found to reverse DNA aberrations that promote neoplastic transformation, particularly for PCa. The epigenetic targets of the actions of flavonoids include oncogenes and tumor suppressor genes, indirectly controlled through the regulation of epigenetic enzymes such as DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC). In addition, flavonoids were found capable of restoring miRNA and lncRNA expression that is altered during diseases. The optimization of the use of flavonoids as natural epigenetic modulators for chemoprevention and as a possible treatment of PCa and other kinds of cancers could represent a promising and valid strategy to inhibit carcinogenesis and fight cancer.
10.3390/nu12041010
The Clinical Application and Potential Roles of Circulating Tumor Cells in Bladder Cancer and Prostate Cancer.
Yan Hang,Dittmar Florian,Schagdarsurengin Undraga,Wagenlehner Florian
Urology
Circulating tumor cells (CTCs) are considered to be promising biomarkers in malignant diseases. Recently, molecular profiles of CTCs in prostate cancer (PCa) and the role of CTCs in neoadjuvant chemotherapy and transurethral resections of bladder cancer (BCa) are intensely studied. However, localized PCa and nonmuscle-invasive BCa are less investigated and discussed. Moreover, the benefit and feasibility of clinical applications of CTCs should be critically questioned and reevaluated. This review focuses mainly on clinical issues and lesser on methodologies, and summarizes the quintessence of available works dealing with clinical applications of CTCs in PCa and BCa management.
10.1016/j.urology.2020.06.039
The emerging role of PARP inhibitors in prostate cancer.
Stellato Marco,Guadalupi Valentina,Sepe Pierangela,Mennitto Alessia,Claps Mélanie,Zattarin Emma,Verzoni Elena,Valdagni Riccardo,De Braud Filippo Gm,Santini Daniele,Tonini Giuseppe,Procopio Giuseppe
Expert review of anticancer therapy
INTRODUCTION:In prostate cancer , there has recently been an emerging interest in mutations in genes belonging to the homologous recombination repair (HRR) pathway and in the inhibition of poly (ADP-ribose) polymerase (PARP) proteins. AREAS COVERED:Mutations in the HRR genes, including BRCA1, BRCA2, and Ataxia-Telangiesctasia mutated (ATM), have been reported in prostate cancer, with different incidence in the localized and advanced settings. The PARP enzyme complex is involved in repair of DNA damage and its inhibition causes the accumulation of DNA mutations in HRR deficient cells. Several PARP inhibitors (PARPi) are under development, such as olaparib, talazoparib, niraparib, rucaparib, and veliparib. In metastatic castration resistant prostate cancer (mCRPC), olaparib has been the most studied and its clinical efficacy has been validated in a phase III clinical trial. Rucaparib and niraparib have also shown promising results in the preliminary analyzes of two phase II trials, while talazoparib is currently under development. EXPERT OPINION:PARPi have become part of the treatment of mCRPC. Early results of combination therapy with PARPi and new hormonal therapy are promising and are supported by a strong biological rationale. Current results need to be validated in randomized phase III-controlled trials in order to translate the use of PARPi into real world practice.
10.1080/14737140.2020.1797497
Long non-coding RNAs in prostate cancer: Functional roles and clinical implications.
Xu Yun-Hua,Deng Jun-Li,Wang Guo,Zhu Yuan-Shan
Cancer letters
Long noncoding RNAs (lncRNAs) are defined as RNA transcripts longer than 200 nucleotides that do not encode proteins. LncRNAs have been documented to exhibit aberrant expression in various types of cancer, including prostate cancer. Currently, screening for prostate cancer results in overdiagnosis. The consequent overtreatment of patients with indolent disease in the clinic is due to the lack of appropriately sensitive and specific biomarkers. Thus, the identification of lncRNAs as novel biomarkers and therapeutic targets for prostate cancer is promising. In the present review, we attempt to summarize the current knowledge of lncRNA expression patterns and mechanisms in prostate cancer. In particular, we focus on lncRNAs regulated by the androgen receptor and the specific molecular mechanism of lncRNAs in prostate cancer to provide a potential clinical therapeutic strategy for prostate cancer.
10.1016/j.canlet.2019.08.010
Lectins applied to diagnosis and treatment of prostate cancer and benign hyperplasia: A review.
Cavada Benildo Sousa,Oliveira Messias Vital,Osterne Vinicius Jose Silva,Pinto-Junior Vanir Reis,Correia-Neto Cornevile,Nascimento Kyria Santiago
International journal of biological macromolecules
Environmental factors, as well as genetic factors, contribute to the increase in prostate cancer cases (PCa), the second leading cause of cancer death in men. This fact calls for the development of more reliable, quick and low-cost early detection tests to distinguish between malignant and benign cases. Abnormal cell glycosylation pattern is a promising PCa marker for this purpose. Proteins, such as lectins can decode the information contained in the glycosylation patterns. Several studies have reported on applications of plant lectins as diagnostic tools for PCa considering the ability to differentiate it from benign cases. In addition, they can be used to detect, separate and differentiate the glycosylation patterns of cells or proteins present in serum, urine and semen. Herein, we present an overview of these studies, showing the lectins that map glycans differentially expressed in PCa, as well as benign hyperplasia (BPH). We further review their applications in biosensors, histochemical tests, immunoassays, chromatography, arrays and, finally, their therapeutic potential. This is the first study to review vegetable lectins applied specifically to PCa.
10.1016/j.ijbiomac.2021.09.011
Targeting Mitochondrial Metabolism in Prostate Cancer with Triterpenoids.
International journal of molecular sciences
Metabolic reprogramming is a hallmark of malignancy. It implements profound metabolic changes to sustain cancer cell survival and proliferation. Although the Warburg effect is a common feature of metabolic reprogramming, recent studies have revealed that tumor cells also depend on mitochondrial metabolism. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is an attractive therapeutic strategy. However, the metabolic flexibility of cancer cells may enable the upregulation of compensatory pathways, such as glycolysis, to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of targeting both mitochondrial metabolism and glycolysis may help overcome such resistance mechanisms. Normal prostate epithelial cells have a distinct metabolism as they use glucose to sustain physiological citrate secretion. During the transformation process, prostate cancer cells consume citrate to mainly power oxidative phosphorylation and fuel lipogenesis. A growing number of studies have assessed the impact of triterpenoids on prostate cancer metabolism, underlining their ability to hit different metabolic targets. In this review, we critically assess the metabolic transformations occurring in prostate cancer cells. We will then address the opportunities and challenges in using triterpenoids as modulators of prostate cancer cell metabolism.
10.3390/ijms22052466
Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer.
Biomolecules
Aberrant activation of the Wnt pathway is emerging as a frequent event during prostate cancer that can facilitate tumor formation, progression, and therapeutic resistance. Recent discoveries indicate that targeting the Wnt pathway to treat prostate cancer may be efficacious. However, the functional consequence of activating the Wnt pathway during the different stages of prostate cancer progression remains unclear. Preclinical work investigating the efficacy of targeting Wnt signaling for the treatment of prostate cancer, both in primary and metastatic lesions, and improving our molecular understanding of treatment responses is crucial to identifying effective treatment strategies and biomarkers that help guide treatment decisions and improve patient care. In this review, we outline the type of genetic alterations that lead to activated Wnt signaling in prostate cancer, highlight the range of laboratory models used to study the role of Wnt genetic drivers in prostate cancer, and discuss new mechanistic insights into how the Wnt cascade facilitates prostate cancer growth, metastasis, and drug resistance.
10.3390/biom12020309
Post-Translational Modifications That Drive Prostate Cancer Progression.
Biomolecules
While a protein primary structure is determined by genetic code, its specific functional form is mostly achieved in a dynamic interplay that includes actions of many enzymes involved in post-translational modifications. This versatile repertoire is widely used by cells to direct their response to external stimuli, regulate transcription and protein localization and to keep proteostasis. Herein, post-translational modifications with evident potency to drive prostate cancer are explored. A comprehensive list of proteome-wide and single protein post-translational modifications and their involvement in phenotypic outcomes is presented. Specifically, the data on phosphorylation, glycosylation, ubiquitination, SUMOylation, acetylation, and lipidation in prostate cancer and the enzymes involved are collected. This type of knowledge is especially valuable in cases when cancer cells do not differ in the expression or mutational status of a protein, but its differential activity is regulated on the level of post-translational modifications. Since their driving roles in prostate cancer, post-translational modifications are widely studied in attempts to advance prostate cancer treatment. Current strategies that exploit the potential of post-translational modifications in prostate cancer therapy are presented.
10.3390/biom11020247
The Tumor Microenvironments of Lethal Prostate Cancer.
Harryman William L,Warfel Noel A,Nagle Raymond B,Cress Anne E
Advances in experimental medicine and biology
Localized prostate cancer (confined to the gland) generally is considered curable, with nearly a 100% 5-year-survival rate. When the tumor escapes the prostate capsule, leading to metastasis, there is a poorer prognosis and higher mortality rate, with 5-year survival dropping to less than 30%. A major research question has been to understand the transition from indolent (low risk) disease to aggressive (high risk) disease. In this chapter, we provide details of the changing tumor microenvironments during prostate cancer invasion and their role in the progression and metastasis of lethal prostate cancer. Four microenvironments covered here include the muscle stroma, perineural invasion, hypoxia, and the role of microvesicles in altering the extracellular matrix environment. The adaptability of prostate cancer to these varied microenvironments and the cues for phenotypic changes are currently understudied areas. Model systems for understanding smooth muscle invasion both in vitro and in vivo are highlighted. Invasive human needle biopsy tissue and mouse xenograft tumors both contain smooth muscle invasion. In combination, the models can be used in an iterative process to validate molecular events for smooth muscle invasion in human tissue. Understanding the complex and interacting microenvironments in the prostate holds the key to early detection of high-risk disease and preventing tumor invasion through escape from the prostate capsule.
10.1007/978-3-030-32656-2_8
Role of Metabolic Syndrome in Prostate Cancer Development.
European urology focus
Prostate cancer and metabolic syndrome are common among men in the Western world. As the population grows older and life expectancy increases, the rates of both diseases are expected to increase. We now recognize that metabolic syndrome and prostate cancer interact. Metabolic syndrome may be a risk factor for prostate cancer and may also worsen outcomes. At the same time, treatment for prostate cancer may exacerbate metabolic syndrome and cardiac disease. This mini-review summarizes current evidence and puts it into clinical prospective. PATIENT SUMMARY: Metabolic syndrome is now a global epidemic. It is characterized by obesity, insulin resistance, high blood pressure, and high blood lipids. There is a complex interaction between metabolic syndrome and the risk of prostate cancer, as treatment of one disease may affect the other.
10.1016/j.euf.2021.04.022
Role of Adiponectin in prostate cancer.
Hu Xiaobo,Hu Cong,Zhang Caiping,Zhang Min,Long Shiyin,Cao Zhaohui
International braz j urol : official journal of the Brazilian Society of Urology
Obesity is defined as a chronic and excessive growth of adipose tissue. It has been associated with a high risk for development and progression of obesity-associated malignancies, while adipokines may mediate this association. Adiponectin is an adipose tissue-derived adipokines, with significant anti-diabetic, anti-inflammatory, anti-atherosclerotic and anti-proliferative properties. Plasma adiponectin levels are decreased in obese individuals, and this feature is closely correlated with development of several metabolic, immunological and neoplastic diseases. Recent studies have shown that prostate cancer patients have lower serum adiponectin levels and decreased expression of adiponectin receptors in tumor tissues, which suggests plasma adiponectin level is a risk factor for prostate cancer. Furthermore, exogenous adiponectin has exhibited therapeutic potential in animal models. In this review, we focus on the potential role of adiponectin and the underlying mechanism of adiponectin in the development and progression of prostate cancer. Exploring the signaling pathways linking adiponectin with tumorigenesis might provide a potential target for therapy.
10.1590/S1677-5538.IBJU.2018.0261
[Tissue biomarkers in prostate cancer.]
Álvarez Múgica Miguel,Jalón Monzón Antonio
Archivos espanoles de urologia
INTRODUCTION:Prostate cancer is themost prevalent and deadliest neoplasm in men, with adiverse clinical presentantion and oncological outcomes.The diagnosis and treatment remains a challenge.New essays about biomarkers show their potential asa tool that may influence in clinical decision making,risk stratification and management of the disease. METHODS:we performed a literature review abouttissue biomarkers in the diagnosis and treatment ofprostate cancer. RESULTS:Within the last years, a wide number ofdiagnostic and prognostic tests in tissue have been developed(ConfirmMDx, Promark, Oncoytype DX, Decipher),creating an opportunity to improve the diagnosis,prognosis and treatment of prostate cancer. CONCLUSIONS:Since prostate cancer is the mostprevalent neoplasm in men, it is mandatory to stratifypatients correctly to prevent unnecessary biopsiesand overtreatment in low risk patients, as well as designthe best strategy in those with high risk disease.Tissue biomarkers may become a useful tool in precisionmedicine to guide decision making.
Estrogens and prostate cancer.
Dobbs Ryan W,Malhotra Neha R,Greenwald David T,Wang Alice Y,Prins Gail S,Abern Michael R
Prostate cancer and prostatic diseases
BACKGROUND:Hormonal influences such as androgens and estrogens are known contributors in the development and progression of prostate cancer (CaP). While much of the research to the hormonal nature of CaP has focused on androgens, estrogens also have critical roles in CaP development, physiology as well as a potential therapeutic intervention. METHODS:In this review, we provide a critical literature review of the current basic science and clinical evidence for the interaction between estrogens and CaP. RESULTS:Estrogenic influences in CaP include synthetic, endogenous, fungi and plant-derived compounds, and represent a family of sex hormones, which cross hydrophobic cell membranes and bind to membrane-associated receptors and estrogen receptors that localize to the nucleus triggering changes in gene expression in various organ systems. CONCLUSIONS:Estrogens represent a under-recognized contributor in CaP development and progression. Further research in this topic may provide opportunities for identification of environmental influencers as well as providing novel therapeutic targets in the treatment of CaP.
10.1038/s41391-018-0081-6
Molecular predictors of metastasis in patients with prostate cancer.
Expert review of molecular diagnostics
INTRODUCTION:Prostate cancer is a serious threat to the health of older adults worldwide. The quality of life and survival time of patients sharply decline once metastasis occurs. Thus, early screening for prostate cancer is very advanced in developed countries. The detection methods used include Prostate-specific antigen (PSA) detection and digital rectal examination. However, the lack of universal access to early screening in some developing countries has resulted in an increased number of patients presenting with metastatic prostate cancer. In addition, the treatment methods for metastatic and localized prostate cancer are considerably different. In many patients, early-stage prostate cancer cells often metastasize due to delayed observation, negative PSA results, and delay in treatment time. Therefore, the identification of patients who are prone to metastasis is important for future clinical studies. AREAS COVERED:this review introduced a large number of predictive molecules related to prostate cancer metastasis. These molecules involve the mutation and regulation of tumor cell genes, changes in the tumor microenvironment, and the liquid biopsy. EXPERT OPINION:In next decade, PSMA PET/CT and liquid biopsy will be the excellent predicting tools, while Lu- PSMA-RLT will be showed excellent anti-tumor efficacy in mPCa patients.
10.1080/14737159.2023.2187289
Reprint of: de novo neuroendocrine features in prostate cancer.
Human pathology
Neuroendocrine tumors of the prostate are rare and encompass a group of entities that are classified based on a combination of morphological and immunohistochemical features. Despite the 2016 World Health Organization classification of prostatic neuroendocrine tumors, variants have been reported that do not fit well in the categorization scheme. While the majority of these tumors arise in the setting of castration-resistant prostate cancer (postandrogen deprivation therapy), de novo cases may occur. In this review, we highlight the most significant pathological and immunohistochemical features, emerging biomarkers, and molecular features of such tumors.
10.1016/j.humpath.2023.02.009
Cancer-Associated Fibroblast: Role in Prostate Cancer Progression to Metastatic Disease and Therapeutic Resistance.
Cells
Prostate cancer (PCa) is one of the most common cancers in European males. Although therapeutic approaches have changed in recent years, and several new drugs have been approved by the Food and Drug Administration (FDA), androgen deprivation therapy (ADT) remains the standard of care. Currently, PCa represents a clinical and economic burden due to the development of resistance to ADT, paving the way to cancer progression, metastasis, and to long-term side effects induced by ADT and radio-chemotherapeutic regimens. In light of this, a growing number of studies are focusing on the tumor microenvironment (TME) because of its role in supporting tumor growth. Cancer-associated fibroblasts (CAFs) have a central function in the TME because they communicate with prostate cancer cells, altering their metabolism and sensitivity to drugs; hence, targeted therapy against the TME, and, in particular, CAFs, could represent an alternative therapeutic approach to defeat therapy resistance in PCa. In this review, we focus on different CAF origins, subsets, and functions to highlight their potential in future therapeutic strategies for prostate cancer.
10.3390/cells12050802
Mitochondrial Alterations in Prostate Cancer: Roles in Pathobiology and Racial Disparities.
International journal of molecular sciences
Prostate cancer (PCa) affects millions of men worldwide and is a major cause of cancer-related mortality. Race-associated PCa health disparities are also common and are of both social and clinical concern. Most PCa is diagnosed early due to PSA-based screening, but it fails to discern between indolent and aggressive PCa. Androgen or androgen receptor-targeted therapies are standard care of treatment for locally advanced and metastatic disease, but therapy resistance is common. Mitochondria, the powerhouse of cells, are unique subcellular organelles that have their own genome. A large majority of mitochondrial proteins are, however, nuclear-encoded and imported after cytoplasmic translation. Mitochondrial alterations are common in cancer, including PCa, leading to their altered functions. Aberrant mitochondrial function affects nuclear gene expression in retrograde signaling and promotes tumor-supportive stromal remodeling. In this article, we discuss mitochondrial alterations that have been reported in PCa and review the literature related to their roles in PCa pathobiology, therapy resistance, and racial disparities. We also discuss the translational potential of mitochondrial alterations as prognostic biomarkers and as effective targets for PCa therapy.
10.3390/ijms24054482
STAT3 signaling in prostate cancer progression and therapy resistance: An oncogenic pathway with diverse functions.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
The categorization of cancers demonstrates that prostate cancer is the most common malignancy in men and it causes high death annually. Prostate cancer patients are diagnosed mainly via biomarkers such as PSA test and patients show poor prognosis. Prostate cancer cells rapidly diffuse into different parts of body and their metastasis is also a reason for death. Current therapies for prostate cancer patients include chemotherapy, surgery and radiotherapy as well as targeted therapy. The progression of prostate cancer cells is regulated by different factors that STAT3 signaling is among them. Growth factors and cytokines such as IL-6 can induce STAT3 signaling and it shows carcinogenic impact. Activation of STAT3 signaling occurs in prostate cancer and it promotes malignant behavior of tumor cells. Induction of STAT3 signaling increases glycolysis and proliferation of prostate cancer cells and prevents apoptosis. Furthermore, STAT3 signaling induces EMT mechanism in increasing cancer metastasis. Activation of STAT3 signaling stimulates drug resistance and the limitation of current works is lack of experiment related to role of STAT3 signaling in radio-resistance in prostate tumor. Calcitriol, capsazepine and β-elemonic are among the compounds capable of targeting STAT3 signaling and its inhibition in prostate cancer therapy. In addition to natural products, small molecules targeting STAT3 signaling have been developed in prostate cancer therapy.
10.1016/j.biopha.2022.114168
Molecular regulation of prostate cancer by Galectin-3 and estrogen receptor.
Frontiers in endocrinology
Prostate cancer remains the most prevalent cancer among men worldwide. This cancer is hormone-dependent; therefore, androgen, estrogen, and their receptors play an important role in development and progression of this disease, and in emergence of the castration-resistant prostate cancer (CRPC). Galectins are a family of β-galactoside-binding proteins which are frequently altered (upregulated or downregulated) in a wide range of tumors, participating in different stages of tumor development and progression, but the molecular mechanisms which regulate its expression are still poorly understood. This review provides an overview of the current and emerging knowledge on Galectin-3 in cancer biology with focus on prostate cancer and the interplay with estrogen receptor (ER) signaling pathways, present in androgen-independent prostate cancer cells. We suggest a molecular mechanism where ER, Galectin-3 and β-catenin can modulate nuclear transcriptional events, such as, proliferation, migration, invasion, and anchorage-independent growth of androgen-independent prostate cancer cells. Despite a number of achievements in targeted therapy for prostate cancer, CRPC may eventually develop, therefore new effective drug targets need urgently to be found. Further understanding of the role of Galectin-3 and ER in prostate cancer will enhance our understanding of the molecular mechanisms of prostate cancer development and the future treatment of this disease.
10.3389/fendo.2023.1124111
GENOMICS OF PROSTATE CANCER: CLINICAL UTILITY AND CHALLENGES.
Acta clinica Croatica
The studying of prostate cancer genomics is important for understanding prostate cancer biology, it can provide clinically relevant stratification into subtypes, the development of new prognostic and predictive markers in the context of precision medicine, and the development of new targeted therapies. Recent studies have provided detailed insight into genomics, epigenomics and proteomics of prostate cancer, both primary and metastatic castration-resistant (mCRPC). Many mutations have been discovered, both those that occur early in the carcinogenesis and progression as well as those responsible for the resistance to therapy occurring later under the influence of treatment. A large number of characteristic mutated signaling pathways has been identified, e.g. the mutations in DNA repair pathway were found in 23% of mCRPC, which suggests potential response to PARP inhibitors. Multifocality and intralesional genomic heterogeneity of prostate cancer make the clinical application of genomics complicated. Although a great progress was made in understanding prostate cancer genomic, and clinical studies related to its routine application are ongoing, prostate cancer genomics still needs to find its standard wide routine application in patients with prostate cancer.
10.20471/acc.2022.61.s3.13
Targeting Glutamine Metabolism in Prostate Cancer.
Frontiers in bioscience (Elite edition)
Glutamine is a conditionally essential amino acid important for cancer cell proliferation through intermediary metabolism leading to synthesis of purine and pyrimidine nucleotides, hexosamine biosytnehsis, fatty acid synthesis through reductive carboxylation, maintenance of redox homeostasis, glutathione synthesis, production of non-essential amino acids, and mitochondrial oxidative phosphorylation. Prostate cancer has increasingly been characterized as a tumor type that is heavily dependent on glutamine for growth and survival. In this review, we highlight the preclinical evidence that supports a relationship between glutamine signaling and prostate cancer progression. We focus on the regulation of glutamine metabolism in prostate cancer through key pathways involving the androgen receptor pathway, , and the PTEN/PI3K/mTOR pathway. We end with a discussion on considerations for translation of targeting glutamine metabolism as a therapeutic strategy to manage prostate cancer. Here, it is important to understand that the tumor microenvironment also plays a role in facilitating glutamine signaling and resultant prostate cancer growth. The druggability of prostate cancer glutamine metabolism is more readily achievable with our greater understanding of tumor metabolism and the advent of selective glutaminase inhibitors that have proven safe and tolerable in early-phase clinical trials.
10.31083/j.fbe1501002
Identification of a prognostic biomarker predicting biochemical recurrence and construction of a novel nomogram for prostate cancer.
Frontiers in oncology
Background:Biochemical recurrence (BCR) is common in prostate cancer (PCa), but its prediction is based predominantly on clinicopathological characteristics with low accuracy. We intend to identify a potential prognostic biomarker related to the BCR and construct a nomogram for improving the risk stratification of PCa patients. Methods:The transcriptome and clinical data of PCa patients were obtained from TCGA and GEO databases. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to screen out differentially expressed genes (DEGs) related to the BCR of PCa. Cox regression analysis was further applied to screen out DEGs related to BCR-free survival (BFS). Time-dependent receiver operating curve (ROC) analysis and Kaplan-Meier (K-M) survival analysis were conducted to assess the prognostic value. Then, a prognostic nomogram was established and evaluated. The clinicopathological correlation analysis, GSEA analysis, and immune analysis were used to explore the biological and clinical significance of the biomarker. Finally, the qRT-PCR, western blotting, and immunohistochemistry (IHC) were conducted to validate the expression of the biomarker. Results:BIRC5 was identified to be the potential prognostic biomarker. The clinical correlation analysis and K-M survival analysis found that the BIRC5 mRNA expression was positively associated with disease progression and negatively associated with the BFS rate. Time-dependent ROC curves verified its accurate prediction performance. The GSEA and immune analysis suggested that the BIRC5 was related to immunity. A nomogram with an accurate prediction for BFS of PCa patients was constructed. qRT-PCR, western blotting, and IHC results validated the expression level of BIRC5 in PCa cells and tissues. Conclusion:Our study identified BIRC5 as a potential prognostic biomarker related to BCR of PCa and constructed an efficacy nomogram for predicting BFS to assist clinical decision-making.
10.3389/fonc.2023.1115718
Bone Biomarkers and Subsequent Survival in Men with Hormone-sensitive Prostate Cancer: Results from the SWOG S1216 Phase 3 Trial of Androgen Deprivation Therapy with or Without Orteronel.
European urology
BACKGROUND:Bone biomarkers are strongly prognostic for overall survival (OS) in men with castration-resistant prostate cancer but not fully established for hormone-sensitive prostate cancer (HSPC). OBJECTIVE:Bone biomarkers in HSPC were prospectively evaluated as part of a phase 3 study of androgen deprivation therapy ± the CYP17 inhibitor orteronel. DESIGN, SETTING, AND PARTICIPANTS:Patients were randomly divided into training (n = 316) and validation (n = 633) sets. Recursive partitioning and Cox proportional hazard models were employed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Bone resorption (C-telopeptide and pyridinoline) and bone formation markers (C-terminal collagen propeptide and bone alkaline phosphatase) were assessed from patient sera. RESULTS AND LIMITATIONS:Of 1279 men, 949 had evaluable baseline bone biomarkers. Optimal cutoffs were identified to define elevated levels of each of the four biomarkers (all p < 0.05) that were associated with worse OS. After adjusting for clinical risk factors in the validation set, elevated bone biomarkers were statistically significantly associated with an increased risk of death (hazard ratios ranging from 1.37 to 1.92). Recursive partitioning algorithms applied to the training set identified three risk groups (low, intermediate, and poor) with differential OS outcomes (median OS: 8.2, 5.1, and 2.1 yr, respectively) based on combinations of bone biomarkers. These results were confirmed in the validation set. CONCLUSIONS:In men with HSPC initiating androgen deprivation therapy, bone biomarkers are strongly and independently prognostic for OS. Bone biomarker levels alone or in combination with clinical covariates identify unique subsets of men with differential OS outcomes. These results validate the clinical value of bone biomarker assessment in the HSPC state, extending bone biomarker utility beyond the castration-resistant state. PATIENT SUMMARY:In men with newly diagnosed metastatic prostate cancer, high levels of bone turnover biomarkers are associated with a shorter lifespan.
10.1016/j.eururo.2023.03.036
Predictive value of prostate calcification for future cancer occurrence: a retrospective long-term follow-up cohort study.
The British journal of radiology
OBJECTIVE:Although prostate calcification is often identified on pelvic CT images, calcification itself is usually not considered clinically significant. A recent histological study proposed an association between prostate calcification and prostate cancer occurrence. Our aim was to determine the predictive value of prostate calcifications for future prostate cancer occurrence. METHODS:We retrospectively analysed male patients (≥50 years old) without prior prostate cancer history, who underwent unenhanced pelvic CT between April 2010 and March 2011, and followed-up until December 2021. Cox proportional hazards models were used to assess prostate cancer risk with prostate calcification (defined as a high-density area larger than 3 mm with CT attenuation values ≥ 130 HU), controlling for age, body mass index (BMI), hypertension and diabetes mellitus. RESULTS:A total of 636 male patients (mean age, 68 years ± 9 [standard deviation]) were evaluated. At the end of follow-up, prostate cancer had been more frequently diagnosed in patients with prostate calcification than those without prostate calcification (6.5% 2.6%). Multivariate analysis revealed that prostate calcification on CT was a significant predictor of future prostate cancer occurrence (hazard ratio [HR], 2.7; 95% CI: 1.20, 5.91; = 0.016). No statistical differences were observed in any other factors. CONCLUSION:Prostate calcification may be a significant predictor of future prostate cancer occurrence, and may be used for risk stratification and to guide screening protocols. ADVANCES IN KNOWLEDGE:Presence of prostate calcification on unenhanced CT scan was associated with increased incidence of prostate cancer occurrence on long term follow-up.
10.1259/bjr.20221110
Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle that can be targeted for therapeutic purposes in prostate cancer.
Molecular oncology
The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1), but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Mouse models, in vitro human PCa cell lines, and human patient-derived organoids (PDOs) were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analyses and gas chromatography-mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and PDOs. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry-based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. These results demonstrate that PCa cells have a hybrid cytoplasmic-mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target.
10.1002/1878-0261.13441
Associations of CTCF and FOXA1 with androgen and IGF pathways in men with localized prostate cancer.
Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society
AIMS:To examine associations between the transcription factors CCCTC-binding factor (CTCF) and forkhead box protein A1 (FOXA1) and the androgen receptor (AR) and their association with components of the insulin-like growth factor (IGF)-pathway in a cohort of men with localized prostate cancer. METHODS:Using prostate tissue samples collected during the Prostate cancer: Evidence of Exercise and Nutrition Trial (PrEvENT) trial (N = 70 to 92, depending on section availability), we assessed the abundance of CTCF, FOXA1, AR, IGFIR, p-mTOR, PTEN and IGFBP-2 proteins using a modified version of the Allred scoring system. Validation studies were performed using large, publicly available datasets (TCGA) (N = 489). RESULTS:We identified a strong correlation between CTCF and AR staining with benign prostate tissue. CTCF also strongly associated with the IGFIR, with PTEN and with phospho-mTOR. FOXA1 was also correlated with staining for the IGF-IR, with IGFBP-2 and with staining for activated phosphor-mTOR. The staining for the IGF-IR was strongly correlated with the AR. CONCLUSION:Our findings emphasise the close and complex links between the endocrine controls, well known to play an important role in prostate cancer, and the transcription factors implicated by the recent genetic evidence.
10.1016/j.ghir.2023.101533
Emerging Roles of Long Non-coding RNAs as Novel Biomarkers in the Diagnosis and Prognosis of Prostate Cancer.
Kan Yi,Li Bingheng,Yang Dongliang,Liu Yirui,Liu Jihai,Yang Chunhua,Mao Lijun
Discovery medicine
New biomarkers for early diagnosis and prognosis are important in improving the diagnosis of metastatic or recurrent prostate cancer. Recent studies have shown important roles of long non-coding RNAs (lncRNAs) in tumorigenesis. Here we provide a comprehensive review of lncRNAs implicated in prostate cancer and discuss their potential as novel biomarkers and therapeutic targets for prostate cancer. In particular, we focus on lncRNAs associated with the androgen/androgen receptor pathway and the epithelial-to-mesenchymal transition. Notably, several lncRNAs such as PCA3, PCAT18, HOTAIR, and CCAT2 are prostate cancer-specific in that they are only upregulated in prostate cancer, and consequently they are promising biomarkers for use in clinical practice.
Comparative Analysis of Genomic Alterations across Castration Sensitive and Castration Resistant Prostate Cancer via Circulating Tumor DNA Sequencing.
Fan Liancheng,Fei Xiaochen,Zhu Yinjie,Pan Jiahua,Sha Jianjun,Chi Chenfei,Gong Yiming,Du Xinxing,Zhou Lixin,Dong Baijun,Xue Wei
The Journal of urology
PURPOSE:To explore the genomic profiles of Chinese patients with castration sensitive prostate cancer and those with metastatic castration resistant prostate cancer via germline and circulating tumor DNA sequencing. MATERIALS AND METHODS:A hybridization capture based next-generation sequencing assay was used to identify germline and somatic alterations in 50 genes including androgen receptor pathway genes, DNA damage repair pathway genes, and . RESULTS:We successfully sequenced DNA from 396 blood samples and 32 matched tumor tissue samples from 396 patients. We observed a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer (8.9% vs 9.8%, p >0.05). There was a high consistency (90.9%) between metastatic tumor tissue and matched circulating tumor DNA. Among patients who were circulating tumor DNA positive we observed significantly higher alteration frequencies of (27.2% vs 6.4%, p <0.001) and (36.8% vs 15.3%, p <0.001) in our metastatic castration resistant prostate cancer cohort compared with the SU2C-PCF (Stand Up to Cancer-Prostate Cancer Foundation) cohort. Alteration frequencies of DNA damage repair pathway genes (66.7% vs 41.5%, p=0.015) and androgen receptor pathway genes (71.9% vs 48.8%, p=0.018) in patients with metastatic castration resistant prostate cancer were higher than in patients with de novo metastatic castration sensitive prostate cancer. Androgen receptor alteration was selectively enriched in metastatic castration resistant prostate cancer. CONCLUSIONS:Through genomic profiling of prostate cancer across clinical states we identified a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer. We explored the genomic diversity of androgen receptor and DNA damage repair pathway genes between patients with metastatic castration sensitive prostate cancer and metastatic castration resistant prostate cancer. Higher alteration frequencies of and were observed in our metastatic castration resistant prostate cancer cohort than in the SU2C-PCF cohort. Our findings support the view that circulating tumor DNA sequencing could guide clinical treatment for metastatic prostate cancer.
10.1097/JU.0000000000001363
Identification of a distinct luminal subgroup diagnosing and stratifying early stage prostate cancer by tissue-based single-cell RNA sequencing.
Molecular cancer
BACKGROUND:The highly intra-tumoral heterogeneity and complex cell origination of prostate cancer greatly limits the utility of traditional bulk RNA sequencing in finding better biomarker for disease diagnosis and stratification. Tissue specimens based single-cell RNA sequencing holds great promise for identification of novel biomarkers. However, this technique has yet been used in the study of prostate cancer heterogeneity. METHODS:Cell types and the corresponding marker genes were identified by single-cell RNA sequencing. Malignant states of different clusters were evaluated by copy number variation analysis and differentially expressed genes of pseudo-bulks sequencing. Diagnosis and stratification of prostate cancer was estimated by receiver operating characteristic curves of marker genes. Expression characteristics of marker genes were verified by immunostaining. RESULTS:Fifteen cell groups including three luminal clusters with different expression profiles were identified in prostate cancer tissues. The luminal cluster with the highest copy number variation level and marker genes enriched in prostate cancer-related metabolic processes was considered the malignant cluster. This cluster contained a distinct subgroup with high expression level of prostate cancer biomarkers and a strong distinguishing ability of normal and cancerous prostates across different pathology grading. In addition, we identified another marker gene, Hepsin (HPN), with a 0.930 area under the curve score distinguishing normal tissue from prostate cancer lesion. This finding was further validated by immunostaining of HPN in prostate cancer tissue array. CONCLUSION:Our findings provide a valuable resource for interpreting tumor heterogeneity in prostate cancer, and a novel candidate marker for prostate cancer management.
10.1186/s12943-020-01264-9
Prostate Cancer Biomarkers: From diagnosis to prognosis and precision-guided therapeutics.
Adamaki Maria,Zoumpourlis Vassilios
Pharmacology & therapeutics
Prostate cancer (PCa) is one of the most commonly diagnosed malignancies and among the leading causes of cancer-related death worldwide. It is a highly heterogeneous disease, ranging from remarkably slow progression or inertia to highly aggressive and fatal disease. As therapeutic decision-making, clinical trial design and outcome highly depend on the appropriate stratification of patients to risk groups, it is imperative to differentiate between benign versus more aggressive states. The incorporation of clinically valuable prognostic and predictive biomarkers is also potentially amenable in this process, in the timely prevention of metastatic disease and in the decision for therapy selection. This review summarizes the progress that has so far been made in the identification of the genomic events that can be used for the classification, prediction and prognostication of PCa, and as major targets for clinical intervention. We include an extensive list of emerging biomarkers for which there is enough preclinical evidence to suggest that they may constitute crucial targets for achieving significant advances in the management of the disease. Finally, we highlight the main challenges that are associated with the identification of clinically significant PCa biomarkers and recommend possible ways to overcome such limitations.
10.1016/j.pharmthera.2021.107932
Screening for Prostate Cancer.
The Medical clinics of North America
This article gives an overview of the current state of the evidence for prostate cancer early detection with prostate-specific antigen (PSA) and summarizes current recommendations from guideline groups. The article reviews the global public health burden and risk factors for prostate cancer with clinical implications as screening tools. Screening studies, novel biomarkers, and MRI are discussed. The article outlines 7 key practice points for primary care physicians and provides a simple schema for facilitating shared decision-making conversations.
10.1016/j.mcna.2020.08.007
An overview of biomarkers in the diagnosis and management of prostate cancer.
Uhr Alex,Glick Lydia,Gomella Leonard G
The Canadian journal of urology
INTRODUCTION:Prostate cancer is a common malignancy with highly variable clinical presentation and outcomes. Diagnosis and management remain a challenge and at times become highly controversial. Novel biomarker assays have shown promise as an adjunctive tool to aid in patient shared decision-making, risk stratification, and disease management. This presentation at the 2020 Jefferson Urology Symposium provided a review of current commonly used biomarkers for prostate cancer. MATERIALS AND METHODS:We reviewed the current literature on the use of biomarkers in the diagnosis and treatment decisions in localized prostate cancer. RESULTS:Biomarker assays were reviewed and presented according to clinical application of each test. In the consideration of initial prostate biopsy the blood tests for PHI, and 4K Score, and urine tests PCA3, Select MDx and ExoDx are available. In the consideration of treatment versus active surveillance in the biopsy positive setting OncotypeDx, Prolaris and Decipher are available. In patients with an initial negative biopsy, 4K score, PCA3, ExoDx and the tissue biopsy based Confirm MDx assay can help guide the decision to perform repeat biopsy. In the consideration for adjuvant radiation following radical prostatectomy the most extensive literature available supports the use of Prolaris or Decipher tissue assays. CONCLUSIONS:With the significant burden of men being diagnosed with prostate cancer, it is desirable to appropriately risk stratify patients to avoid unnecessary biopsies and over-treatment in low risk patients and guide appropriate treatment strategies in high risk patients. Selected biomarkers presented are useful adjunctive precision medicine tools to aid in shared decision making and to direct treatment decisions.
Biomarkers in prostate cancer - Current clinical utility and future perspectives.
Kretschmer Alexander,Tilki Derya
Critical reviews in oncology/hematology
Current tendencies in the treatment course of prostate cancer patients increase the need for reliable biomarkers that help in decision-making in a challenging clinical setting. Within the last decade, several novel biomarkers have been introduced. In the following comprehensive review article, we focus on diagnostic (PHI, 4K score, SelectMDx, ConfirmMDx, PCA3, MiPS, ExoDX, mpMRI) and prognostic (OncotypeDX GPS, Prolaris, ProMark, DNA-ploidy, Decipher) biomarkers that are in widespread clinical use and are supported by evidence. Hereby, we focus on multiple clinical situations in which innovative biomarkers may guide decision-making in prostate cancer therapy. In addition, we describe novel liquid biopsy approaches (circulating tumor cells, cell-free DNA) that have been described as predictive biomarkers in metastatic castration-resistant prostate cancer and might support an individual patient-centred oncological approach in the nearer future.
10.1016/j.critrevonc.2017.11.007
Microbiota and prostate cancer.
Seminars in cancer biology
Prostate cancer remains the most frequently diagnosed non-skin malignancy in male patients, still representing one of the main causes of cancer-related death worldwide. Evidence is mounting that suggests the putative role of microbiota in the carcinogenesis as well as in modulating the efficacy and activity of anticancer treatments (e.g., chemotherapy, immune checkpoint inhibitors, targeted therapies) in a large number of hematological and solid tumors. However, few data are available regarding the interactions between prostate cancer and microbiome so far, in particular in terms of the impact of microbiota on disease development, pathogenesis, and response to medical treatments in this genitourinary malignancy. Herein, we provide an overview of current knowledge, novel insights and emerging therapeutic approaches related to gastrointestinal and genitourinary microbiome in prostate cancer patients, especially focusing on available evidence and published trials on this topic.
10.1016/j.semcancer.2021.09.007
WNT signalling in prostate cancer.
Murillo-Garzón Virginia,Kypta Robert
Nature reviews. Urology
Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours - particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer.
10.1038/nrurol.2017.144