Proteomic characterization of the colorectal cancer response to chemoradiation and targeted therapies reveals potential therapeutic strategies.
Cell reports. Medicine
Chemoradiation and targeted therapies are the major treatments for colorectal cancer (CRC); however, molecular properties associated with therapy resistance are incompletely characterized. Here, we profile the proteome of 254 tumor tissues from patients with CRC undergoing chemotherapy, chemoradiation, or chemotherapy combined with targeted therapy. Proteome-based classification reveals four subtypes featured with distinct biological and therapeutic characteristics. The integrative analysis of CRC cell lines and clinical samples indicates that immune regulation is significantly associated with drug sensitivity. HSF1 can increase DNA damage repair and cell cycle, thus inducing resistance to radiation, while high expression of HDAC6 is negatively associated with response of cetuximab. Furthermore, we develop prognostic models with high accuracy to predict the therapeutic response, further validated by parallel reaction monitoring (PRM) assay in an independent validation cohort. This study provides a rich resource for investigating the mechanisms and indicators of chemoradiation and targeted therapy in CRC.
10.1016/j.xcrm.2023.101311
Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells.
Wei Ruiran,Zhao Yueqin,Wang Juan,Yang Xu,Li Shunlin,Wang Yinyuan,Yang Xingzhi,Fei Jimin,Hao Xiaojiang,Zhao Yuhan,Gui Liming,Ding Xiao
International journal of biological sciences
Colorectal cancer (CRC) is a common malignant tumor of the digestive system. However, the efficacy of surgery and chemotherapy is limited. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD) and plays a vital role in tumor suppression. Ferroptosis inducing agents have been studied extensively as a novel promising way to fight against therapy resistant cancers. The aim of this study is to investigate the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in tumor suppression. The response of CRC cells to tagitinin C was assessed by cell viability assay, clonogenic assay, transwell migration assay, cell cycle assay and apoptosis assay. Molecular approaches including Western blot, RNA sequencing, quantitative real-time PCR and immunofluorescence were employed as well. Tagitinin C, a sesquiterpene lactone isolated from , inhibits the growth of colorectal cancer cells including HCT116 cells, and induced an oxidative cellular microenvironment resulting in ferroptosis of HCT116 cells. Tagitinin C-induced ferroptosis was accompanied with the attenuation of glutathione (GSH) levels and increased in lipid peroxidation. Mechanistically, tagitinin C induced endoplasmic reticulum (ER) stress and oxidative stress, thus activating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). As a downstream gene (effector) of Nrf2, heme oxygenase-1 (HO-1) expression increased significantly with the treatment of tagitinin C. Upregulated HO-1 led to the increase in the labile iron pool, which promoted lipid peroxidation, meanwhile tagitinin C showed synergistic anti-tumor effect together with erastin. In summary, we provided the evidence that tagitinin C induces ferroptosis in colorectal cancer cells and has synergistic effect together with erastin. Mechanistically, tagitinin C induces ferroptosis through ER stress-mediated activation of PERK-Nrf2-HO-1 signaling pathway. Tagitinin C, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents.
10.7150/ijbs.59404
Intestinal microbiota and colorectal carcinoma: Implications for pathogenesis, diagnosis, and therapy.
Montalban-Arques Ana,Scharl Michael
EBioMedicine
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and leading cause of cancer-related deaths worldwide. In recent years, there has been a growing realisation that lifestyle plays a major role for CRC development and that intestinal microbiota, which are shaped by lifestyle and nutrition habits, may be critically involved in the pathogenesis of CRC. Although the precise mechanisms for how the microbiota contribute to CRC development and progression remain elusive, increasing evidence suggests a direct causative role for the intestinal microbiota in modulating signalling pathways, anti-tumour immune responses and cell proliferation. Recent advances in understanding host-microbe interactions have shed light onto the putative use of intestinal microbiota as a powerful tool in CRC diagnosis and therapy. Here, we will discuss the role of the intestinal microbiota in CRC pathogenesis, their potential utility as diagnostic markers, and consider how microbes could be used in therapeutic approaches for the treatment of CRC.
10.1016/j.ebiom.2019.09.050
The prognostic and therapeutic potential of vimentin in colorectal cancer.
Molecular biology reports
Several cells and molecules in the tumor microenvironment have been introduced as effective factors in the prognosis and progression of colorectal cancer. As a key element of the intermediate filament family, vimentin is expressed by mesenchymal cells in a ubiquitous manner and contributes significantly to cellular integrity and stress resistance in colorectal cancer. Recent studies have shown that alterations in the expression patterns of intermediate filaments are significantly related to cancer progression, especially in phenotypes associated with cellular migration and invasion. In addition to its multiple biological roles, vimentin also has a substantial function in mediating the epithelial-mesenchymal transition. Therefore, evaluating vimentin as an effective factor involved in the prognosis of colorectal cancer and targeting it as a novel approach to cancer therapy have become one of the main goals of many researchers worldwide. In this article, we will review the various biological functions of vimentin, as well as its relationship with colorectal cancer with the aim of providing novel insights into its clinical importance in the prognosis and treatment of colorectal cancer.
10.1007/s11033-024-09965-w
Pharmacogenomics and -genetics in colorectal cancer.
Pohl Alexandra,Lurje Georg,Manegold Philipp C,Lenz Heinz-Josef
Advanced drug delivery reviews
Despite recent progress in our knowledge about the development and therapy of colorectal cancer (CRC), it still remains one of the major cancer related deaths throughout the world. With the introduction of new cytotoxic and targeting agents a significant improvement in progression-free and overall survival has been achieved. However, a significant percentage (40-50%) of patients do not experience beneficial effects and suffer from severe toxicities. It will be critical to identify molecular markers, which may help to assess therapeutic response and outcome in CRC. Validation of predictive and prognostic molecular markers will enable oncologists to tailor patient specific treatment strategies for the individual patient according to the molecular profile of both the patient and their tumor. Individualized therapy will help to improve therapeutic efficacy and to minimize toxicities and therapeutic expenses.
10.1016/j.addr.2008.10.002
Genetic and epigenetic biomarkers of colorectal cancer.
Choong Miew Keen,Tsafnat Guy
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
Cancer is a heterogeneous disease caused, in part, by genetic and epigenetic alterations. These changes have been explored in studies of the pathogenesis of colorectal cancer (CRC) and have led to the identification of many biomarkers of disease progression. However, the number of biomarkers that have been incorporated into clinical practice is surprisingly small. We review the genetic and epigenetic mechanisms of colorectal cancer and discuss molecular markers recommended for use in early detection, screening, diagnosis, determination of prognosis, and prediction of treatment outcomes. We also review important areas for future research.
10.1016/j.cgh.2011.04.020
Epigenetic modifications in colorectal cancer: molecular insights and therapeutic challenges.
Vaiopoulos Aristeidis G,Athanasoula Kalliopi Ch,Papavassiliou Athanasios G
Biochimica et biophysica acta
Colorectal cancer, a leading cause of mortality worldwide, is a multistep disorder that results from the alteration of genetic and epigenetic mechanisms under contextual influence. Epigenetic aberrations, including DNA methylation, histone modifications, chromatin remodeling and non-coding RNAs, affect every aspect of tumor development from initiation to metastasis. Cancer stem cell promotion is also included in the wide spectrum of epigenetic dysregulations. Elucidation of this complex crosstalk network may offer new insights in the molecular interactions involved in the pathogenesis of colorectal carcinogenesis. In the era of translational medicine new horizons are opened for the pursuit of personalized therapeutic approaches and the development of novel and accurate diagnostic, prognostic and therapy-assessment markers. This review discusses the implications of epigenetic mechanisms in tumor biology and their applications "from bench to bedside".
10.1016/j.bbadis.2014.02.006
Evolving treatment of advanced colorectal cancer.
Cercek Andrea,Saltz Leonard
Current oncology reports
Advances in colorectal cancer treatment have led to improved outcomes for patients. A number of cytotoxic agents, alone and in combination, have shown activity. The addition of the newer, so-called "targeted" agents to standard chemotherapy drugs and regimens has also modestly improved outcomes. Progress in our knowledge and understanding of molecular pathways has led to the identification of markers critical in determining response or nonresponse to some of the targeted agents. This review discusses the available therapies in metastatic colorectal cancer and describes some of the molecular markers implicated in activity and resistance to current targeted therapies.
10.1007/s11912-010-0096-1
Molecular biology of colorectal cancer.
Gryfe R,Swallow C,Bapat B,Redston M,Gallinger S,Couture J
Current problems in cancer
Colorectal cancer is a significant cause of morbidity and mortality in Western populations. This cancer develops as a result of the pathologic transformation of normal colonic epithelium to an adenomatous polyp and ultimately an invasive cancer. The multistep progression requires years and possibly decades and is accompanied by a number of recently characterized genetic alterations. Mutations in two classes of genes, tumor-suppressor genes and proto-oncogenes, are thought to impart a proliferative advantage to cells and contribute to development of the malignant phenotype. Inactivating mutations of both copies (alleles) of the adenomatous polyposis coli (APC) gene--a tumor-suppressor gene on chromosome 5q--mark one of the earliest events in colorectal carcinogenesis. Germline mutation of the APC gene and subsequent somatic mutation of the second APC allele cause the inherited familial adenomatous polyposis syndrome. This syndrome is characterized by the presence of hundreds to thousands of colonic adenomatous polyps. If these polyps are left untreated, colorectal cancer develops. Mutation leading to dysregulation of the K-ras protooncogene is also thought to be an early event in colon cancer formation. Conversely, loss of heterozygosity on the long arm of chromosome 18 (18q) occurs later in the sequence of development from adenoma to carcinoma, and this mutation may predict poor prognosis. Loss of the 18q region is thought to contribute to inactivation of the DCC tumor-suppressor gene. More recent evidence suggests that other tumor-suppressor genes--DPC4 and MADR2 of the transforming growth factor beta (TGF-beta) pathway--also may be inactivated by allelic loss on chromosome 18q. In addition, mutation of the tumor-suppressor gene p53 on chromosome 17p appears to be a late phenomenon in colorectal carcinogenesis. This mutation may allow the growing tumor with multiple genetic alterations to evade cell cycle arrest and apoptosis. Neoplastic progression is probably accompanied by additional, undiscovered genetic events, which are indicated by allelic loss on chromosomes 1q, 4p, 6p, 8p, 9q, and 22q in 25% to 50% of colorectal cancers. Recently, a third class of genes, DNA repair genes, has been implicated in tumorigenesis of colorectal cancer. Study findings suggest that DNA mismatch repair deficiency, due to germline mutation of the hMSH2, hMLH1, hPMS1, or hPMS2 genes, contributes to development of hereditary nonpolyposis colorectal cancer. The majority of tumors in patients with this disease and 10% to 15% of sporadic colon cancers display microsatellite instability, also know as the replication error positive (RER+) phenotype. This molecular marker of DNA mismatch repair deficiency may predict improved patient survival. Mismatch repair deficiency is thought to lead to mutation and inactivation of the genes for type II TGF-beta receptor and insulin-like growth-factor II receptor. Individuals from families at high risk for colorectal cancer (hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis) should be offered genetic counseling, predictive molecular testing, and when indicated, endoscopic surveillance at appropriate intervals. Recent studies have examined colorectal carcinogenesis in the light of other genetic processes. Telomerase activity is present in almost all cancers, including colorectal cancer, but rarely in benign lesions such as adenomatous polyps or normal tissues. Furthermore, genetic alterations that allow transformed colorectal epithelial cells to escape cell cycle arrest or apoptosis also have been recognized. In addition, hypomethylation or hypermethylation of DNA sequences may alter gene expression without nucleic acid mutation.
10.1016/s0147-0272(97)80003-7
Novel biotechnology approaches in colorectal cancer diagnosis and therapy.
Kavousipour Soudabeh,Khademi Fathemeh,Zamani Mozhdeh,Vakili Bahareh,Mokarram Pooneh
Biotechnology letters
With ever-increasing molecular information about colorectal cancer (CRC), there is an expectation to detect more sensitive and specific molecular markers for new advanced diagnostic methods that can surpass the limitations of current screening tests. Moreover, enhanced molecular pathology knowledge about cancer has led to the development of targeted therapies, designed to interfere with specific aberrant biological pathways in cancer. Furthermore, biotechnology has opened a new window in CRC diagnosis and treatment by introducing different application of antibodies, antibody fragments, non-Ig scaffold proteins, and aptamers in targeted therapy and drug delivery. This review summarizes the molecular diagnostic and therapeutic approaches in CRC with a focus on genetic and epigenetic alterations, protein and metabolite markers as well as targeted therapy and drug delivery by Ig-scaffold proteins, non-Ig scaffold proteins, nanobodies, and aptamers.
10.1007/s10529-017-2303-8
Multigene assays in metastatic colorectal cancer.
Deeb Kristin K,Sram Jakub P,Gao Hanlin,Fakih Marwan G
Journal of the National Comprehensive Cancer Network : JNCCN
Specific genomic colorectal cancer alterations are increasingly linked to prognosis and/or response to specific anticancer agents. The identification of KRAS mutations as markers of resistance to epidermal growth factor receptor (EGFR) inhibitors has paved the way to the interrogation of numerous other markers of resistance to anti-EGFR therapy, such as NRAS, BRAF, and PI3KCA mutations. Other genomic and protein expression alterations have recently been identified as potential targets of treatment or as markers of chemotherapy or targeted-therapy resistance, including ERCC1 expression, c-Met expression, PTEN expression, HER2 amplification, HER3 expression, and rare KRAS mutations. As the number of distinct validated intratumor genomic assays increases, numerous molecular assays will need to be compiled into one multigene panel assay. Several companies and academic centers are now offering multigene assays to patients with metastatic colorectal cancer and other solid tumors. This article discusses the technology behind multigene assays, its limitations, its current advantages, and its potential in the clinical care of metastatic colorectal cancer.
Microbial markers in colorectal cancer detection and/or prognosis.
World journal of gastroenterology
Colorectal cancer (CRC) is the second leading cause of cancer worldwide. CRC is still associated with a poor prognosis among patients with advanced disease. On the contrary, due to its slow progression from detectable precancerous lesions, the prognosis for patients with early stages of CRC is encouraging. While most robust methods are invasive and costly, actual patient-friendly screening methods for CRC suffer of lack of sensitivity and specificity. Therefore, the development of sensitive, non-invasive and cost-effective methods for CRC detection and prognosis are necessary for increasing the chances of a cure. Beyond its beneficial functions for the host, increasing evidence suggests that the intestinal microbiota is a key factor associated with carcinogenesis. Many clinical studies have reported a disruption in the gut microbiota balance and an alteration in the faecal metabolome of CRC patients, suggesting the potential use of a microbial-based test as a non-invasive diagnostic and/or prognostic tool for CRC screening. This review aims to discuss the microbial signatures associated with CRC known to date, including dysbiosis and faecal metabolome alterations, and the potential use of microbial variation markers for non-invasive early diagnosis and/or prognostic assessment of CRC and advanced adenomas. We will finally discuss the possible use of these markers as predicators for treatment response and their limitations.
10.3748/wjg.v24.i22.2327
Recent Developments in Diagnostic and Prognostic Biomarkers for Colorectal Cancer: A Narrative Review.
Oncology
BACKGROUND:Colorectal cancer was reported as the second most common cause of cancer death worldwide, in the year 2020. This disease is an important public health problem considering its high incidence and mortality rates. SUMMARY:The molecular events that lead to colorectal cancer include genetic and epigenetic abnormalities. Some of the most important molecular mechanisms involved include the APC/β-catenin pathway, the microsatellite pathway, and the CpG island hypermethylation. Evidence in the literature supports a role for the microbiota in the development of colon carcinogenesis, and specific microbes may contribute to or prevent carcinogenesis. Progress in prevention, screening, and management has improved the overall prognosis of the disease when diagnosed at an early stage; yet metastatic disease continues to have a poor long-term prognosis due to late-stage diagnosis and treatment failure. Biomarkers are a key tool for early detection and prognosis and aim to reduce morbidity and mortality associated with colorectal cancer. The main focus of this narrative review is to provide an update on the recent development of diagnostic and prognostic biomarkers in stool, blood, and tumor tissue samples. KEY MESSAGES:The review focuses on recent investigations in microRNAs, cadherins, Piwi-interacting RNAs, circulating cell-free DNA, and microbiome biomarkers which can be applied for the diagnosis and prognosis of colorectal cancer.
10.1159/000531474
DNA methylation biomarkers in colorectal cancer: Clinical applications for precision medicine.
International journal of cancer
Colorectal cancer (CRC) is the second leading cause of cancer death worldwide that is attributed to gradual long-term accumulation of both genetic and epigenetic changes. To reduce the mortality rate of CRC and to improve treatment efficacy, it will be important to develop accurate noninvasive diagnostic tests for screening, acute and personalized diagnosis. Epigenetic changes such as DNA methylation play an important role in the development and progression of CRC. Over the last decade, a panel of DNA methylation markers has been reported showing a high accuracy and reproducibility in various semi-invasive or noninvasive biosamples. Research to obtain comprehensive panels of markers allowing a highly sensitive and differentiating diagnosis of CRC is ongoing. Moreover, the epigenetic alterations for cancer therapy, as a precision medicine strategy will increase their therapeutic potential over time. Here, we discuss the current state of DNA methylation-based biomarkers and their impact on CRC diagnosis. We emphasize the need to further identify and stratify methylation-biomarkers and to develop robust and effective detection methods that are applicable for a routine clinical setting of CRC diagnostics particularly at the early stage of the disease.
10.1002/ijc.34186
Cancer stem cells in colorectal cancer: a review.
Munro Matthew J,Wickremesekera Susrutha K,Peng Lifeng,Tan Swee T,Itinteang Tinte
Journal of clinical pathology
Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men. Adenocarcinoma accounts for 90% of CRC cases. There has been accumulating evidence in support of the cancer stem cell (CSC) concept of cancer which proposes that CSCs are central in the initiation of cancer. CSCs have been the focus of study in a range of cancers, including CRC. This has led to the identification and understanding of genes involved in the induction and maintenance of pluripotency of stem cells, and markers for CSCs, including those investigated specifically in CRC. Knowledge of the expression pattern of CSCs in CRC has been increasing in recent years, revealing a heterogeneous population of cells within CRC ranging from pluripotent to differentiated cells, with overlapping and sometimes unique combinations of markers. This review summarises current literature on the understanding of CSCs in CRC, including evidence of the presence of CSC subpopulations, and the stem cell markers currently used to identify and localise these CSC subpopulations. Future research into this field may lead to improved methods for early detection of CRC, novel therapy and monitoring of treatment for CRC and other cancer types.
10.1136/jclinpath-2017-204739
Long non-coding RNAs - SNHG6 emerge as potential marker in colorectal cancer.
Biochimica et biophysica acta. Reviews on cancer
Colorectal cancer (CRC) ranks among the leading cancers in terms of incidence and mortality in the Western world. Currently, there are no sufficient diagnostic markers that would enable an early diagnosis and efficient therapy. Unfortunately, a significant number of new CRC cases is detected in late stages, with distant metastases, therefore, new therapeutic approaches, which would alleviate the prognosis for advanced stages of CRC, are highly in demand. SNHG6 belongs to the group of long non-coding RNAs, which are a larger entity of RNAs consisting of >200 nucleotides. SNHG6 is expressed mainly in the cell cytoplasm, where it acts as a regulator of numerous processes: modulation of crucial protein hubs; sponging miRNAs and upregulating the expression of their target mRNAs; and interacting with various cellular pathways including TGF-β/Smad and Wnt/β-catenin. SNHG6 is an oncogene, substantially overexpressed in CRC tissues and cancerous cell lines as compared to healthy samples. Its overexpression is associated with higher grade, lymphovascular invasion and tumor size. Taking into consideration the role of SNHG6 in the colorectal tumorigenesis, invasion and metastasis, we summarized its role in CRC and conclude that it could serve as a potential biomarker in CRC diagnosis and prognosis assessment.
10.1016/j.bbcan.2023.189056
Value of methylation markers in colorectal cancer (Review).
Kong Can,Fu Tao
Oncology reports
Colorectal cancer (CRC) is a multifactorial and multistage process that occurs due to both genetic and epigenetic variations in normal epithelial cells. Analysis of the CRC epigenome has revealed that almost all CRC types have a large number of abnormally methylated genes. Hypermethylation of cell‑free DNA from CRC in the blood or stool is considered as a potential non‑invasive cancer biomarker, and various methylation markers have shown high sensitivity and specificity. The aim of the present review was to examine potential methylation markers in CRC that have been used or are expected to be used in the clinical setting, focusing on their screening, predictive, prognostic and therapeutic roles in CRC.
10.3892/or.2021.8128
Targeting Colorectal Cancer Stem Cells as an Effective Treatment for Colorectal Cancer.
Ma Yu-Shui,Li Wen,Liu Yu,Shi Yi,Lin Qin-Lu,Fu Da
Technology in cancer research & treatment
As one of the common cancers that threaten human life, the recurrence and metastasis of colorectal cancer seriously affect the prognosis of patients. Although new drugs and comprehensive treatments have been adopted, the current treatment effect on this tumor, especially in advanced colorectal cancer, is still not satisfactory. More and more evidence shows that tumors are likely to be a stem cell disease. In recent years, the rise of cancer stem cell theory has provided a new way for cancer treatment. Studies have found that a small number of special cells in colorectal cancer tissues that induce tumorigenesis, proliferation, and promote tumor migration and metastasis, namely, colorectal cancer stem cells. Colorectal cancer stem cells are defined with a group of cell-surface markers, such as CD44, CD133, CD24, epithelial cell adhesion factor molecule, LGR5, and acetaldehyde dehydrogenase. They are highly tumorigenic, aggressive, and chemoresistant and thus are critical in the metastasis and recurrence of colorectal cancer. Therefore, targeting colorectal cancer stem cells may become an important research direction for the future cure of colorectal cancer.
10.1177/1533033819892261
Colorectal cancer stem cells.
Yeung Trevor M,Mortensen Neil J
Diseases of the colon and rectum
PURPOSE:The cancer stem cell hypothesis predicts that only a subpopulation of cells within a tumor is responsible for driving growth. If this hypothesis were true, it would have a significant impact on our current treatment of cancer because conventional chemotherapy and radiotherapy target rapidly proliferating cells making up the bulk of the tumor, not specifically cancer stem cells. The aims of this review are to highlight the current evidence supporting the existence of cancer stem cells in colorectal cancer, to consider the relative merits of current cancer stem cell markers, and to discuss the implications of this on our current treatment of cancer. METHODS:Published scientific articles were selected by searching the PubMed database by use of the terms "colorectal," "cancer," and "stem cells," and by use of the bibliographies of extracted articles. RESULTS AND CONCLUSION:CD133, a glycosylated cell surface protein, has been demonstrated to isolate for a subpopulation of colorectal tumor cells enriched in cancer stem cells. However, only 1 in 262 CD133+ cells are able to initiate tumors. Other cancer stem cell markers have been investigated, but an overall need exists to identify more specific markers to allow further characterization of these cancer stem cells. We discuss how increased understanding of the distribution and behavior of cancer stem cells within tumors could have significant implications for the management of colorectal cancer, including screening, resection margins, sentinel node biopsy, determination of prognosis, and the development of novel therapeutic targets.
10.1007/DCR.0b013e3181a8738c
MSI colorectal cancer, all you need to know.
Clinics and research in hepatology and gastroenterology
Colorectal cancer management has been dramatically impacted by molecular profiling these last years. Among these molecular subgroups, patients with microsatellite instability (MSI) are of particular interest, owing to the prognostic and predictive value of this tumor biomarker. This review article explains the molecular abnormalities underlying MSI phenotype and the consequences of such molecular abnormalities on carcinogenesis, genetic instability and immune infiltration. It details the diagnostic methods for identifying MSI colorectal cancer patients and describes how the prognostic and theranostic values of this marker are impacting treatment decision-making for these patients in 2022.
10.1016/j.clinre.2022.101983
Colorectal cancer.
Cunningham David,Atkin Wendy,Lenz Heinz-Josef,Lynch Henry T,Minsky Bruce,Nordlinger Bernard,Starling Naureen
Lancet (London, England)
Substantial progress has been made in colorectal cancer in the past decade. Screening, used to identify individuals at an early stage, has improved outcome. There is greater understanding of the genetic basis of inherited colorectal cancer and identification of patients at risk. Optimisation of surgery for patients with localised disease has had a major effect on survival at 5 years and 10 years. For rectal cancer, identification of patients at greatest risk of local failure is important in the selection of patients for preoperative chemoradiation, a strategy proven to improve outcomes in these patients. Stringent postoperative follow-up helps the early identification of potentially radically treatable oligometastatic disease and improves long-term survival. Treatment with adjuvant fluoropyrimidine for colon and rectal cancers further improves survival, more so in stage III than in stage II disease, and oxaliplatin-based combination chemotherapy is now routinely used for stage III disease, although efficacy must be carefully balanced against toxicity. In stage II disease, molecular markers such as microsatellite instability might help select patients for treatment. The integration of targeted treatments with conventional cytotoxic drugs has expanded the treatment of metastatic disease resulting in incremental survival gains. However, biomarker development is essential to aid selection of patients likely to respond to therapy, thereby rationalising treatments and improving outcomes.
10.1016/S0140-6736(10)60353-4
The evolving role of microsatellite instability in colorectal cancer: A review.
Gelsomino Fabio,Barbolini Monica,Spallanzani Andrea,Pugliese Giuseppe,Cascinu Stefano
Cancer treatment reviews
Microsatellite instability (MSI) is a molecular marker of a deficient mismatch repair (MMR) system and occurs in approximately 15% of colorectal cancers (CRCs), more frequently in early than late-stage of disease. While in sporadic cases (about two-thirds of MSI-H CRCs) MMR deficiency is caused by an epigenetic inactivation of MLH1 gene, the remainder are associated with Lynch syndrome, that is linked to a germ-line mutation of one of the MMR genes (MLH1, MSH2, MSH6, PMS2). MSI-H colorectal cancers have distinct clinical and pathological features such as proximal location, early-stage (predominantly stage II), poor differentiation, mucinous histology and association with BRAF mutations. In early-stage CRC, MSI can select a group of tumors with a better prognosis, while in metastatic disease it seems to confer a negative prognosis. Although with conflicting results, a large amount of preclinical and clinical evidence suggests a possible resistance to 5-FU in these tumors. The higher mutational load in MSI-H CRC can elicit an endogenous immune anti-tumor response, counterbalanced by the expression of immune inhibitory signals, such as PD-1 or PD-L1, that resist tumor elimination. Based on these considerations, MSI-H CRCs seem to be particularly responsive to immunotherapy, such as anti-PD-1, opening a new era in the treatment landscape for patients with metastatic CRC.
10.1016/j.ctrv.2016.10.005
Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer.
Picard Emilie,Verschoor Chris P,Ma Grace W,Pawelec Graham
Frontiers in immunology
Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.
10.3389/fimmu.2020.00369
Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances.
Lech Gustaw,Słotwiński Robert,Słodkowski Maciej,Krasnodębski Ireneusz Wojciech
World journal of gastroenterology
Colorectal cancer (CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments.
10.3748/wjg.v22.i5.1745