Autophagy and cancer cell metabolism.
Lozy Fred,Karantza Vassiliki
Seminars in cell & developmental biology
Autophagy is a catabolic process involving lysosomal turnover of proteins and organelles for maintenance of cellular homeostasis and mitigation of metabolic stress. Autophagy defects are linked to diseases, such as liver failure, neurodegeneration, inflammatory bowel disease, aging and cancer. The role of autophagy in tumorigenesis is complex and likely context-dependent. Human breast, ovarian and prostate cancers have allelic deletions of the essential autophagy regulator BECN1 and Becn1(+/-) and other autophagy-deficient transgenic mice are tumor-prone, whereas tumors with constitutive Ras activation, including human pancreatic cancers, upregulate basal autophagy and are commonly addicted to this pathway for survival and growth; furthermore, autophagy suppression by Fip200 deletion compromises PyMT-induced mammary tumorigenesis. The double-edged sword function of autophagy in cancer has been attributed to both cell- and non-cell-autonomous mechanisms, as autophagy defects promote cancer progression in association with oxidative and ER stress, DNA damage accumulation, genomic instability and persistence of inflammation, while functional autophagy enables cancer cell survival under stress and likely contributes to treatment resistance. In this review, we will focus on the intimate link between autophagy and cancer cell metabolism, a topic of growing interest in recent years, which has been recognized as highly clinically relevant and has become the focus of intense investigation in translational cancer research. Many tumor-associated conditions, including intermittent oxygen and nutrient deprivation, oxidative stress, fast growth and cell death suppression, modulate, in parallel and in interconnected ways, both cellular metabolism and autophagy to enable cancer cells to rapidly adapt to environmental stressors, maintain uncontrolled proliferation and evade the toxic effects of radiation and/or chemotherapy. Elucidating the interplay between autophagy and tumor cell metabolism will provide unique opportunities to identify new therapeutic targets and develop synthetically lethal treatment strategies that preferentially target cancer cells, while sparing normal tissues.
10.1016/j.semcdb.2012.01.005
Metabolic Reprogramming of Immune Cells in Cancer Progression.
Biswas Subhra K
Immunity
Immune cells play a key role in host defense against infection and cancer. Upon encountering danger signals, these cells undergo activation leading to a modulation in their immune functions. However, recent studies reveal that immune cells upon activation also show distinct metabolic changes that impact their immune functions. Such metabolic reprogramming and its functional effects are well known for cancer cells. Given that immune cells have emerged as crucial players in cancer progression, it is important to understand whether immune cells also undergo metabolic reprogramming in tumors and how this might affect their contribution in cancer progression. This emerging aspect of tumor-associated immune cells is reviewed here, discussing metabolic reprogramming of different immune cell types, the key pathways involved, and its impact on tumor progression.
10.1016/j.immuni.2015.09.001
Mitochondrial Transfer in Cancer: A Comprehensive Review.
Zampieri Luca X,Silva-Almeida Catarina,Rondeau Justin D,Sonveaux Pierre
International journal of molecular sciences
Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.
10.3390/ijms22063245
Metabolic dysfunction and obesity-related cancer: Beyond obesity and metabolic syndrome.
Obesity (Silver Spring, Md.)
OBJECTIVES:The metabolic dysfunction driven by obesity, including hyperglycemia and dyslipidemia, increases risk for developing at least 13 cancer types. The concept of "metabolic dysfunction" is often defined by meeting various combinations of criteria for metabolic syndrome. However, the lack of a unified definition of metabolic dysfunction makes it difficult to compare findings across studies. This review summarizes 129 studies that evaluated variable definitions of metabolic dysfunction in relation to obesity-related cancer risk and mortality after a cancer diagnosis. Strategies for metabolic dysfunction management are also discussed. METHODS:A comprehensive search of relevant publications in MEDLINE (PubMed) and Google Scholar with review of references was conducted. RESULTS:Metabolic dysfunction, defined as metabolic syndrome diagnosis or any number of metabolic syndrome criteria out of clinical range, inflammatory biomarkers, or markers of metabolic organ function, has been associated with risk for, and mortality from, colorectal, pancreatic, postmenopausal breast, and bladder cancers. Metabolic dysfunction associations with breast and colorectal cancer risk have been observed independently of BMI, with increased risk in individuals with metabolically unhealthy normal weight or overweight/obesity compared with metabolically healthy normal weight. CONCLUSION:Metabolic dysfunction is a key risk factor for obesity-related cancer, regardless of obesity status. Nonetheless, a harmonized definition of metabolic dysfunction will further clarify the magnitude of the relationship across cancer types, enable better comparisons across studies, and further guide criteria for obesity-related cancer risk stratification.
10.1002/oby.23444
Emerging roles of lipid metabolism in cancer metastasis.
Luo Xiangjian,Cheng Can,Tan Zheqiong,Li Namei,Tang Min,Yang Lifang,Cao Ya
Molecular cancer
Cancer cells frequently display fundamentally altered cellular metabolism, which provides the biochemical foundation and directly contributes to tumorigenicity and malignancy. Rewiring of metabolic programmes, such as aerobic glycolysis and increased glutamine metabolism, are crucial for cancer cells to shed from a primary tumor, overcome the nutrient and energy deficit, and eventually survive and form metastases. However, the role of lipid metabolism that confers the aggressive properties of malignant cancers remains obscure. The present review is focused on key enzymes in lipid metabolism associated with metastatic disease pathogenesis. We also address the function of an important membrane structure-lipid raft in mediating tumor aggressive progression. We enumerate and integrate these recent findings into our current understanding of lipid metabolic reprogramming in cancer metastasis accompanied by new and exciting therapeutic implications.
10.1186/s12943-017-0646-3
Metabolic regulation of cell growth and proliferation.
Nature reviews. Molecular cell biology
Cellular metabolism is at the foundation of all biological activities. The catabolic processes that support cellular bioenergetics and survival have been well studied. By contrast, how cells alter their metabolism to support anabolic biomass accumulation is less well understood. During the commitment to cell proliferation, extensive metabolic rewiring must occur in order for cells to acquire sufficient nutrients such as glucose, amino acids, lipids and nucleotides, which are necessary to support cell growth and to deal with the redox challenges that arise from the increased metabolic activity associated with anabolic processes. Defining the mechanisms of this metabolic adaptation for cell growth and proliferation is now a major focus of research. Understanding the principles that guide anabolic metabolism may ultimately enhance ways to treat diseases that involve deregulated cell growth and proliferation, such as cancer.
10.1038/s41580-019-0123-5
Fatty Acid Metabolism and Cancer.
Jin Zhenning,Chai Yang D,Hu Shen
Advances in experimental medicine and biology
Although normal cells depend on exogenous lipids to function and survive, excessive amount of body fat has been associated with increased risk for certain human cancers. Cancer cells can redirect metabolic pathways to meet energy demands through the regulation of fatty acid metabolism. The importance of de novo fatty acid synthesis and fatty acid oxidation in cancer cells suggests fatty acid metabolism may be targeted for anticancer treatment through the use of pharmacological blockade to limit cell proliferation, growth, and transformation. However, our current knowledge about fatty acid metabolism in cancer cells remains limited, and the investigations of such processes and related pathways are certainly warranted to reveal the clinical relevance of fatty acid metabolism in cancer diagnosis and therapy.
10.1007/978-3-030-51652-9_16
Tumor cell metabolism: cancer's Achilles' heel.
Kroemer Guido,Pouyssegur Jacques
Cancer cell
The essential hallmarks of cancer are intertwined with an altered cancer cell-intrinsic metabolism, either as a consequence or as a cause. As an example, the resistance of cancer mitochondria against apoptosis-associated permeabilization and the altered contribution of these organelles to metabolism are closely related. Similarly, the constitutive activation of signaling cascades that stimulate cell growth has a profound impact on anabolic metabolism. Here, we review the peculiarities of tumor cell metabolism that might be taken advantage of for cancer treatment. Specifically, we discuss the alterations in signal transduction pathways and/or enzymatic machineries that account for metabolic reprogramming of transformed cells.
10.1016/j.ccr.2008.05.005
Adipocyte and lipid metabolism in cancer drug resistance.
Cao Yihai
The Journal of clinical investigation
Development of novel and effective therapeutics for treating various cancers is probably the most congested and challenging enterprise of pharmaceutical companies. Diverse drugs targeting malignant and nonmalignant cells receive clinical approval each year from the FDA. Targeting cancer cells and nonmalignant cells unavoidably changes the tumor microenvironment, and cellular and molecular components relentlessly alter in response to drugs. Cancer cells often reprogram their metabolic pathways to adapt to environmental challenges and facilitate survival, proliferation, and metastasis. While cancer cells' dependence on glycolysis for energy production is well studied, the roles of adipocytes and lipid metabolic reprogramming in supporting cancer growth, metastasis, and drug responses are less understood. This Review focuses on emerging mechanisms involving adipocytes and lipid metabolism in altering the response to cancer treatment. In particular, we discuss mechanisms underlying cancer-associated adipocytes and lipid metabolic reprogramming in cancer drug resistance.
10.1172/JCI127201
The Emerging Hallmarks of Cancer Metabolism.
Pavlova Natalya N,Thompson Craig B
Cell metabolism
Tumorigenesis is dependent on the reprogramming of cellular metabolism as both direct and indirect consequence of oncogenic mutations. A common feature of cancer cell metabolism is the ability to acquire necessary nutrients from a frequently nutrient-poor environment and utilize these nutrients to both maintain viability and build new biomass. The alterations in intracellular and extracellular metabolites that can accompany cancer-associated metabolic reprogramming have profound effects on gene expression, cellular differentiation, and the tumor microenvironment. In this Perspective, we have organized known cancer-associated metabolic changes into six hallmarks: (1) deregulated uptake of glucose and amino acids, (2) use of opportunistic modes of nutrient acquisition, (3) use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, (4) increased demand for nitrogen, (5) alterations in metabolite-driven gene regulation, and (6) metabolic interactions with the microenvironment. While few tumors display all six hallmarks, most display several. The specific hallmarks exhibited by an individual tumor may ultimately contribute to better tumor classification and aid in directing treatment.
10.1016/j.cmet.2015.12.006
Ageing and the free radical theory.
Wickens A P
Respiration physiology
The free radical theory proposes that ageing is the cumulative result of oxidative damage to the cells and tissues of the body that arises primarily as a result of aerobic metabolism. Several lines of evidence have been used to support this hypothesis including the claims that: (1) variation in species life span is correlated with metabolic rate and protective antioxidant activity; (2) enhanced expression of antioxidative enzymes in experimental animals can produce a significant increase in longevity; (3) cellular levels of free radical damage increases with age; and (4) reduced calorie intake leads to a decline in the production of reactive oxygen species and an increase in life span. The free radical theory may also be used to explain many of the structural features that develop with ageing including the lipid peroxidation of membranes, formation of age pigments, cross-linkage of proteins, DNA damage and decline of mitochondrial function. Despite this, many uncertainties concerning the role of oxidative damage in ageing remain and alternative explanations cannot be ruled out. Free radicals only occur in trace quantities in biological tissues, their cellular levels and actions cannot be measured in vivo, and definitive proof that oxidised molecules are the primary cause of ageing is lacking. Moreover, ageing is also likely to be a multifactorial process and not reducible to any one single cause. Thus, despite its positive features, the evidence for the free radical theory is either correlative or inconclusive.
Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging.
Signal transduction and targeted therapy
Epigenetic alterations and metabolic dysfunction are two hallmarks of aging. However, the mechanism of how their interaction regulates aging, particularly in mammals, remains largely unknown. Here we show ELOVL fatty acid elongase 2 (Elovl2), a gene whose epigenetic alterations are most highly correlated with age prediction, contributes to aging by regulating lipid metabolism. We applied artificial intelligence to predict the protein structure of ELOVL2 and the interaction with its substrate. Impaired Elovl2 function disturbs lipid synthesis with increased endoplasmic reticulum stress and mitochondrial dysfunction, leading to key aging phenotypes at both cellular and physiological level. Furthermore, restoration of mitochondrial activity can rescue age-related macular degeneration (AMD) phenotypes induced by Elovl2 deficiency in human retinal pigmental epithelial (RPE) cells; this indicates a conservative mechanism in both human and mouse. Taken together, we revealed an epigenetic-metabolism axis contributing to aging and illustrate the power of an AI-based approach in structure-function studies.
10.1038/s41392-022-00964-6
Precise Metabolomics Reveals a Diversity of Aging-Associated Metabolic Features.
Small methods
Mass spectrometry-based metabolomics has emerged as a powerful technique for biomedical research, although technical issues with its analytical precision and structural characterization remain. Herein, a robust non-targeted strategy for accurate quantitation and precise profiling of metabolomes is developed and applied to investigate plasma metabolic features associated with human aging. A comprehensive set of isotope-labeled standards (ISs) covering major metabolic pathways is incorporated to quantify polar metabolites. Matching rules to select ISs for calibration follow a primary criterion of minimal coefficients of variations (COVs). If minimal COVs between specific ISs for a particular metabolite fall within 5% window, a further selection of ISs is conducted based on structural similarities and proximity in retention time. The introduction and refined selection of appropriate ISs for quantitation reduces the COVs of 480 identified metabolites in quality control samples from 14.3% to 9.8% and facilitates identification of additional metabolite. Finally, the precise metabolomics approach reveals perturbations in a diverse array of metabolic pathways across aging that principally implicate steroid metabolism, amino acid metabolism, lipid metabolism, and purine metabolism, which allows the authors to draw correlates to the pathology of various age-related diseases. These findings provide clues for the prevention and treatment of these age-related diseases.
10.1002/smtd.202200130
Making sense of the ageing methylome.
Nature reviews. Genetics
Over time, the human DNA methylation landscape accrues substantial damage, which has been associated with a broad range of age-related diseases, including cardiovascular disease and cancer. Various age-related DNA methylation changes have been described, including at the level of individual CpGs, such as differential and variable methylation, and at the level of the whole methylome, including entropy and correlation networks. Here, we review these changes in the ageing methylome as well as the statistical tools that can be used to quantify them. We detail the evidence linking DNA methylation to ageing phenotypes and the longevity strategies aimed at altering both DNA methylation patterns and machinery to extend healthspan and lifespan. Lastly, we discuss theories on the mechanistic causes of epigenetic ageing.
10.1038/s41576-022-00477-6
Axonal energy metabolism, and the effects in aging and neurodegenerative diseases.
Molecular neurodegeneration
Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of aging (NDAs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Glucose is the major brain fuel and glucose hypometabolism has been observed in brain regions vulnerable to aging and NDAs. Many neurodegenerative susceptible regions are in the topological central hub of the brain connectome, linked by densely interconnected long-range axons. Axons, key components of the connectome, have high metabolic needs to support neurotransmission and other essential activities. Long-range axons are particularly vulnerable to injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy is often an early sign of neurodegeneration. Recent studies ascribe axonal maintenance failures to local bioenergetic dysregulation. With this review, we aim to stimulate research in exploring metabolically oriented neuroprotection strategies to enhance or normalize bioenergetics in NDA models. Here we start by summarizing evidence from human patients and animal models to reveal the correlation between glucose hypometabolism and connectomic disintegration upon aging/NDAs. To encourage mechanistic investigations on how axonal bioenergetic dysregulation occurs during aging/NDAs, we first review the current literature on axonal bioenergetics in distinct axonal subdomains: axon initial segments, myelinated axonal segments, and axonal arbors harboring pre-synaptic boutons. In each subdomain, we focus on the organization, activity-dependent regulation of the bioenergetic system, and external glial support. Second, we review the mechanisms regulating axonal nicotinamide adenine dinucleotide (NAD) homeostasis, an essential molecule for energy metabolism processes, including NAD biosynthetic, recycling, and consuming pathways. Third, we highlight the innate metabolic vulnerability of the brain connectome and discuss its perturbation during aging and NDAs. As axonal bioenergetic deficits are developing into NDAs, especially in asymptomatic phase, they are likely exaggerated further by impaired NAD homeostasis, the high energetic cost of neural network hyperactivity, and glial pathology. Future research in interrogating the causal relationship between metabolic vulnerability, axonopathy, amyloid/tau pathology, and cognitive decline will provide fundamental knowledge for developing therapeutic interventions.
10.1186/s13024-023-00634-3
MAP4K3/GLK in autoimmune disease, cancer and aging.
Chuang Huai-Chia,Tan Tse-Hua
Journal of biomedical science
MAP4K3 (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22 years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and proinflammatory cytokines. The data derived from GLK-overexpressing or shRNA-knockdown cell lines suggest that GLK may be involved in cell proliferation through mTOR signaling. GLK phosphorylates the transcription factor TFEB and retains TFEB in the cytoplasm, leading to inhibition of cell autophagy. After generating and characterizing GLK-deficient mice, the important in vivo roles of GLK in T-cell activation were revealed. In T cells, GLK directly interacts with and activates PKCθ through phosphorylating PKCθ at Ser-538 residue, leading to activation of IKK/NF-κB. Thus, GLK-deficient mice display impaired T-cell-mediated immune responses and decreased inflammatory phenotypes in autoimmune disease models. Consistently, the percentage of GLK-overexpressing T cells is increased in the peripheral blood from autoimmune disease patients; the GLK-overexpressing T cell population is correlated with disease severity of patients. The pathogenic mechanism of autoimmune disease by GLK overexpression was unraveled by characterizing T-cell-specific GLK transgenic mice and using biochemical analyses. GLK overexpression selectively promotes IL-17A transcription by inducing the AhR-RORγt complex in T cells. In addition, GLK overexpression in cancer tissues is correlated with cancer recurrence of human lung cancer and liver cancer; the predictive power of GLK overexpression for cancer recurrence is higher than that of pathologic stage. GLK directly phosphorylates and activates IQGAP1, resulting in induction of Cdc42-mediated cell migration and cancer metastasis. Furthermore, treatment of GLK inhibitor reduces disease severity of mouse autoimmune disease models and decreases IL-17A production of human autoimmune T cells. Due to the inhibitory function of HPK1/MAP4K1 in T-cell activation and the promoting effects of GLK on tumorigenesis, HPK1 and GLK dual inhibitors could be useful therapeutic drugs for cancer immunotherapy. In addition, GLK deficiency results in extension of lifespan in Caenorhabditis elegans and mice. Taken together, targeting MAP4K3 (GLK) may be useful for treating/preventing autoimmune disease, cancer metastasis/recurrence, and aging.
10.1186/s12929-019-0570-5
Polyploidy: the link between senescence and cancer.
Mosieniak G,Sikora E
Current pharmaceutical design
Polyploidy, a state of increased number of chromosomes, occurs often in plants and less frequently in animals. Polyploidization is recognized as a part of a developmental program and can be achieved via different mechanisms bypassing certain stages of the cell cycle. However, polyploidization also accompanies some pathological conditions as well as ageing. It is believed that tetraploid cells precede aneuploid ones in the early phases of tumor development. Division of tetraploid cells is restricted by the active tetraploid (4N G1) checkpoint. Tetraploid cells that are able to overcome this checkpoint give rise to increased genomic instability and tumor progression. Recently a cellular senescence program activated by oncogene expression was shown to act as a natural barrier against cancer development. Senescent cells were detected in many benign, but not malignant, human and animal tumors. Senescence can actually block cell transformation provided the 4N G1 checkpoint is active. Cancer cells that escaped the 4N G1 block are still able to undergo senescence upon anticancer treatment. Induction of cancer cell senescence is often correlated with high ploidy formation. Some polyploid cells can escape senescence and give progeny with numerical changes of chromosomes. Divisions of polyploid cancer cells on the road to senescence can be responsible for the ineffectiveness of anticancer therapy. Altogether, this implies polyploidy as a link between cellular senescence, cancer development and possible cancer renewal after treatment.
Cellular parabiosis and the latency of age-related diseases.
Radman Miroslav
Open biology
Cellular parabiosis is tissue-based phenotypic suppression of cellular dysfunction by intercellular molecular traffic keeping initiated age-related diseases and conditions in long latency. Interruption of cellular parabiosis (e.g. by chronic inflammation) promotes the onset of initiated pathologies. The stability of initiated latent cancers and other age-related diseases (ARD) hints to phenotypically silent genome alterations. I propose that latency in the onset of ageing and ARD is largely due to phenotypic suppression of cellular dysfunctions via molecular traffic among neighbouring cells. Intercellular trafficking ranges from the transfer of ions and metabolites (via gap junctions) to entire organelles (via tunnelling nanotubes). Any mechanism of cell-to-cell communication resulting in functional cross-complementation among the cells is called cellular parabiosis. Such 'cellular solidarity' creates tissue homeostasis by buffering defects and averaging cellular functions within the tissues. Chronic inflammation is known to (i) interrupt cellular parabiosis by the activity of extracellular proteases, (ii) activate dormant pathologies and (iii) shorten disease latency, as in tumour promotion and inflammaging. Variation in cellular parabiosis and protein oxidation can account for interspecies correlations between body mass, ARD latency and longevity. Now, prevention of ARD onset by phenotypic suppression, and healing by phenotypic reversion, become conceivable.
10.1098/rsob.180250
Tumor cell senescence-induced macrophage CD73 expression is a critical metabolic immune checkpoint in the aging tumor microenvironment.
Theranostics
The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy and chemotherapy, can induce cellular senescence. Cellular interactions are widespread in the TME, and tumor cells reprogram immune cells metabolically by producing metabolites. However, how senescent cells remodel the metabolism of TME remains unclear. This study aimed to explore precise targets to enhance senescent cells-induced anti-tumor immunity from a metabolic perspective. The senescence model was induced by 8 Gy×3 radiotherapy or cisplatin chemotherapy, and the model was induced by 10 Gy-irradiation or cisplatin treatment. Metabonomic analysis and ELISA assay on tumor interstitial fluid were performed for metabolites screening. Marker expression and immune cell infiltration in the TME were analyzed by flow cytometry. Cell co-culture system and senescence-conditioned medium were used for crosstalk validation . RNA sequencing and rescue experiments were conducted for mechanism excavation. Immunofluorescence staining and single-cell transcriptome profiling analysis were performed for clinical validation. We innovatively reveal the metabolic landscape of the senescent TME, characterized with the elevation of adenosine. It is attributed to the senescent tumor cell-induced CD73 upregulation of tumor-associated macrophages (TAMs). CD73 expression in TAMs is evoked by SASP-related pro-inflammatory cytokines, especially IL-6, and regulated by JAK/STAT3 pathway. Consistently, a positive correlation between tumor cells senescence and TAMs CD73 expression is identified in lung cancer clinical specimens and databases. Lastly, blocking CD73 in a senescent background suppresses tumors and activates CD8 T cell-mediated antitumor immunity. TAMs expressed CD73 contributes significantly to the adenosine accumulation in the senescent TME, suggesting targeting CD73 is a novel synergistic anti-tumor strategy in the aging microenvironment.
10.7150/thno.91119
Principles of DNA methylation and their implications for biology and medicine.
Dor Yuval,Cedar Howard
Lancet (London, England)
DNA methylation represents an annotation system for marking the genetic text, thus providing instruction as to how and when to read the information and control transcription. Unlike sequence information, which is inherited, methylation patterns are established in a programmed process that continues throughout development, thus setting up stable gene expression profiles. This DNA methylation paradigm is a key player in medicine. Some changes in methylation closely correlate with age providing a marker for biological ageing, and these same sites could also play a part in cancer. The genome continues to undergo programmed variation in methylation after birth in response to environmental inputs, serving as a memory device that could affect ageing and predisposition to various metabolic, autoimmune, and neurological diseases. Taking advantage of tissue-specific differences, methylation can be used to detect cell death and thereby monitor many common diseases with a simple cell-free circulating-DNA blood test.
10.1016/S0140-6736(18)31268-6
Role of Telomeres and Telomerase in Aging and Cancer.
Cancer discovery
UNLABELLED:Telomeres progressively shorten throughout life. A hallmark of advanced malignancies is the ability for continuous cell divisions that almost universally correlates with the stabilization of telomere length by the reactivation of telomerase. The repression of telomerase and shorter telomeres in humans may have evolved, in part, as an anticancer protection mechanism. Although there is still much we do not understand about the regulation of telomerase, it remains a very attractive and novel target for cancer therapeutics. This review focuses on the current state of advances in the telomerase area, identifies outstanding questions, and addresses areas and methods that need refinement. SIGNIFICANCE:Despite many recent advances, telomerase remains a challenging target for cancer therapy. There are few telomerase-directed therapies, and many of the assays used to measure telomeres and telomerase have serious limitations. This review provides an overview of the current state of the field and how recent advances could affect future research and treatment approaches. Cancer Discov; 6(6); 584-93. ©2016 AACR.
10.1158/2159-8290.CD-16-0062