Pub Date : 2021-03-01Epub Date: 2020-12-04DOI: 10.1146/annurev-cancerbio-042920-104912
Kevin Kos, Karin E de Visser
The microenvironment of breast cancer hosts a dynamic cross talk between diverse players of the immune system. While cytotoxic immune cells are equipped to control tumor growth and metastasis, tumor-corrupted immunosuppressive immune cells strive to impair effective immunity and promote tumor progression. Of these, regulatory T cells (Tregs), the gatekeepers of immune homeostasis, emerge as multifaceted players involved in breast cancer. Intriguingly, clinical observations suggest that blood and intratumoral Tregs can have strong prognostic value, dictated by breast cancer subtype. Accordingly, emerging preclinical evidence shows that Tregs occupy a central role in breast cancer initiation and progression and provide critical support to metastasis formation. Here, Tregs are not only important for immune escape but also promote tumor progression independent of their immune regulatory capacity. Combining insights into Treg biology with advances made across the rapidly growing field of immuno-oncology is expected to set the stage for the design of more effective immunotherapy strategies.
{"title":"The Multifaceted Role of Regulatory T Cells in Breast Cancer.","authors":"Kevin Kos, Karin E de Visser","doi":"10.1146/annurev-cancerbio-042920-104912","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-042920-104912","url":null,"abstract":"<p><p>The microenvironment of breast cancer hosts a dynamic cross talk between diverse players of the immune system. While cytotoxic immune cells are equipped to control tumor growth and metastasis, tumor-corrupted immunosuppressive immune cells strive to impair effective immunity and promote tumor progression. Of these, regulatory T cells (T<sub>regs</sub>), the gatekeepers of immune homeostasis, emerge as multifaceted players involved in breast cancer. Intriguingly, clinical observations suggest that blood and intratumoral T<sub>regs</sub> can have strong prognostic value, dictated by breast cancer subtype. Accordingly, emerging preclinical evidence shows that T<sub>regs</sub> occupy a central role in breast cancer initiation and progression and provide critical support to metastasis formation. Here, T<sub>regs</sub> are not only important for immune escape but also promote tumor progression independent of their immune regulatory capacity. Combining insights into T<sub>reg</sub> biology with advances made across the rapidly growing field of immuno-oncology is expected to set the stage for the design of more effective immunotherapy strategies.</p>","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":"5 ","pages":"291-310"},"PeriodicalIF":7.7,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/annurev-cancerbio-042920-104912","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39504279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-03-01Epub Date: 2020-11-30DOI: 10.1146/annurev-cancerbio-070820-035832
Luke T Izzo, Hayley C Affronti, Kathryn E Wellen
Metabolic and epigenetic reprogramming are characteristics of cancer cells that, in many cases, are linked. Oncogenic signaling, diet, and tumor microenvironment each influence the availability of metabolites that are substrates or inhibitors of epigenetic enzymes. Reciprocally, altered expression or activity of chromatin-modifying enzymes can exert direct and indirect effects on cellular metabolism. In this article, we discuss the bidirectional relationship between epigenetics and metabolism in cancer. First, we focus on epigenetic control of metabolism, highlighting evidence that alterations in histone modifications, chromatin remodeling, or the enhancer landscape can drive metabolic features that support growth and proliferation. We then discuss metabolic regulation of chromatin-modifying enzymes and roles in tumor growth and progression. Throughout, we highlight proposed therapeutic and dietary interventions that leverage metabolic-epigenetic cross talk and have the potential to improve cancer therapy.
{"title":"The Bidirectional Relationship Between Cancer Epigenetics and Metabolism.","authors":"Luke T Izzo, Hayley C Affronti, Kathryn E Wellen","doi":"10.1146/annurev-cancerbio-070820-035832","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-070820-035832","url":null,"abstract":"<p><p>Metabolic and epigenetic reprogramming are characteristics of cancer cells that, in many cases, are linked. Oncogenic signaling, diet, and tumor microenvironment each influence the availability of metabolites that are substrates or inhibitors of epigenetic enzymes. Reciprocally, altered expression or activity of chromatin-modifying enzymes can exert direct and indirect effects on cellular metabolism. In this article, we discuss the bidirectional relationship between epigenetics and metabolism in cancer. First, we focus on epigenetic control of metabolism, highlighting evidence that alterations in histone modifications, chromatin remodeling, or the enhancer landscape can drive metabolic features that support growth and proliferation. We then discuss metabolic regulation of chromatin-modifying enzymes and roles in tumor growth and progression. Throughout, we highlight proposed therapeutic and dietary interventions that leverage metabolic-epigenetic cross talk and have the potential to improve cancer therapy.</p>","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":"5 1","pages":"235-257"},"PeriodicalIF":7.7,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/annurev-cancerbio-070820-035832","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39080206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-03-01Epub Date: 2020-12-02DOI: 10.1146/annurev-cancerbio-060820-090737
Winnie M C van den Boogaard, Marry M van den Heuvel-Eibrink, Jan H J Hoeijmakers, Wilbert P Vermeij
Dietary restriction (DR) is the most successful nutritional intervention for extending lifespan and preserving health in numerous species. Reducing food intake triggers a protective response that shifts energy resources from growth to maintenance and resilience mechanisms. This so-called survival response has been shown to particularly increase life- and health span and decrease DNA damage in DNA repair-deficient mice exhibiting accelerated aging. Accumulation of DNA damage is the main cause of aging, but also of cancer. Moreover, radiotherapies and most chemotherapies are based on damaging DNA, consistent with their ability to induce toxicity and accelerate aging. Since fasting and DR decrease DNA damage and its effects, nutritional preconditioning holds promise for improving (cancer) therapy and preventing short- and long-term side effects of anticancer treatments. This review provides an overview of the link between aging and cancer, highlights important preclinical studies applying such nutritional preconditioning, and summarizes the first clinical trials implementing nutritional preconditioning in cancer treatment.
{"title":"Nutritional Preconditioning in Cancer Treatment in Relation to DNA Damage and Aging.","authors":"Winnie M C van den Boogaard, Marry M van den Heuvel-Eibrink, Jan H J Hoeijmakers, Wilbert P Vermeij","doi":"10.1146/annurev-cancerbio-060820-090737","DOIUrl":"10.1146/annurev-cancerbio-060820-090737","url":null,"abstract":"<p><p>Dietary restriction (DR) is the most successful nutritional intervention for extending lifespan and preserving health in numerous species. Reducing food intake triggers a protective response that shifts energy resources from growth to maintenance and resilience mechanisms. This so-called survival response has been shown to particularly increase life- and health span and decrease DNA damage in DNA repair-deficient mice exhibiting accelerated aging. Accumulation of DNA damage is the main cause of aging, but also of cancer. Moreover, radiotherapies and most chemotherapies are based on damaging DNA, consistent with their ability to induce toxicity and accelerate aging. Since fasting and DR decrease DNA damage and its effects, nutritional preconditioning holds promise for improving (cancer) therapy and preventing short- and long-term side effects of anticancer treatments. This review provides an overview of the link between aging and cancer, highlights important preclinical studies applying such nutritional preconditioning, and summarizes the first clinical trials implementing nutritional preconditioning in cancer treatment.</p>","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":"5 1","pages":"161-179"},"PeriodicalIF":4.7,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46081931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-09DOI: 10.1146/annurev-cancerbio-030518-055627
Warren L. Wu, T. Papagiannakopoulos
The unregulated proliferative capacity of many tumors is dependent on dysfunctional nutrient utilization and ROS (reactive oxygen species) signaling to sustain a deranged metabolic state. Although it is clear that cancers broadly rely on these survival and signaling pathways, how they achieve these aims varies dramatically. Mutations in the KEAP1/NRF2 pathway represent a potent cancer adaptation to exploit native cytoprotective pathways that involve both nutrient metabolism and ROS regulation. Despite activating these advantageous processes, mutations within KEAP1/ NRF2 are not universally selected for across cancers and instead appear to interact with particular tumor driver mutations and tissues of origin. Here, we highlight the relationship between the KEAP1/NRF2 signaling axis and tumor biology with a focus on genetic mutation, metabolism, immune regulation, and treatment implications and opportunities. Understanding the dysregulation of KEAP1 and NRF2 provides not only insight into a commonly mutated tumor suppressor pathway but also a window into the factors dictating the development and evolution of many cancers.
{"title":"The Pleiotropic Role of the KEAP1/NRF2 Pathway in Cancer","authors":"Warren L. Wu, T. Papagiannakopoulos","doi":"10.1146/annurev-cancerbio-030518-055627","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-030518-055627","url":null,"abstract":"The unregulated proliferative capacity of many tumors is dependent on dysfunctional nutrient utilization and ROS (reactive oxygen species) signaling to sustain a deranged metabolic state. Although it is clear that cancers broadly rely on these survival and signaling pathways, how they achieve these aims varies dramatically. Mutations in the KEAP1/NRF2 pathway represent a potent cancer adaptation to exploit native cytoprotective pathways that involve both nutrient metabolism and ROS regulation. Despite activating these advantageous processes, mutations within KEAP1/ NRF2 are not universally selected for across cancers and instead appear to interact with particular tumor driver mutations and tissues of origin. Here, we highlight the relationship between the KEAP1/NRF2 signaling axis and tumor biology with a focus on genetic mutation, metabolism, immune regulation, and treatment implications and opportunities. Understanding the dysregulation of KEAP1 and NRF2 provides not only insight into a commonly mutated tumor suppressor pathway but also a window into the factors dictating the development and evolution of many cancers.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2020-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/annurev-cancerbio-030518-055627","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45147842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-09DOI: 10.1146/annurev-cancerbio-030419-033502
Asmin Tulpule, T. Bivona
The last decade has witnessed a transformation in the treatment of advanced-stage lung cancer from a largely palliative approach to one where long-term durable remissions and even cures might be within reach. In this review, we discuss the current state of oncogene-directed precision medicine therapies in lung cancer and focus on the major cause of mortality for lung cancer patients: acquired resistance. We consider the multifaceted resistance mechanisms tumors utilize, often simultaneously. We then present areas for future scientific and clinical investigation with an emphasis on population dynamics, early detection, combinatorial therapies targeting resistance mechanisms, and understanding the drug-tolerant persister state.
{"title":"Acquired Resistance in Lung Cancer","authors":"Asmin Tulpule, T. Bivona","doi":"10.1146/annurev-cancerbio-030419-033502","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-030419-033502","url":null,"abstract":"The last decade has witnessed a transformation in the treatment of advanced-stage lung cancer from a largely palliative approach to one where long-term durable remissions and even cures might be within reach. In this review, we discuss the current state of oncogene-directed precision medicine therapies in lung cancer and focus on the major cause of mortality for lung cancer patients: acquired resistance. We consider the multifaceted resistance mechanisms tumors utilize, often simultaneously. We then present areas for future scientific and clinical investigation with an emphasis on population dynamics, early detection, combinatorial therapies targeting resistance mechanisms, and understanding the drug-tolerant persister state.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2020-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/annurev-cancerbio-030419-033502","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46474088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-09DOI: 10.1146/annurev-cancerbio-030419-033405
K. Macleod
The process of mitophagy, in which mitochondria are selectively turned over at the autophagolysosome, plays a central role in both eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive response to key physiological stresses, such as hypoxia, nutrient deprivation, and DNA damage. Defects in mitophagy have been linked to altered mitochondrial metabolism, production of excess reactive oxygen species and ferroptosis, heightened inflammasome activation, altered cell fate decisions, and senescence, among other cellular consequences. Consequently, functional mitophagy contributes to proper tissue differentiation and repair and metabolic homeostasis, limiting inflammatory responses and modulating tumor progression and metastasis. This review examines the major pathways that control mitophagy, including PINK1-dependent mitophagy and BNIP3/NIX-dependent mitophagy. It also discusses the cellular signaling mechanisms used to sense mitochondrial dysfunction to activate mitophagy and how defective mitophagy results in deregulated tumor cell growth and cancer.
{"title":"Mitophagy and Mitochondrial Dysfunction in Cancer","authors":"K. Macleod","doi":"10.1146/annurev-cancerbio-030419-033405","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-030419-033405","url":null,"abstract":"The process of mitophagy, in which mitochondria are selectively turned over at the autophagolysosome, plays a central role in both eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive response to key physiological stresses, such as hypoxia, nutrient deprivation, and DNA damage. Defects in mitophagy have been linked to altered mitochondrial metabolism, production of excess reactive oxygen species and ferroptosis, heightened inflammasome activation, altered cell fate decisions, and senescence, among other cellular consequences. Consequently, functional mitophagy contributes to proper tissue differentiation and repair and metabolic homeostasis, limiting inflammatory responses and modulating tumor progression and metastasis. This review examines the major pathways that control mitophagy, including PINK1-dependent mitophagy and BNIP3/NIX-dependent mitophagy. It also discusses the cellular signaling mechanisms used to sense mitochondrial dysfunction to activate mitophagy and how defective mitophagy results in deregulated tumor cell growth and cancer.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2020-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/annurev-cancerbio-030419-033405","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49282993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-09DOI: 10.1146/annurev-cancerbio-030419-033510
G. Kelly, A. Strasser
Apoptosis is critical for embryonic development, tissue homeostasis, and the removal of infected or otherwise dangerous cells. It is controlled by three subgroups of the BCL-2 protein family—the BH3-only proteins that initiate cell death; the effectors of cell killing, BAX and BAK; and the antiapoptotic guardians, including MCL-1 and BCL-2. Defects in apoptosis can promote tumorigenesis and render malignant cells refractory to anticancer therapeutics. Activation of cell death by inhibiting antiapoptotic BCL-2 family members has emerged as an attractive strategy for cancer therapy, with the BCL-2 inhibitor venetoclax leading the way. Large-scale cancer genome analyses have revealed frequent amplification of the locus encoding antiapoptotic MCL-1 in human cancers, and functional studies have shown that MCL-1 is essential for the sustained survival and expansion of many types of tumor cells. Structural analysis and medicinal chemistry have led to the development of three distinct small-molecule inhibitors of MCL-1 that are currently undergoing clinical testing.
{"title":"Toward Targeting Antiapoptotic MCL-1 for Cancer Therapy","authors":"G. Kelly, A. Strasser","doi":"10.1146/annurev-cancerbio-030419-033510","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-030419-033510","url":null,"abstract":"Apoptosis is critical for embryonic development, tissue homeostasis, and the removal of infected or otherwise dangerous cells. It is controlled by three subgroups of the BCL-2 protein family—the BH3-only proteins that initiate cell death; the effectors of cell killing, BAX and BAK; and the antiapoptotic guardians, including MCL-1 and BCL-2. Defects in apoptosis can promote tumorigenesis and render malignant cells refractory to anticancer therapeutics. Activation of cell death by inhibiting antiapoptotic BCL-2 family members has emerged as an attractive strategy for cancer therapy, with the BCL-2 inhibitor venetoclax leading the way. Large-scale cancer genome analyses have revealed frequent amplification of the locus encoding antiapoptotic MCL-1 in human cancers, and functional studies have shown that MCL-1 is essential for the sustained survival and expansion of many types of tumor cells. Structural analysis and medicinal chemistry have led to the development of three distinct small-molecule inhibitors of MCL-1 that are currently undergoing clinical testing.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2020-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/annurev-cancerbio-030419-033510","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44418727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-09DOI: 10.1146/annurev-cancerbio-030419-033612
M. Sciacovelli, Christin Schmidt, E. Maher, C. Frezza
Cancer is a multifaceted disease in which inherited genetic variants can be important drivers of tumorigenesis. The discovery that germline mutations of metabolic genes predispose to familial forms of cancer caused a shift in our understanding of how metabolism contributes to tumorigenesis, providing evidence that metabolic alterations can be oncogenic. In this review, we focus on mitochondrial enzymes whose mutations predispose to familial cancer, and we fully appraise their involvement in cancer formation and progression. Elucidating the molecular mechanisms that orchestrate transformation in these diverse tumors may answer key biological questions about tumor formation and evolution, leading to the identification of new therapeutic targets of intervention.
{"title":"Metabolic Drivers in Hereditary Cancer Syndromes","authors":"M. Sciacovelli, Christin Schmidt, E. Maher, C. Frezza","doi":"10.1146/annurev-cancerbio-030419-033612","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-030419-033612","url":null,"abstract":"Cancer is a multifaceted disease in which inherited genetic variants can be important drivers of tumorigenesis. The discovery that germline mutations of metabolic genes predispose to familial forms of cancer caused a shift in our understanding of how metabolism contributes to tumorigenesis, providing evidence that metabolic alterations can be oncogenic. In this review, we focus on mitochondrial enzymes whose mutations predispose to familial cancer, and we fully appraise their involvement in cancer formation and progression. Elucidating the molecular mechanisms that orchestrate transformation in these diverse tumors may answer key biological questions about tumor formation and evolution, leading to the identification of new therapeutic targets of intervention.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2020-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/annurev-cancerbio-030419-033612","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43463458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-09DOI: 10.1146/annurev-cancerbio-030419-033333
Allison N. Lau, M. V. Heiden
Experiments in culture systems where one cell type is provided with abundant nutrients and oxygen have been used to inform much of our understanding of cancer metabolism. However, many differences have been observed between the metabolism of tumors and the metabolism of cancer cells grown in monoculture. These differences reflect, at least in part, the presence of nonmalignant cells in the tumor microenvironment and the interactions between those cells and cancer cells. However, less is known about how the metabolism of various tumor stromal cell types differs from that of cancer cells, and how this difference might inform therapeutic targeting of metabolic pathways. Emerging data have identified both cooperative and competitive relationships between different cell types in a tumor, and this review examines how four abundant stromal cell types in the tumor microenvironment, fibroblasts, T cells, macrophages, and endothelial cells, contribute to the metabolism of tumors.
{"title":"Metabolism in the Tumor Microenvironment","authors":"Allison N. Lau, M. V. Heiden","doi":"10.1146/annurev-cancerbio-030419-033333","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-030419-033333","url":null,"abstract":"Experiments in culture systems where one cell type is provided with abundant nutrients and oxygen have been used to inform much of our understanding of cancer metabolism. However, many differences have been observed between the metabolism of tumors and the metabolism of cancer cells grown in monoculture. These differences reflect, at least in part, the presence of nonmalignant cells in the tumor microenvironment and the interactions between those cells and cancer cells. However, less is known about how the metabolism of various tumor stromal cell types differs from that of cancer cells, and how this difference might inform therapeutic targeting of metabolic pathways. Emerging data have identified both cooperative and competitive relationships between different cell types in a tumor, and this review examines how four abundant stromal cell types in the tumor microenvironment, fibroblasts, T cells, macrophages, and endothelial cells, contribute to the metabolism of tumors.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2020-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/annurev-cancerbio-030419-033333","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43044355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-09DOI: 10.1146/annurev-cancerbio-030419-033525
Charles A. Ishak, D. D. Carvalho
Domesticated retroelements contribute extensively as regulatory elements within host gene networks. Upon germline integration, retroelement mobilization is restricted through epigenetic silencing, mutational degradation, and innate immune defenses described as the viral mimicry response. Recent discoveries reveal how early events in tumorigenesis reactivate retroelements to facilitate onco-exaptation, replication stress, retrotransposition, mitotic errors, and sterile inflammation, which collectively disrupt genome integrity. The characterization of altered epigenetic homeostasis at retroelements in cancer cells also reveals new epigenetic targets whose inactivation can bolster responses to cancer therapies. Recent discoveries reviewed here frame reactivated retroelements as both drivers of tumorigenesis and therapy responses, where their reactivation by emerging epigenetic therapies can potentiate immune checkpoint blockade, cancer vaccines, and other standard therapies.
{"title":"Reactivation of Endogenous Retroelements in Cancer Development and Therapy","authors":"Charles A. Ishak, D. D. Carvalho","doi":"10.1146/annurev-cancerbio-030419-033525","DOIUrl":"https://doi.org/10.1146/annurev-cancerbio-030419-033525","url":null,"abstract":"Domesticated retroelements contribute extensively as regulatory elements within host gene networks. Upon germline integration, retroelement mobilization is restricted through epigenetic silencing, mutational degradation, and innate immune defenses described as the viral mimicry response. Recent discoveries reveal how early events in tumorigenesis reactivate retroelements to facilitate onco-exaptation, replication stress, retrotransposition, mitotic errors, and sterile inflammation, which collectively disrupt genome integrity. The characterization of altered epigenetic homeostasis at retroelements in cancer cells also reveals new epigenetic targets whose inactivation can bolster responses to cancer therapies. Recent discoveries reviewed here frame reactivated retroelements as both drivers of tumorigenesis and therapy responses, where their reactivation by emerging epigenetic therapies can potentiate immune checkpoint blockade, cancer vaccines, and other standard therapies.","PeriodicalId":54233,"journal":{"name":"Annual Review of Cancer Biology-Series","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2020-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1146/annurev-cancerbio-030419-033525","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41915754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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