Pub Date : 2024-12-13DOI: 10.1016/j.semcancer.2024.11.004
Minling Gao, Haiou Li, Jinfang Zhang
The Retinoblastoma (RB) protein is crucial for regulating gene transcription and chromatin remodeling, impacting cell cycle progression, cellular senescence, and tumorigenesis. Cellular senescence, characterized by irreversible growth arrest and phenotypic alterations, serves as a vital barrier against tumor progression and age-related diseases. RB is crucial in mediating senescence and tumor suppression by modulating the RB-E2F pathway and cross talking with other key senescence effectors such as p53 and p16INK4a. The interplay between RB-mediated cell cycle arrest and cellular senescence offers critical insights into tumorigenesis and potential therapeutic strategies. Leveraging RB-mediated senescence presents promising opportunities for cancer therapy, including novel approaches in tumor immunotherapy designed to enhance treatment efficacy. This review highlights recent advancements in the RB signaling pathway, focusing on its roles in cellular senescence and tumor suppression, and discusses its potential to improve tumor management and clinical outcomes.
{"title":"RB functions as a key regulator of senescence and tumor suppression.","authors":"Minling Gao, Haiou Li, Jinfang Zhang","doi":"10.1016/j.semcancer.2024.11.004","DOIUrl":"10.1016/j.semcancer.2024.11.004","url":null,"abstract":"<p><p>The Retinoblastoma (RB) protein is crucial for regulating gene transcription and chromatin remodeling, impacting cell cycle progression, cellular senescence, and tumorigenesis. Cellular senescence, characterized by irreversible growth arrest and phenotypic alterations, serves as a vital barrier against tumor progression and age-related diseases. RB is crucial in mediating senescence and tumor suppression by modulating the RB-E2F pathway and cross talking with other key senescence effectors such as p53 and p16<sup>INK4a</sup>. The interplay between RB-mediated cell cycle arrest and cellular senescence offers critical insights into tumorigenesis and potential therapeutic strategies. Leveraging RB-mediated senescence presents promising opportunities for cancer therapy, including novel approaches in tumor immunotherapy designed to enhance treatment efficacy. This review highlights recent advancements in the RB signaling pathway, focusing on its roles in cellular senescence and tumor suppression, and discusses its potential to improve tumor management and clinical outcomes.</p>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":" ","pages":"1-7"},"PeriodicalIF":12.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-23DOI: 10.1016/j.semcancer.2024.11.002
Yijiang He , Yue Qiu , Xiansong Yang , Guimei Lu , Shan-Shan Zhao
Cellular senescence is a response to various stress signals, which is characterized by stable cell cycle arrest, alterations in cellular morphology, metabolic reprogramming and production of senescence-associated secretory phenotype (SASP). When it occurs in the immune system, it is called immunosenescence. Cervical cancer is a common gynecological malignancy, and cervical cancer screening is generally recommended before the age of 65. Elderly women (≥65 years) are more often diagnosed with advanced disease and have poorer prognosis compared to younger patients. Despite extensive research, the tumor microenvironment requires more in-depth exploration, particularly in elderly patients. In cervical cancer, senescent cells have a double-edged sword effect on tumor progression. Induction of preneoplastic cell senescence prevents tumor initiation, and several treatment approaches of cervical cancer act in part by inducing cancer cell senescence. However, senescent immune cell populations within the tumor microenvironment facilitate tumor development, recurrence, treatment resistance, etc. Amplification of beneficial effects and inhibition of aging-related pro-tumorigenic pathways contribute to improving antitumor effects. This review discusses senescent cancer and immune cells present in the tumor microenvironment of cervical cancer and how these senescent cells and their SASP remodel the tumor microenvironment, influence antitumor immunity and tumor initiation and development. Moreover, we discuss the significance of senotherapeutics that enable to eliminate senescent cells and prevent tumor progression and development through improving antitumor immunity and affecting the tumor microenvironment.
{"title":"Remodeling of tumor microenvironment by cellular senescence and immunosenescence in cervical cancer","authors":"Yijiang He , Yue Qiu , Xiansong Yang , Guimei Lu , Shan-Shan Zhao","doi":"10.1016/j.semcancer.2024.11.002","DOIUrl":"10.1016/j.semcancer.2024.11.002","url":null,"abstract":"<div><div>Cellular senescence is a response to various stress signals, which is characterized by stable cell cycle arrest, alterations in cellular morphology, metabolic reprogramming and production of senescence-associated secretory phenotype (SASP). When it occurs in the immune system, it is called immunosenescence. Cervical cancer is a common gynecological malignancy, and cervical cancer screening is generally recommended before the age of 65. Elderly women (≥65 years) are more often diagnosed with advanced disease and have poorer prognosis compared to younger patients. Despite extensive research, the tumor microenvironment requires more in-depth exploration, particularly in elderly patients. In cervical cancer, senescent cells have a double-edged sword effect on tumor progression. Induction of preneoplastic cell senescence prevents tumor initiation, and several treatment approaches of cervical cancer act in part by inducing cancer cell senescence. However, senescent immune cell populations within the tumor microenvironment facilitate tumor development, recurrence, treatment resistance, etc. Amplification of beneficial effects and inhibition of aging-related pro-tumorigenic pathways contribute to improving antitumor effects. This review discusses senescent cancer and immune cells present in the tumor microenvironment of cervical cancer and how these senescent cells and their SASP remodel the tumor microenvironment, influence antitumor immunity and tumor initiation and development. Moreover, we discuss the significance of senotherapeutics that enable to eliminate senescent cells and prevent tumor progression and development through improving antitumor immunity and affecting the tumor microenvironment.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"108 ","pages":"Pages 17-32"},"PeriodicalIF":12.1,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142704851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cellular senescence is a state of permanent proliferative arrest that occurs in response to DNA damage-inducing endogenous and exogenous stresses, and is often accompanied by dynamic molecular changes such as a senescence-associated secretory phenotype (SASP). Accumulating evidence indicates that age-associated increases in the upstream and downstream signals of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, are closely related to the induction of cellular senescence and its phenotype. Furthermore, elevated levels of pro-inflammatory SASP factors with aging can be both a cause and consequence of several cell death modes, suggesting the reciprocal effects of cellular senescence and cells undergoing regulated cell death. Here, we review the critical molecular pathways of the regulated cell death forms and describe the crosstalk between aging-related signals and cancer. In addition, we discuss how targeting regulated cell death could be harnessed in therapeutic interventions for cancer.
Abbreviations
Abbreviations that are not standard in this field are defined at their first occurrence in the article and are used consistently throughout the article.
细胞衰老是一种永久性增殖停滞状态，是对 DNA 损伤诱导的内源性和外源性压力的反应，通常伴随着动态分子变化，如衰老相关分泌表型（SASP）。越来越多的证据表明，与年龄相关的细胞死亡调控上游和下游信号（包括细胞凋亡、坏死、热凋亡和铁凋亡）的增加与细胞衰老及其表型的诱导密切相关。此外，随着衰老而升高的促炎 SASP 因子既可能是多种细胞死亡模式的原因，也可能是其结果，这表明细胞衰老和细胞发生调控性细胞死亡之间存在相互影响。在此，我们回顾了调节性细胞死亡形式的关键分子通路，并描述了衰老相关信号与癌症之间的相互影响。此外，我们还讨论了如何利用调节性细胞死亡进行癌症治疗干预。缩略语：非本领域标准缩写在文章中首次出现时定义，并在全文中统一使用。
{"title":"The interplay between cell death and senescence in cancer","authors":"Kouhei Shimizu , Hiroyuki Inuzuka , Fuminori Tokunaga","doi":"10.1016/j.semcancer.2024.11.001","DOIUrl":"10.1016/j.semcancer.2024.11.001","url":null,"abstract":"<div><div>Cellular senescence is a state of permanent proliferative arrest that occurs in response to DNA damage-inducing endogenous and exogenous stresses, and is often accompanied by dynamic molecular changes such as a senescence-associated secretory phenotype (SASP). Accumulating evidence indicates that age-associated increases in the upstream and downstream signals of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, are closely related to the induction of cellular senescence and its phenotype. Furthermore, elevated levels of pro-inflammatory SASP factors with aging can be both a cause and consequence of several cell death modes, suggesting the reciprocal effects of cellular senescence and cells undergoing regulated cell death. Here, we review the critical molecular pathways of the regulated cell death forms and describe the crosstalk between aging-related signals and cancer. In addition, we discuss how targeting regulated cell death could be harnessed in therapeutic interventions for cancer.</div></div><div><h3>Abbreviations</h3><div>Abbreviations that are not standard in this field are defined at their first occurrence in the article and are used consistently throughout the article.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"108 ","pages":"Pages 1-16"},"PeriodicalIF":12.1,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.semcancer.2024.10.004
Li Liu , Wentao Yao , Mi Wang , Baohui Wang , Fanming Kong , Zhongguo Fan , Guanwei Fan
Immunotherapy has revolutionized the management of various types of cancers, even those previously deemed untreatable. Nonetheless, these medications have been associated with inflammation and damage across various organs. These challenges are exemplified by the adverse cardiovascular impacts of cancer immunotherapy, which need comprehensive understanding, clarification, and management integrated into the overall care of cancer patients. Numerous anticancer immunotherapies have been linked to the prevalence and severity of cardiovascular toxicity. These challenges emphasize the importance of conducting fundamental and applied research to elucidate disease causes, discover prognostic indicators, enhance diagnostic methods, and create successful therapies. Despite the acknowledged importance of T cells, there remains a knowledge gap regarding the inciting antigens, the reasons for their recognition, and the mechanisms of how they contribute to cardiac cell injury. In this review, we summarize the molecular mechanism, epidemiology, diagnosis, pathophysiology and corresponding treatment of cardiovascular toxicity induced by immunotherapy, including immune checkpoint inhibitors (ICIs), adoptive cell therapies (ACT), and bi-specific T-cell engagers (BiTEs) among others. By elucidating these aspects, we aim to provide a better understanding of immunotherapies in cancer treatment and offer guidance for their clinical application.
免疫疗法彻底改变了各种癌症的治疗，甚至包括以前被认为无法治疗的癌症。然而，这些药物也与各种器官的炎症和损伤有关。癌症免疫疗法对心血管的不良影响就是这些挑战的例证，需要对其进行全面的了解、澄清和管理，并将其纳入癌症患者的整体护理中。许多抗癌免疫疗法都与心血管毒性的发生率和严重程度有关。这些挑战强调了开展基础研究和应用研究的重要性，以阐明疾病原因、发现预后指标、改进诊断方法并创造成功的疗法。尽管 T 细胞的重要性已得到公认，但在诱发抗原、识别 T 细胞的原因以及 T 细胞导致心脏细胞损伤的机制等方面仍存在知识空白。在这篇综述中，我们总结了免疫疗法诱发心血管毒性的分子机制、流行病学、诊断、病理生理学和相应的治疗方法，包括免疫检查点抑制剂（ICIs）、采纳性细胞疗法（ACT）和双特异性 T 细胞诱导剂（BiTEs）等。通过阐明这些方面，我们希望更好地了解癌症治疗中的免疫疗法，并为其临床应用提供指导。
{"title":"A systematic review of cardiovascular toxicities induced by cancer immune therapies: Underlying mechanisms, clinical manifestations and therapeutic approaches","authors":"Li Liu , Wentao Yao , Mi Wang , Baohui Wang , Fanming Kong , Zhongguo Fan , Guanwei Fan","doi":"10.1016/j.semcancer.2024.10.004","DOIUrl":"10.1016/j.semcancer.2024.10.004","url":null,"abstract":"<div><div>Immunotherapy has revolutionized the management of various types of cancers, even those previously deemed untreatable. Nonetheless, these medications have been associated with inflammation and damage across various organs. These challenges are exemplified by the adverse cardiovascular impacts of cancer immunotherapy, which need comprehensive understanding, clarification, and management integrated into the overall care of cancer patients. Numerous anticancer immunotherapies have been linked to the prevalence and severity of cardiovascular toxicity. These challenges emphasize the importance of conducting fundamental and applied research to elucidate disease causes, discover prognostic indicators, enhance diagnostic methods, and create successful therapies. Despite the acknowledged importance of T cells, there remains a knowledge gap regarding the inciting antigens, the reasons for their recognition, and the mechanisms of how they contribute to cardiac cell injury. In this review, we summarize the molecular mechanism, epidemiology, diagnosis, pathophysiology and corresponding treatment of cardiovascular toxicity induced by immunotherapy, including immune checkpoint inhibitors (ICIs), adoptive cell therapies (ACT), and bi-specific T-cell engagers (BiTEs) among others. By elucidating these aspects, we aim to provide a better understanding of immunotherapies in cancer treatment and offer guidance for their clinical application.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"106 ","pages":"Pages 179-191"},"PeriodicalIF":12.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142507078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis and rising global deaths. Late diagnosis, due to absent early symptoms and biomarkers, limits treatment mainly to chemotherapy, which soon encounters resistance. PDAC treatment innovation is hampered by its complex and heterogeneous resistant nature, including mutations in key genes and a stromal-rich, immunosuppressive tumour microenvironment. Recent studies on PDAC resistance stress the need for suitable in vitro and ex vivo models to replicate its complex molecular and microenvironmental landscape. This review summarises advances in these models, which can aid in combating chemoresistance and serve as platforms for discovering new therapeutics. Immortalised cell lines offer homogeneity, unlimited proliferation, and reproducibility, but while many gemcitabine-resistant PDAC cell lines exist, fewer models are available for resistance to other drugs. Organoids from PDAC patients show promise in mimicking tumour heterogeneity and chemosensitivity. Bioreactors, co-culture systems and organotypic slices, incorporating stromal and immune cells, are being developed to understand tumour-stroma interactions and the tumour microenvironment's role in drug resistance. Lastly, another innovative approach is three-dimensional bioprinting, which creates tissue-like structures resembling PDAC architecture, allowing for drug screening. These advanced models can guide researchers in selecting optimal in vitro tests, potentially improving therapeutic strategies and patient outcomes.
{"title":"Unravelling the complexities of resistance mechanism in pancreatic cancer: Insights from in vitro and ex-vivo model systems","authors":"Giulia Lencioni , Alessandro Gregori , Belén Toledo , Rita Rebelo , Benoît Immordino , Manoj Amrutkar , Cristina P.R. Xavier , Anja Kocijančič , Deo Prakash Pandey , Macarena Perán , Justo P. Castaño , Naomi Walsh , Elisa Giovannetti","doi":"10.1016/j.semcancer.2024.09.002","DOIUrl":"10.1016/j.semcancer.2024.09.002","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis and rising global deaths. Late diagnosis, due to absent early symptoms and biomarkers, limits treatment mainly to chemotherapy, which soon encounters resistance. PDAC treatment innovation is hampered by its complex and heterogeneous resistant nature, including mutations in key genes and a stromal-rich, immunosuppressive tumour microenvironment. Recent studies on PDAC resistance stress the need for suitable in vitro and ex vivo models to replicate its complex molecular and microenvironmental landscape. This review summarises advances in these models, which can aid in combating chemoresistance and serve as platforms for discovering new therapeutics. Immortalised cell lines offer homogeneity, unlimited proliferation, and reproducibility, but while many gemcitabine-resistant PDAC cell lines exist, fewer models are available for resistance to other drugs. Organoids from PDAC patients show promise in mimicking tumour heterogeneity and chemosensitivity. Bioreactors, co-culture systems and organotypic slices, incorporating stromal and immune cells, are being developed to understand tumour-stroma interactions and the tumour microenvironment's role in drug resistance. Lastly, another innovative approach is three-dimensional bioprinting, which creates tissue-like structures resembling PDAC architecture, allowing for drug screening. These advanced models can guide researchers in selecting optimal in vitro tests, potentially improving therapeutic strategies and patient outcomes.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"106 ","pages":"Pages 217-233"},"PeriodicalIF":12.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.semcancer.2024.10.006
Junyan Zhang , Xiaojiao Guan , Xinwen Zhong
Increasing lifespans and external environmental factors have contributed to the increase of age-related diseases, particularly cancer. A decrease in immune surveillance and clearance of cancer cells is the result of immunosenescence, which involves the remodeling of immune organs, the changes and functional decline of immune cell subsets, in association with systemic low-grade chronic inflammation. Stem cells aging in bone marrow and thymic involution are the most important causes of immunosenescence. Senescent cancer cells promote the differentiation, recruitment, and functional upregulation of immune-suppressive cell subsets e.g. regulatory T cells (Tregs), myeloid-derived suppressor cell (MDSC), tumor-associated macrophages (TAMS) through senescence-associated secretory phenotype (SASP) further exacerbating the immunosuppressive microenvironment. For digestive system cancers, age-related damage to the intestinal mucosal barrier, the aging of gut-associated lymphoid tissue (GALT), exposure to xenobiotic stimuli throughout life, and dysbiosis make the local immune microenvironment more vulnerable. This article systematically reviews the research progress of immunosenescence and immune microenvironment in digestive system cancers, as well as the exploration of related therapy strategies, hoping to point out new directions for research in the digestive system cancers.
寿命的延长和外部环境因素导致与年龄有关的疾病，特别是癌症的增加。免疫衰老是免疫监视和清除癌细胞能力下降的结果，包括免疫器官的重塑、免疫细胞亚群的变化和功能衰退，以及全身性低度慢性炎症。骨髓中的干细胞衰老和胸腺内陷是免疫衰老的最重要原因。衰老的癌细胞通过衰老相关分泌表型（SASP）促进免疫抑制细胞亚群（如调节性 T 细胞（Tregs）、髓源抑制细胞（MDSC）、肿瘤相关巨噬细胞（TAMS））的分化、招募和功能上调，进一步加剧了免疫抑制微环境。对于消化系统癌症而言，与年龄相关的肠粘膜屏障损伤、肠道相关淋巴组织（GALT）的衰老、终生暴露于异物刺激以及菌群失调都会使局部免疫微环境变得更加脆弱。本文系统回顾了消化系统癌症中免疫衰老和免疫微环境的研究进展，以及相关治疗策略的探索，希望能为消化系统癌症的研究指明新的方向。
{"title":"Immunosenescence in digestive system cancers: Mechanisms, research advances, and therapeutic strategies","authors":"Junyan Zhang , Xiaojiao Guan , Xinwen Zhong","doi":"10.1016/j.semcancer.2024.10.006","DOIUrl":"10.1016/j.semcancer.2024.10.006","url":null,"abstract":"<div><div>Increasing lifespans and external environmental factors have contributed to the increase of age-related diseases, particularly cancer. A decrease in immune surveillance and clearance of cancer cells is the result of immunosenescence, which involves the remodeling of immune organs, the changes and functional decline of immune cell subsets, in association with systemic low-grade chronic inflammation. Stem cells aging in bone marrow and thymic involution are the most important causes of immunosenescence. Senescent cancer cells promote the differentiation, recruitment, and functional upregulation of immune-suppressive cell subsets e.g. regulatory T cells (Tregs), myeloid-derived suppressor cell (MDSC), tumor-associated macrophages (TAMS) through senescence-associated secretory phenotype (SASP) further exacerbating the immunosuppressive microenvironment. For digestive system cancers, age-related damage to the intestinal mucosal barrier, the aging of gut-associated lymphoid tissue (GALT), exposure to xenobiotic stimuli throughout life, and dysbiosis make the local immune microenvironment more vulnerable. This article systematically reviews the research progress of immunosenescence and immune microenvironment in digestive system cancers, as well as the exploration of related therapy strategies, hoping to point out new directions for research in the digestive system cancers.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"106 ","pages":"Pages 234-250"},"PeriodicalIF":12.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.semcancer.2024.10.005
Renju Pun , Niti Kumari , Rodaina Hazem Monieb, Sachin Wagh, Brian J. North
Aging is a significant risk factor for cancer which is due, in part, to heightened genomic instability. Mitotic surveillance proteins such as BubR1 play a pivotal role in ensuring accurate chromosomal segregation and preventing aneuploidy. BubR1 levels have been shown to naturally decline with age and its loss is associated with various age-related pathologies. Sirtuins, a class of NAD+-dependent deacylases, are implicated in cancer and genomic instability. Among them, SIRT2 acts as an upstream regulator of BubR1, offering a critical pathway that can potentially mitigate age-related diseases, including cancer. In this review, we explore BubR1 as a key regulator of cellular processes crucial for aging-related phenotypes. We delve into the intricate mechanisms through which BubR1 influences genomic stability and cellular senescence. Moreover, we highlight the role of NAD+ and SIRT2 in modulating BubR1 expression and function, emphasizing its potential as a therapeutic target. The interaction between BubR1 and SIRT2 not only serves as a fundamental regulatory pathway in cellular homeostasis but also represents a promising avenue for developing targeted therapies against age-related diseases, particularly cancer.
{"title":"BubR1 and SIRT2: Insights into aneuploidy, aging, and cancer","authors":"Renju Pun , Niti Kumari , Rodaina Hazem Monieb, Sachin Wagh, Brian J. North","doi":"10.1016/j.semcancer.2024.10.005","DOIUrl":"10.1016/j.semcancer.2024.10.005","url":null,"abstract":"<div><div>Aging is a significant risk factor for cancer which is due, in part, to heightened genomic instability. Mitotic surveillance proteins such as BubR1 play a pivotal role in ensuring accurate chromosomal segregation and preventing aneuploidy. BubR1 levels have been shown to naturally decline with age and its loss is associated with various age-related pathologies. Sirtuins, a class of NAD<sup>+</sup>-dependent deacylases, are implicated in cancer and genomic instability. Among them, SIRT2 acts as an upstream regulator of BubR1, offering a critical pathway that can potentially mitigate age-related diseases, including cancer. In this review, we explore BubR1 as a key regulator of cellular processes crucial for aging-related phenotypes. We delve into the intricate mechanisms through which BubR1 influences genomic stability and cellular senescence. Moreover, we highlight the role of NAD<sup>+</sup> and SIRT2 in modulating BubR1 expression and function, emphasizing its potential as a therapeutic target. The interaction between BubR1 and SIRT2 not only serves as a fundamental regulatory pathway in cellular homeostasis but also represents a promising avenue for developing targeted therapies against age-related diseases, particularly cancer.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"106 ","pages":"Pages 201-216"},"PeriodicalIF":12.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.semcancer.2024.10.002
Jin Young Lee , Tien Peng
Aging is associated with stereotyped changes in the tissue microenvironment that increase susceptibility to diseases of the elderly, including organ fibrosis and cancer. From a tissue perspective, fibrosis and cancer can both be viewed as non-healing wounds with pathogenic activation of tissue repair pathways in the stroma. If fibrosis and cancer represent an example of the convergent evolution of maladaptive stromal responses in distinct pathologies, what are the analogous cell types that might emerge in both diseases that share similarities in identity and function? In this review, we explore how senescent fibroblasts form a nexus that connects the aging organ with both fibrosis and cancer. The advent of single cell sequencing, coupled with improved detection of cell types with senescent traits in vivo, have allowed us to identify senescent fibroblasts with similar identities in both fibrosis and cancer that share pro-fibrotic programs. In addition to their ability to reorganize the extracellular matrix in diseased states, these pro-fibrotic senescent fibroblasts can also promote epithelial reprogramming and immune rewiring, which drive disease progression in fibrosis and cancer. Finally, the identification of common pathogenic cell types in fibrosis and cancer also presents a therapeutic opportunity to target both diseases with a shared approach.
{"title":"Convergent evolution of senescent fibroblasts in fibrosis and cancer with aging","authors":"Jin Young Lee , Tien Peng","doi":"10.1016/j.semcancer.2024.10.002","DOIUrl":"10.1016/j.semcancer.2024.10.002","url":null,"abstract":"<div><div>Aging is associated with stereotyped changes in the tissue microenvironment that increase susceptibility to diseases of the elderly, including organ fibrosis and cancer. From a tissue perspective, fibrosis and cancer can both be viewed as non-healing wounds with pathogenic activation of tissue repair pathways in the stroma. If fibrosis and cancer represent an example of the convergent evolution of maladaptive stromal responses in distinct pathologies, what are the analogous cell types that might emerge in both diseases that share similarities in identity and function? In this review, we explore how senescent fibroblasts form a nexus that connects the aging organ with both fibrosis and cancer. The advent of single cell sequencing, coupled with improved detection of cell types with senescent traits in vivo, have allowed us to identify senescent fibroblasts with similar identities in both fibrosis and cancer that share pro-fibrotic programs. In addition to their ability to reorganize the extracellular matrix in diseased states, these pro-fibrotic senescent fibroblasts can also promote epithelial reprogramming and immune rewiring, which drive disease progression in fibrosis and cancer. Finally, the identification of common pathogenic cell types in fibrosis and cancer also presents a therapeutic opportunity to target both diseases with a shared approach.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"106 ","pages":"Pages 192-200"},"PeriodicalIF":12.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1016/j.semcancer.2024.10.001
Sergio Rey-Keim , Luana Schito
Hypoxia (insufficient O2) is a pivotal factor in cancer progression, triggering genetic, transcriptional, translational and epigenetic adaptations associated to therapy resistance, metastasis and patient mortality. In this review, we outline the microenvironmental origins and molecular mechanisms responsible for hypoxic cancer cell adaptations in situ and in vitro, whilst outlining current approaches to stratify, quantify and therapeutically target hypoxia in the context of precision oncology.
{"title":"Origins and molecular effects of hypoxia in cancer","authors":"Sergio Rey-Keim , Luana Schito","doi":"10.1016/j.semcancer.2024.10.001","DOIUrl":"10.1016/j.semcancer.2024.10.001","url":null,"abstract":"<div><div>Hypoxia (insufficient O<sub>2</sub>) is a pivotal factor in cancer progression, triggering genetic, transcriptional, translational and epigenetic adaptations associated to therapy resistance, metastasis and patient mortality. In this review, we outline the microenvironmental origins and molecular mechanisms responsible for hypoxic cancer cell adaptations <em>in situ</em> and <em>in vitro</em>, whilst outlining current approaches to stratify, quantify and therapeutically target hypoxia in the context of precision oncology.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"106 ","pages":"Pages 166-178"},"PeriodicalIF":12.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-16DOI: 10.1016/j.semcancer.2024.10.003
Yao Wang , Xinran Cao , Chunbaixue Yang , Jianchun Fan , Xingmei Zhang , Xueliang Wu , Wei Guo , Shoutian Sun , Ming Liu , Lifen Zhang , Tian Li
Colorectal cancer (CRC), ranked as the globe’s third leading malignancy. Despite advancements in therapeutic approaches, the mortality rate remains distressingly high for those afflicted with advanced stages of the disease. Ferroptosis is a programmed form of cell death. The ways of ferroptosis mainly include promoting the accumulation of cellular ROS and increasing the level of cellular Labile iron pool (LIP). Immunosenescence is characterized by a gradual deterioration of the immune system’s ability to respond to pathogens and maintain surveillance against cancer cells. In CRC, this decline is exacerbated by the tumor microenvironment, which can suppress the immune response and promote tumor progression. This paper reviews the relationship between iron prolapse and immune senescence in colorectal cancer, focusing on the following aspects: firstly, the different pathways that induce iron prolapse in colorectal cancer; secondly, immune-immune senescence in colorectal cancer; and lastly, the interactions between immune senescence and iron prolapse in colorectal cancer, e.g., immune-immune senescent cells often exhibit increased oxidative stress, leading to the accumulation of ROS, and consequently to lipid peroxidation and induction of iron-induced cell death. At the same time, ferroptosis induces immune cell senescence as well as alterations in the immune microenvironment by promoting the death of damaged or diseased cells and leading to the inflammation usually associated with it. In conclusion, by exploring the potential targets of ferroptosis and immune senescence in colorectal cancer therapy, we hope to provide a reference for future research.
{"title":"Ferroptosis and immunosenescence in colorectal cancer","authors":"Yao Wang , Xinran Cao , Chunbaixue Yang , Jianchun Fan , Xingmei Zhang , Xueliang Wu , Wei Guo , Shoutian Sun , Ming Liu , Lifen Zhang , Tian Li","doi":"10.1016/j.semcancer.2024.10.003","DOIUrl":"10.1016/j.semcancer.2024.10.003","url":null,"abstract":"<div><div>Colorectal cancer (CRC), ranked as the globe’s third leading malignancy. Despite advancements in therapeutic approaches, the mortality rate remains distressingly high for those afflicted with advanced stages of the disease. Ferroptosis is a programmed form of cell death. The ways of ferroptosis mainly include promoting the accumulation of cellular ROS and increasing the level of cellular Labile iron pool (LIP). Immunosenescence is characterized by a gradual deterioration of the immune system’s ability to respond to pathogens and maintain surveillance against cancer cells. In CRC, this decline is exacerbated by the tumor microenvironment, which can suppress the immune response and promote tumor progression. This paper reviews the relationship between iron prolapse and immune senescence in colorectal cancer, focusing on the following aspects: firstly, the different pathways that induce iron prolapse in colorectal cancer; secondly, immune-immune senescence in colorectal cancer; and lastly, the interactions between immune senescence and iron prolapse in colorectal cancer, e.g., immune-immune senescent cells often exhibit increased oxidative stress, leading to the accumulation of ROS, and consequently to lipid peroxidation and induction of iron-induced cell death. At the same time, ferroptosis induces immune cell senescence as well as alterations in the immune microenvironment by promoting the death of damaged or diseased cells and leading to the inflammation usually associated with it. In conclusion, by exploring the potential targets of ferroptosis and immune senescence in colorectal cancer therapy, we hope to provide a reference for future research.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"106 ","pages":"Pages 156-165"},"PeriodicalIF":12.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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