Pub Date : 2025-08-01Epub Date: 2025-05-11DOI: 10.1016/j.semcancer.2025.05.008
Kenneth K.W. To , Seda S. Tolu , Longling Wang , Hang Zhang , William C. Cho , Susan E. Bates
Histone deacetylase inhibitors (HDACIs) are epigenetic drugs that regulate the acetylation status of histones and non-histone proteins, thereby leading to chromatin remodeling and transcriptional regulation of key apoptotic and cell cycle regulatory genes. There are currently five HDACIs clinically approved by the major regulatory authorities for treating hematological cancers, primarily as monotherapy. While HDACIs have been particularly effective in T-cell lymphomas, their clinical efficacies have not yet extended to solid tumors. The development of HDACIs continues, including for the treatment of a non-malignant conditions, with givinostat recently approved by the US FDA. However, the early development of HDACIs was limited by concerns about cardiotoxicity including QT interval prolongation. Yet, paradoxically, the latest research suggests some cardioprotective effect of HDACIs in ischemic heart disease or heart failure. This review presents the latest update about the cardiotoxicity of the clinically approved HDACIs. The mechanisms leading to HDACI-induced cardiotoxic adverse events and clinical strategies for their management are discussed. We will also deliberate the potential repurposing use of HDACIs and their HDAC isoform selectivity for treating ischemia-reperfusion cardiac muscle injury, cardiac hypertrophy, and fibrosis.
{"title":"HDAC inhibitors: Cardiotoxicity and paradoxical cardioprotective effect in ischemia-reperfusion myocardiocyte injury","authors":"Kenneth K.W. To , Seda S. Tolu , Longling Wang , Hang Zhang , William C. Cho , Susan E. Bates","doi":"10.1016/j.semcancer.2025.05.008","DOIUrl":"10.1016/j.semcancer.2025.05.008","url":null,"abstract":"<div><div>Histone deacetylase inhibitors (HDACIs) are epigenetic drugs that regulate the acetylation status of histones and non-histone proteins, thereby leading to chromatin remodeling and transcriptional regulation of key apoptotic and cell cycle regulatory genes. There are currently five HDACIs clinically approved by the major regulatory authorities for treating hematological cancers, primarily as monotherapy. While HDACIs have been particularly effective in T-cell lymphomas, their clinical efficacies have not yet extended to solid tumors. The development of HDACIs continues, including for the treatment of a non-malignant conditions, with givinostat recently approved by the US FDA. However, the early development of HDACIs was limited by concerns about cardiotoxicity including QT interval prolongation. Yet, paradoxically, the latest research suggests some cardioprotective effect of HDACIs in ischemic heart disease or heart failure. This review presents the latest update about the cardiotoxicity of the clinically approved HDACIs. The mechanisms leading to HDACI-induced cardiotoxic adverse events and clinical strategies for their management are discussed. We will also deliberate the potential repurposing use of HDACIs and their HDAC isoform selectivity for treating ischemia-reperfusion cardiac muscle injury, cardiac hypertrophy, and fibrosis.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"113 ","pages":"Pages 25-38"},"PeriodicalIF":12.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941863","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 : 2025-08-01Epub Date: 2025-05-15DOI: 10.1016/j.semcancer.2025.05.010
Jia Cheng , Jian Zheng , Chen Ma , Yongzhang Li , Hua Hao
Immunosenescence is the dysfunction of the immune system that occurs with age, a process that is complex and characterized by several features, of which T-cell senescence is one of the key manifestations. In the tumor microenvironment, senescent T cells lead to the inability of tumor cells to be effectively eliminated, triggering immunosuppression, which in turn affects the efficacy of immunotherapy. This is a strong indication that T-cell senescence significantly weakens the immune function of the body, making individuals, especially elderly patients with cancer, more vulnerable to cancer attacks. Despite the many challenges, T-cell senescence is important as a potential therapeutic target. This review provides insights into the molecular mechanisms of T-cell senescence and its research advances in patients with cancer, especially in older adults, and systematically analyzes potential intervention strategies, including molecular mechanism-based interventions, the use of immune checkpoint inhibitors, and CAR-T cell therapy. It is hoped that this will establish a theoretical framework for T-cell senescence in the field of tumor immunology and provide a scientific and prospective reference basis for subsequent in-depth research and clinical practice on senescent T cells.
{"title":"T-cell senescence: Unlocking the tumor immune “Dark Box” - A multidimensional analysis from mechanism to tumor immunotherapeutic intervention","authors":"Jia Cheng , Jian Zheng , Chen Ma , Yongzhang Li , Hua Hao","doi":"10.1016/j.semcancer.2025.05.010","DOIUrl":"10.1016/j.semcancer.2025.05.010","url":null,"abstract":"<div><div>Immunosenescence is the dysfunction of the immune system that occurs with age, a process that is complex and characterized by several features, of which T-cell senescence is one of the key manifestations. In the tumor microenvironment, senescent T cells lead to the inability of tumor cells to be effectively eliminated, triggering immunosuppression, which in turn affects the efficacy of immunotherapy. This is a strong indication that T-cell senescence significantly weakens the immune function of the body, making individuals, especially elderly patients with cancer, more vulnerable to cancer attacks. Despite the many challenges, T-cell senescence is important as a potential therapeutic target. This review provides insights into the molecular mechanisms of T-cell senescence and its research advances in patients with cancer, especially in older adults, and systematically analyzes potential intervention strategies, including molecular mechanism-based interventions, the use of immune checkpoint inhibitors, and CAR-T cell therapy. It is hoped that this will establish a theoretical framework for T-cell senescence in the field of tumor immunology and provide a scientific and prospective reference basis for subsequent in-depth research and clinical practice on senescent T cells.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"113 ","pages":"Pages 190-209"},"PeriodicalIF":12.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094694","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 : 2025-07-01Epub Date: 2025-03-28DOI: 10.1016/j.semcancer.2025.03.005
Matteo Tacelli , Manuel Gentiluomo , Paolo Biamonte , Justo P. Castano , Maja Cigrovski Berković , Mauro Cives , Sanja Kapitanović , Ilaria Marinoni , Sonja Marinovic , Ilias Nikas , Lenka Nosáková , Sergio Pedraza-Arevalo , Eleonora Pellè , Aurel Perren , Jonathan Strosberg , Daniele Campa , Gabriele Capurso
Pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous tumors arising from neuroendocrine cells, representing approximately 10 % of all Gastro-Entero-Pancreatic neuroendocrine neoplasms. While most pNENs are sporadic, a subset is associated with genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) or von Hippel-Lindau disease (VHL). pNENs are further classified into functioning and non-functioning tumors, with distinct clinical behaviors, prognoses, and treatment approaches. This review explores genetic and environmental biomarkers that influence the risk, prognosis, and therapeutic responses in pNENs. The epidemiology of pNENs reveals an increasing incidence, primarily due to advancements in imaging techniques. Genetic factors play a pivotal role, with germline mutations in MEN1, VHL, and other genes contributing to familial pNENs. Somatic mutations, including alterations in the mTOR pathway and DNA maintenance genes such as DAXX and ATRX, are critical in sporadic pNENs. These mutations, along with epigenetic dysregulation and transcriptomic alterations, underpin the diverse clinical and molecular phenotypes of pNENs. Emerging evidence suggests that epigenetic changes, including DNA methylation profiles, can stratify pNEN subtypes and predict disease progression. Environmental and lifestyle factors, such as diabetes, smoking, and chronic pancreatitis, have been linked to an increased risk of sporadic pNENs. While the association between these factors and tumor progression is still under investigation, their potential role in influencing therapeutic outcomes warrants further study. Advances in systemic therapies, including somatostatin analogs, mTOR inhibitors, and tyrosine kinase inhibitors, have improved disease management. Biomarkers such as Ki-67, somatostatin receptor expression, and O6-methylguanine-DNA methyltransferase (MGMT) status are being evaluated for their predictive value. Novel approaches, including the use of circulating biomarkers (NETest, circulating tumor cells, and ctDNA) and polygenic risk scores, offer promising avenues for non-invasive diagnosis and monitoring. Despite these advancements, challenges remain, including the need for large, well-annotated datasets and validated biomarkers. Future research should integrate multi-omics approaches and leverage liquid biopsy technologies to refine diagnostic, prognostic, and therapeutic strategies. Interdisciplinary collaborations and global consortia are crucial for overcoming current limitations and translating research findings into clinical practice. These insights hold promise for improving prevention, early detection, and tailored treatments, ultimately enhancing patient outcomes.
{"title":"Pancreatic neuroendocrine neoplasms (pNENs): Genetic and environmental biomarkers for risk of occurrence and prognosis","authors":"Matteo Tacelli , Manuel Gentiluomo , Paolo Biamonte , Justo P. Castano , Maja Cigrovski Berković , Mauro Cives , Sanja Kapitanović , Ilaria Marinoni , Sonja Marinovic , Ilias Nikas , Lenka Nosáková , Sergio Pedraza-Arevalo , Eleonora Pellè , Aurel Perren , Jonathan Strosberg , Daniele Campa , Gabriele Capurso","doi":"10.1016/j.semcancer.2025.03.005","DOIUrl":"10.1016/j.semcancer.2025.03.005","url":null,"abstract":"<div><div>Pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous tumors arising from neuroendocrine cells, representing approximately 10 % of all Gastro-Entero-Pancreatic neuroendocrine neoplasms. While most pNENs are sporadic, a subset is associated with genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) or von Hippel-Lindau disease (VHL). pNENs are further classified into functioning and non-functioning tumors, with distinct clinical behaviors, prognoses, and treatment approaches. This review explores genetic and environmental biomarkers that influence the risk, prognosis, and therapeutic responses in pNENs. The epidemiology of pNENs reveals an increasing incidence, primarily due to advancements in imaging techniques. Genetic factors play a pivotal role, with germline mutations in MEN1, VHL, and other genes contributing to familial pNENs. Somatic mutations, including alterations in the mTOR pathway and DNA maintenance genes such as DAXX and ATRX, are critical in sporadic pNENs. These mutations, along with epigenetic dysregulation and transcriptomic alterations, underpin the diverse clinical and molecular phenotypes of pNENs. Emerging evidence suggests that epigenetic changes, including DNA methylation profiles, can stratify pNEN subtypes and predict disease progression. Environmental and lifestyle factors, such as diabetes, smoking, and chronic pancreatitis, have been linked to an increased risk of sporadic pNENs. While the association between these factors and tumor progression is still under investigation, their potential role in influencing therapeutic outcomes warrants further study. Advances in systemic therapies, including somatostatin analogs, mTOR inhibitors, and tyrosine kinase inhibitors, have improved disease management. Biomarkers such as Ki-67, somatostatin receptor expression, and O6-methylguanine-DNA methyltransferase (MGMT) status are being evaluated for their predictive value. Novel approaches, including the use of circulating biomarkers (NETest, circulating tumor cells, and ctDNA) and polygenic risk scores, offer promising avenues for non-invasive diagnosis and monitoring. Despite these advancements, challenges remain, including the need for large, well-annotated datasets and validated biomarkers. Future research should integrate multi-omics approaches and leverage liquid biopsy technologies to refine diagnostic, prognostic, and therapeutic strategies. Interdisciplinary collaborations and global consortia are crucial for overcoming current limitations and translating research findings into clinical practice. These insights hold promise for improving prevention, early detection, and tailored treatments, ultimately enhancing patient outcomes.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"112 ","pages":"Pages 112-125"},"PeriodicalIF":12.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739065","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 : 2025-07-01Epub Date: 2025-04-05DOI: 10.1016/j.semcancer.2025.03.007
Pierrick Martinez , William B. Grant
Obesity is an important risk factor for incidence and death for many types of cancer. Vitamin D reduces risk of incidence and death for many types of cancer. This review outlines the mechanisms by which obesity increases risk of cancer, how vitamin D reduces risk of cancer, and the extent to which vitamin D counters the effects of obesity in cancer. Vitamin D is a partial ally against some of obesity's pro-carcinogenic effects, notably by reducing inflammation and regulating sex hormone receptors, leptin resistance, cellular energy metabolism, the microbiome, and hypoxia. However, it can act stronger in against the renin-angiotensin system, insulin resistance, and oxidative stress in cancer. Additionally, excess fat tissue sequesters vitamin D and, along with its dilution in increased body volume, further reduces its bioavailability and serum concentration, limiting its protective effects against cancer. In conclusion, while vitamin D cannot reverse obesity, it plays a significant role in mitigating its pro-carcinogenic effects by targeting several mechanisms.
{"title":"Vitamin D: What role in obesity-related cancer?","authors":"Pierrick Martinez , William B. Grant","doi":"10.1016/j.semcancer.2025.03.007","DOIUrl":"10.1016/j.semcancer.2025.03.007","url":null,"abstract":"<div><div>Obesity is an important risk factor for incidence and death for many types of cancer. Vitamin D reduces risk of incidence and death for many types of cancer. This review outlines the mechanisms by which obesity increases risk of cancer, how vitamin D reduces risk of cancer, and the extent to which vitamin D counters the effects of obesity in cancer. Vitamin D is a partial ally against some of obesity's pro-carcinogenic effects, notably by reducing inflammation and regulating sex hormone receptors, leptin resistance, cellular energy metabolism, the microbiome, and hypoxia. However, it can act stronger in against the renin-angiotensin system, insulin resistance, and oxidative stress in cancer. Additionally, excess fat tissue sequesters vitamin D and, along with its dilution in increased body volume, further reduces its bioavailability and serum concentration, limiting its protective effects against cancer. In conclusion, while vitamin D cannot reverse obesity, it plays a significant role in mitigating its pro-carcinogenic effects by targeting several mechanisms.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"112 ","pages":"Pages 135-149"},"PeriodicalIF":12.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799978","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 : 2025-07-01Epub Date: 2025-03-26DOI: 10.1016/j.semcancer.2025.03.002
Neil Daniel , Riccardo Farinella , Flavia Belluomini , Almir Fajkic , Cosmeri Rizzato , Pavel Souček , Daniele Campa , David J. Hughes
Pancreatic cancers have high mortality and rising incidence rates which may be related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and obesity rates. Recent data also suggest a role for the gut microbiome in the development of pancreatic cancer. Here, we review the experimental and observational evidence for the roles of the oral, gut and intratumoural microbiomes, impaired gut barrier function and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to pancreatic disease with a focus on pancreatic ductal adenocarcinoma (PDAC) initiation and progression. We also highlight some emerging gut microbiome editing techniques currently being investigated in the context of pancreatic disease. Notably, while the gut microbiome is significantly altered in PDAC and its precursor diseases, its utility as a diagnostic and prognostic tool is hindered by a lack of reproducibility and the potential for reverse causality in case-control cohorts. Future research should emphasise longitudinal and mechanistic studies as well as integrating lifestyle exposure and multi-omics data to unravel complex host-microbiome interactions. This will allow for deeper aetiologic and mechanistic insights that can inform treatments and guide public health recommendations.
{"title":"The relationship of the microbiome, associated metabolites and the gut barrier with pancreatic cancer","authors":"Neil Daniel , Riccardo Farinella , Flavia Belluomini , Almir Fajkic , Cosmeri Rizzato , Pavel Souček , Daniele Campa , David J. Hughes","doi":"10.1016/j.semcancer.2025.03.002","DOIUrl":"10.1016/j.semcancer.2025.03.002","url":null,"abstract":"<div><div>Pancreatic cancers have high mortality and rising incidence rates which may be related to unhealthy western-type dietary and lifestyle patterns as well as increasing body weights and obesity rates. Recent data also suggest a role for the gut microbiome in the development of pancreatic cancer. Here, we review the experimental and observational evidence for the roles of the oral, gut and intratumoural microbiomes, impaired gut barrier function and exposure to inflammatory compounds as well as metabolic dysfunction as contributors to pancreatic disease with a focus on pancreatic ductal adenocarcinoma (PDAC) initiation and progression. We also highlight some emerging gut microbiome editing techniques currently being investigated in the context of pancreatic disease. Notably, while the gut microbiome is significantly altered in PDAC and its precursor diseases, its utility as a diagnostic and prognostic tool is hindered by a lack of reproducibility and the potential for reverse causality in case-control cohorts. Future research should emphasise longitudinal and mechanistic studies as well as integrating lifestyle exposure and multi-omics data to unravel complex host-microbiome interactions. This will allow for deeper aetiologic and mechanistic insights that can inform treatments and guide public health recommendations.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"112 ","pages":"Pages 43-57"},"PeriodicalIF":12.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735264","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 : 2025-07-01Epub Date: 2025-03-27DOI: 10.1016/j.semcancer.2025.03.003
Heng Wang, Fang Xu, Chao Wang
The tumor microenvironment (TME) is a complex ecosystem that plays a crucial role in tumor progression and response to therapy. The metabolic characteristics of the TME are fundamental to its function, influencing not only cancer cell proliferation and survival but also the behavior of immune cells within the tumor. Metabolic reprogramming—where cancer cells adapt their metabolic pathways to support rapid growth and immune evasion—has emerged as a key factor in cancer immunotherapy. Recently, the potential of engineered bacteria in cancer immunotherapy has gained increasing recognition, offering a novel strategy to modulate TME metabolism and enhance antitumor immunity. This review summarizes the metabolic properties and adaptations of tumor and immune cells within the TME and summarizes the strategies by which engineered bacteria regulate tumor metabolism. We discuss how engineered bacteria can overcome the immunosuppressive TME by reprogramming its metabolism to improve antitumor therapy. Furthermore, we examine the advantages, potential challenges, and future clinical translation of engineered bacteria in reshaping TME metabolism.
{"title":"Metabolic reprogramming of tumor microenviroment by engineered bacteria","authors":"Heng Wang, Fang Xu, Chao Wang","doi":"10.1016/j.semcancer.2025.03.003","DOIUrl":"10.1016/j.semcancer.2025.03.003","url":null,"abstract":"<div><div>The tumor microenvironment (TME) is a complex ecosystem that plays a crucial role in tumor progression and response to therapy. The metabolic characteristics of the TME are fundamental to its function, influencing not only cancer cell proliferation and survival but also the behavior of immune cells within the tumor. Metabolic reprogramming—where cancer cells adapt their metabolic pathways to support rapid growth and immune evasion—has emerged as a key factor in cancer immunotherapy. Recently, the potential of engineered bacteria in cancer immunotherapy has gained increasing recognition, offering a novel strategy to modulate TME metabolism and enhance antitumor immunity. This review summarizes the metabolic properties and adaptations of tumor and immune cells within the TME and summarizes the strategies by which engineered bacteria regulate tumor metabolism. We discuss how engineered bacteria can overcome the immunosuppressive TME by reprogramming its metabolism to improve antitumor therapy. Furthermore, we examine the advantages, potential challenges, and future clinical translation of engineered bacteria in reshaping TME metabolism.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"112 ","pages":"Pages 58-70"},"PeriodicalIF":12.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739064","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 : 2025-07-01Epub Date: 2025-04-05DOI: 10.1016/j.semcancer.2025.03.008
Pushan Dasgupta, Vinay K. Puduvalli
Gliomas carry a dismal prognosis and have proven difficult to treat. Current treatments and efforts to target individual signaling pathways have failed. This is thought to be due to genetic and epigenetic heterogeneity and resistance. Therefore, interest has grown in developing a deeper understanding of the metabolic alterations that represent drivers and dependencies in gliomas. Therapies that target glioma-specific metabolic dependencies overcome the challenges of disease heterogeneity. Here, we present the diverse metabolic features of each current clinical subtype of glioma. We believe that this approach will enable the development of novel strategies to specifically target the various clinical and molecular subtypes of glioma using these metabolic features.
{"title":"Diversity of metabolic features and relevance to clinical subtypes of gliomas","authors":"Pushan Dasgupta, Vinay K. Puduvalli","doi":"10.1016/j.semcancer.2025.03.008","DOIUrl":"10.1016/j.semcancer.2025.03.008","url":null,"abstract":"<div><div>Gliomas carry a dismal prognosis and have proven difficult to treat. Current treatments and efforts to target individual signaling pathways have failed. This is thought to be due to genetic and epigenetic heterogeneity and resistance. Therefore, interest has grown in developing a deeper understanding of the metabolic alterations that represent drivers and dependencies in gliomas. Therapies that target glioma-specific metabolic dependencies overcome the challenges of disease heterogeneity. Here, we present the diverse metabolic features of each current clinical subtype of glioma. We believe that this approach will enable the development of novel strategies to specifically target the various clinical and molecular subtypes of glioma using these metabolic features.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"112 ","pages":"Pages 126-134"},"PeriodicalIF":12.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792343","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 recognized as one of the most lethal malignancies, characterized by late-stage diagnosis and limited therapeutic options. Risk stratification has traditionally been performed using epidemiological studies and genetic analyses, through which key risk factors, including smoking, diabetes, chronic pancreatitis, and inherited predispositions, have been identified. However, the multifactorial nature of PDAC has often been insufficiently addressed by these methods, leading to limited precision in individualized risk assessments. Advances in artificial intelligence (AI) have been proposed as a transformative approach, allowing the integration of diverse datasets—spanning genetic, clinical, lifestyle, and imaging data into dynamic models capable of uncovering novel interactions and risk profiles. In this review, the evolution of PDAC risk stratification is explored, with classical epidemiological frameworks compared to AI-driven methodologies. Genetic insights, including genome-wide association studies and polygenic risk scores, are discussed, alongside AI models such as machine learning, radiomics, and deep learning. Strengths and limitations of these approaches are evaluated, with challenges in clinical translation, such as data scarcity, model interpretability, and external validation, addressed. Finally, future directions are proposed for combining classical and AI-driven methodologies to develop scalable, personalized predictive tools for PDAC, with the goal of improving early detection and patient outcomes.
{"title":"From classical approaches to artificial intelligence, old and new tools for PDAC risk stratification and prediction","authors":"Riccardo Farinella , Alessio Felici , Giulia Peduzzi , Sabrina Gloria Giulia Testoni , Eithne Costello , Paolo Aretini , Ricardo Blazquez-Encinas , Elif Oz , Aldo Pastore , Matteo Tacelli , Burçak Otlu , Daniele Campa , Manuel Gentiluomo","doi":"10.1016/j.semcancer.2025.03.004","DOIUrl":"10.1016/j.semcancer.2025.03.004","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is recognized as one of the most lethal malignancies, characterized by late-stage diagnosis and limited therapeutic options. Risk stratification has traditionally been performed using epidemiological studies and genetic analyses, through which key risk factors, including smoking, diabetes, chronic pancreatitis, and inherited predispositions, have been identified. However, the multifactorial nature of PDAC has often been insufficiently addressed by these methods, leading to limited precision in individualized risk assessments. Advances in artificial intelligence (AI) have been proposed as a transformative approach, allowing the integration of diverse datasets—spanning genetic, clinical, lifestyle, and imaging data into dynamic models capable of uncovering novel interactions and risk profiles. In this review, the evolution of PDAC risk stratification is explored, with classical epidemiological frameworks compared to AI-driven methodologies. Genetic insights, including genome-wide association studies and polygenic risk scores, are discussed, alongside AI models such as machine learning, radiomics, and deep learning. Strengths and limitations of these approaches are evaluated, with challenges in clinical translation, such as data scarcity, model interpretability, and external validation, addressed. Finally, future directions are proposed for combining classical and AI-driven methodologies to develop scalable, personalized predictive tools for PDAC, with the goal of improving early detection and patient outcomes.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"112 ","pages":"Pages 71-92"},"PeriodicalIF":12.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731586","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 : 2025-07-01Epub Date: 2025-03-07DOI: 10.1016/j.semcancer.2025.02.013
Wenzheng Guo, Zhibing Duan, Jingjing Wu, Binhua P. Zhou
Epithelial-mesenchymal transition (EMT) is a cellular de-differentiation process that provides cells with the increased plasticity and stem cell-like traits required during embryonic development, tissue remodeling, wound healing and metastasis. Morphologically, EMT confers tumor cells with fibroblast-like properties that lead to the rearrangement of cytoskeleton (loss of stiffness) and decrease of membrane rigidity by incorporating high level of poly-unsaturated fatty acids (PUFA) in their phospholipid membrane. Although large amounts of PUFA in membrane reduces rigidity and offers capabilities for tumor cells with the unbridled ability to stretch, bend and twist in metastasis, these PUFA are highly susceptible to lipid peroxidation, which leads to the breakdown of membrane integrity and, ultimately results in ferroptosis. To escape the ferroptotic risk, EMT also triggers the rewiring of metabolic program, particularly in lipid metabolism, to enforce the epigenetic regulation of EMT and mitigate the potential damages from ferroptosis. Thus, the interplay among EMT, lipid metabolism, and ferroptosis highlights a new layer of intricated regulation in cancer biology and metastasis. Here we summarize the latest findings and discuss these mutual interactions. Finally, we provide perspectives of how these interplays contribute to cellular plasticity and ferroptosis resistance in metastatic tumor cells that can be explored for innovative therapeutic interventions.
{"title":"Epithelial-mesenchymal transition promotes metabolic reprogramming to suppress ferroptosis","authors":"Wenzheng Guo, Zhibing Duan, Jingjing Wu, Binhua P. Zhou","doi":"10.1016/j.semcancer.2025.02.013","DOIUrl":"10.1016/j.semcancer.2025.02.013","url":null,"abstract":"<div><div>Epithelial-mesenchymal transition (EMT) is a cellular de-differentiation process that provides cells with the increased plasticity and stem cell-like traits required during embryonic development, tissue remodeling, wound healing and metastasis. Morphologically, EMT confers tumor cells with fibroblast-like properties that lead to the rearrangement of cytoskeleton (loss of stiffness) and decrease of membrane rigidity by incorporating high level of poly-unsaturated fatty acids (PUFA) in their phospholipid membrane. Although large amounts of PUFA in membrane reduces rigidity and offers capabilities for tumor cells with the unbridled ability to stretch, bend and twist in metastasis, these PUFA are highly susceptible to lipid peroxidation, which leads to the breakdown of membrane integrity and, ultimately results in ferroptosis. To escape the ferroptotic risk, EMT also triggers the rewiring of metabolic program, particularly in lipid metabolism, to enforce the epigenetic regulation of EMT and mitigate the potential damages from ferroptosis. Thus, the interplay among EMT, lipid metabolism, and ferroptosis highlights a new layer of intricated regulation in cancer biology and metastasis. Here we summarize the latest findings and discuss these mutual interactions. Finally, we provide perspectives of how these interplays contribute to cellular plasticity and ferroptosis resistance in metastatic tumor cells that can be explored for innovative therapeutic interventions.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"112 ","pages":"Pages 20-35"},"PeriodicalIF":12.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586697","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}
Cancer remains the second leading cause of death worldwide, emphasizing the critical need for effective treatment and control strategies. Essential minerals such as copper, iron, zinc, selenium, phosphorous, calcium, and magnesium are integral to various biological processes and significantly influence cancer progression through altered metabolic pathways. For example, dysregulated copper levels promote tumor growth, while cancer cells exhibit an increased dependency on iron for signaling and redox reactions. Zinc influences tumor development through pathways such as Akt-p21. Selenium, primarily through its role in selenoproteins, exhibits anticancer potential but may also contribute to tumor progression. Similarly, dietary phosphate exacerbates tumorigenesis, metastasis, and angiogenesis through signaling pathway activation. Calcium, the most abundant mineral in the body, is tightly regulated within cells, and its dysregulation is a hallmark of various cancers. Magnesium deficiency, on the other hand, promotes cancer progression by fostering inflammation and free radical-induced DNA mutations. Interestingly, magnesium also plays a dual role, with low levels enhancing epithelial-mesenchymal transition (EMT), a critical process in cancer metastasis. This complex interplay of essential minerals underscores their potential as therapeutic targets. Dysregulation of these minerals and their pathways could be exploited to selectively target cancer cells, offering novel therapeutic strategies. This review summarizes current research on the abnormal accumulation or depletion of these microelements in tumor biology, drawing evidence from animal models, cell lines, and clinical samples. We also highlight the potential of these minerals as biomarkers for cancer diagnosis and prognosis, as well as therapeutic approaches involving metal chelators, pharmacological agents, and nanotechnology. By highlighting the intricate roles of these minerals in cancer biology, we aim to inspire further research in this critical yet underexplored area of oncology.
{"title":"Targeting mineral metabolism in cancer: Insights into signaling pathways and therapeutic strategies","authors":"Kartik Bhatnagar , Sharon Raju , Ninad Patki , Rajender K. Motiani , Sarika Chaudhary","doi":"10.1016/j.semcancer.2025.02.011","DOIUrl":"10.1016/j.semcancer.2025.02.011","url":null,"abstract":"<div><div>Cancer remains the second leading cause of death worldwide, emphasizing the critical need for effective treatment and control strategies. Essential minerals such as copper, iron, zinc, selenium, phosphorous, calcium, and magnesium are integral to various biological processes and significantly influence cancer progression through altered metabolic pathways. For example, dysregulated copper levels promote tumor growth, while cancer cells exhibit an increased dependency on iron for signaling and redox reactions. Zinc influences tumor development through pathways such as Akt-p21. Selenium, primarily through its role in selenoproteins, exhibits anticancer potential but may also contribute to tumor progression. Similarly, dietary phosphate exacerbates tumorigenesis, metastasis, and angiogenesis through signaling pathway activation. Calcium, the most abundant mineral in the body, is tightly regulated within cells, and its dysregulation is a hallmark of various cancers. Magnesium deficiency, on the other hand, promotes cancer progression by fostering inflammation and free radical-induced DNA mutations. Interestingly, magnesium also plays a dual role, with low levels enhancing epithelial-mesenchymal transition (EMT), a critical process in cancer metastasis. This complex interplay of essential minerals underscores their potential as therapeutic targets. Dysregulation of these minerals and their pathways could be exploited to selectively target cancer cells, offering novel therapeutic strategies. This review summarizes current research on the abnormal accumulation or depletion of these microelements in tumor biology, drawing evidence from animal models, cell lines, and clinical samples. We also highlight the potential of these minerals as biomarkers for cancer diagnosis and prognosis, as well as therapeutic approaches involving metal chelators, pharmacological agents, and nanotechnology. By highlighting the intricate roles of these minerals in cancer biology, we aim to inspire further research in this critical yet underexplored area of oncology.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"112 ","pages":"Pages 1-19"},"PeriodicalIF":12.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537635","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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