Seminars in cancer biology最新文献

{"title":"Deregulated transcription factors in the emerging cancer hallmarks","authors":"Adria Hasan ,&nbsp;Naushad Ahmad Khan ,&nbsp;Shahab Uddin ,&nbsp;Abdul Q. Khan ,&nbsp;Martin Steinhoff","doi":"10.1016/j.semcancer.2023.12.001","DOIUrl":"10.1016/j.semcancer.2023.12.001","url":null,"abstract":"<div><p>Cancer progression is a multifaceted process that entails several stages and demands the persistent expression or activation of transcription factors (TFs) to facilitate growth and survival. TFs are a cluster of proteins with DNA-binding domains that attach to promoter or enhancer DNA strands to start the transcription of genes by collaborating with RNA polymerase and other supporting proteins. They are generally acknowledged as the major regulatory molecules that coordinate biological homeostasis and the appropriate functioning of cellular components, subsequently contributing to human physiology. TFs proteins are crucial for controlling transcription during the embryonic stage and development, and the stability of different cell types depends on how they function in different cell types. The development and progression of cancer cells and tumors might be triggered by any anomaly in transcription factor function. It has long been acknowledged that cancer development is accompanied by the dysregulated activity of TF alterations which might result in faulty gene expression. Recent studies have suggested that dysregulated transcription factors play a major role in developing various human malignancies by altering and rewiring metabolic processes, modifying the immune response, and triggering oncogenic signaling cascades. This review emphasizes the interplay between TFs involved in metabolic and epigenetic reprogramming, evading immune attacks, cellular senescence, and the maintenance of cancer stemness in cancerous cells. The insights presented herein will facilitate the development of innovative therapeutic modalities to tackle the dysregulated transcription factors underlying cancer.</p></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"98 ","pages":"Pages 31-50"},"PeriodicalIF":14.5,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044579X2300158X/pdfft?md5=8d19160c82caf1bfc8b7e2414e89ebac&pid=1-s2.0-S1044579X2300158X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138740901","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}

{"title":"Hypoxia as a potential inducer of immune tolerance, tumor plasticity and a driver of tumor mutational burden: Impact on cancer immunotherapy","authors":"Raefa Abou Khouzam ,&nbsp;Bassam Janji ,&nbsp;Jerome Thiery ,&nbsp;Rania Faouzi Zaarour ,&nbsp;Ali N. Chamseddine ,&nbsp;Hemma Mayr ,&nbsp;Pierre Savagner ,&nbsp;Claudine Kieda ,&nbsp;Sophie Gad ,&nbsp;Stéphanie Buart ,&nbsp;Jean–Marie Lehn ,&nbsp;Perparim Limani ,&nbsp;Salem Chouaib","doi":"10.1016/j.semcancer.2023.11.008","DOIUrl":"10.1016/j.semcancer.2023.11.008","url":null,"abstract":"<div><p>In cancer patients, immune cells<span> are often functionally compromised due to the immunosuppressive features of the tumor microenvironment (TME) which contribute to the failures in cancer therapies. Clinical and experimental evidence indicates that developing tumors adapt to the immunological environment and create a local microenvironment that impairs immune function by inducing immune tolerance<span><span> and invasion. In this context, microenvironmental hypoxia, which is an established hallmark of solid tumors, significantly contributes to tumor aggressiveness and therapy resistance through the induction of tumor plasticity/heterogeneity and, more importantly, through the differentiation and expansion of immune-suppressive stromal cells. We and others have provided evidence indicating that hypoxia also drives </span>genomic instability<span><span> in cancer cells and interferes with DNA damage response<span> and repair suggesting that hypoxia could be a potential driver of tumor mutational burden. Here, we reviewed the current knowledge on how hypoxic stress in the TME impacts tumor angiogenesis, heterogeneity, plasticity, and immune resistance, with a special interest in tumor immunogenicity and hypoxia targeting. An integrated understanding of the complexity of the effect of hypoxia on the immune and microenvironmental components could lead to the identification of better adapted and more effective combinational strategies in </span></span>cancer immunotherapy. Clearly, the discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance and the identification of critical hypoxia-associated pathways could generate targets that are undeniably attractive for combined cancer immunotherapy approaches.</span></span></span></p></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"97 ","pages":"Pages 104-123"},"PeriodicalIF":14.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138462425","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}

{"title":"Mutual regulation of TGFβ-induced oncogenic EMT, cell cycle progression and the DDR","authors":"Harald Schuhwerk ,&nbsp;Thomas Brabletz","doi":"10.1016/j.semcancer.2023.11.009","DOIUrl":"10.1016/j.semcancer.2023.11.009","url":null,"abstract":"<div><p>TGFβ signaling and the DNA damage response (DDR) are two cellular toolboxes with a strong impact on cancer biology. While TGFβ as a pleiotropic cytokine affects essentially all hallmarks of cancer, the multifunctional DDR mostly orchestrates cell cycle progression, DNA repair, chromatin remodeling and cell death. One oncogenic effect of TGFβ is the partial activation of epithelial-to-mesenchymal transition (EMT), conferring invasiveness, cellular plasticity and resistance to various noxae. Several reports show that both individual networks as well as their interface affect chemo-/radiotherapies. However, the underlying mechanisms remain poorly resolved. EMT often correlates with TGFβ-induced slowing of proliferation, yet numerous studies demonstrate that particularly the co-activated EMT transcription factors counteract anti-proliferative signaling in a partially non-redundant manner. Collectively, evidence piled up over decades underscore a multifaceted, reciprocal inter-connection of TGFβ signaling / EMT with the DDR / cell cycle progression, which we will discuss here. Altogether, we conclude that full cell cycle arrest is barely compatible with the propagation of oncogenic EMT traits and further propose that ‘EMT-linked DDR plasticity’ is a crucial, yet intricate facet of malignancy, decisively affecting metastasis formation and therapy resistance.</p></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"97 ","pages":"Pages 86-103"},"PeriodicalIF":14.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044579X23001499/pdfft?md5=36548423bca3bf1d1048418a0e30fb2f&pid=1-s2.0-S1044579X23001499-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138462426","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}

{"title":"One label is all you need: Interpretable AI-enhanced histopathology for oncology","authors":"Thomas E. Tavolara,&nbsp;Ziyu Su,&nbsp;Metin N. Gurcan,&nbsp;M. Khalid Khan Niazi","doi":"10.1016/j.semcancer.2023.09.006","DOIUrl":"10.1016/j.semcancer.2023.09.006","url":null,"abstract":"<div><p><span><span>Artificial Intelligence (AI)-enhanced histopathology presents unprecedented opportunities to benefit oncology through interpretable methods that require only one overall label per hematoxylin and eosin (H&amp;E) slide with no tissue-level annotations. We present a structured review of these methods organized by their degree of verifiability and by commonly recurring application areas in oncological characterization. First, we discuss morphological markers (tumor presence/absence, metastases, subtypes, grades) in which AI-identified regions of interest (ROIs) within whole slide images (WSIs) verifiably overlap with pathologist-identified ROIs. Second, we discuss </span>molecular markers<span> (gene expression, molecular subtyping) that are not verified via H&amp;E but rather based on overlap with positive regions on adjacent tissue. Third, we discuss genetic markers (mutations, mutational burden, microsatellite instability, chromosomal instability) that current technologies cannot verify if AI methods spatially resolve specific </span></span>genetic alterations. Fourth, we discuss the direct prediction of survival to which AI-identified histopathological features quantitatively correlate but are nonetheless not mechanistically verifiable. Finally, we discuss in detail several opportunities and challenges for these one-label-per-slide methods within oncology. Opportunities include reducing the cost of research and clinical care, reducing the workload of clinicians, personalized medicine, and unlocking the full potential of histopathology through new imaging-based biomarkers. Current challenges include explainability and interpretability, validation via adjacent tissue sections, reproducibility, data availability, computational needs, data requirements, domain adaptability, external validation, dataset imbalances, and finally commercialization and clinical potential. Ultimately, the relative ease and minimum upfront cost with which relevant data can be collected in addition to the plethora of available AI methods for outcome-driven analysis will surmount these current limitations and achieve the innumerable opportunities associated with AI-driven histopathology for the benefit of oncology.</p></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"97 ","pages":"Pages 70-85"},"PeriodicalIF":14.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41211345","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}

{"title":"Tumor hypoxia and radiotherapy: A major driver of resistance even for novel radiotherapy modalities","authors":"Claire Beckers ,&nbsp;Martin Pruschy,&nbsp;Irene Vetrugno","doi":"10.1016/j.semcancer.2023.11.006","DOIUrl":"10.1016/j.semcancer.2023.11.006","url":null,"abstract":"<div><p>Hypoxia in solid tumors is an important predictor of poor clinical outcome to radiotherapy. Both physicochemical and biological processes contribute to a reduced sensitivity of hypoxic tumor cells to ionizing radiation and hypoxia-related treatment resistances. A conventional low-dose fractionated radiotherapy regimen exploits iterative reoxygenation in between the individual fractions, nevertheless tumor hypoxia still remains a major hurdle for successful treatment outcome. The technological advances achieved in image guidance and highly conformal dose delivery make it nowadays possible to prescribe larger doses to the tumor as part of single high-dose or hypofractionated radiotherapy, while keeping an acceptable level of normal tissue complication in the co-irradiated organs at risk. However, we insufficiently understand the impact of tumor hypoxia to single high-doses of RT and hypofractionated RT. So-called FLASH radiotherapy, which delivers ionizing radiation at ultrahigh dose rates (&gt; 40 Gy/sec), has recently emerged as an important breakthrough in the radiotherapy field to reduce normal tissue toxicity compared to irradiation at conventional dose rates (few Gy/min). Not surprisingly, oxygen consumption and tumor hypoxia also seem to play an intriguing role for FLASH radiotherapy. Here we will discuss the role of tumor hypoxia for radiotherapy in general and in the context of novel radiotherapy treatment approaches.</p></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"98 ","pages":"Pages 19-30"},"PeriodicalIF":14.5,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044579X23001451/pdfft?md5=b5e463df282eb76618a7cb3054579cb0&pid=1-s2.0-S1044579X23001451-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138470788","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}

{"title":"Epigenetic remodelling under hypoxia","authors":"Roxane Verdikt ,&nbsp;Bernard Thienpont","doi":"10.1016/j.semcancer.2023.10.005","DOIUrl":"10.1016/j.semcancer.2023.10.005","url":null,"abstract":"<div><p>Hypoxia is intrinsic to tumours and contributes to malignancy and metastasis while hindering the efficiency of existing treatments. Epigenetic mechanisms play a crucial role in the regulation of hypoxic cancer cell programs, both in the initial phases of sensing the decrease in oxygen levels and during adaptation to chronic lack of oxygen. During the latter, the epigenetic regulation of tumour biology intersects with hypoxia-sensitive transcription factors in a complex network of gene regulation that also involves metabolic reprogramming. Here, we review the current literature on the epigenetic control of gene programs in hypoxic cancer cells. We highlight common themes and features of such epigenetic remodelling and discuss their relevance for the development of therapeutic strategies.</p></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"98 ","pages":"Pages 1-10"},"PeriodicalIF":14.5,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044579X23001463/pdfft?md5=d330a409327656be9a091b8fac3b01a7&pid=1-s2.0-S1044579X23001463-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138462423","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}

{"title":"Harnessing the effects of hypoxia-like inhibition on homology-directed DNA repair","authors":"Gary Altwerger ,&nbsp;Maddie Ghazarian ,&nbsp;Peter M. Glazer","doi":"10.1016/j.semcancer.2023.11.007","DOIUrl":"10.1016/j.semcancer.2023.11.007","url":null,"abstract":"<div><p>Hypoxia is a hallmark feature of the tumor microenvironment which can promote mutagenesis and instability. This increase in mutational burden occurs as a result of the downregulation of DNA repair systems. Deficits in the DNA damage response can be exploited to induce cytotoxicity and treat advanced stage cancers. With the advent of precision medicine, agents such as Poly (ADP-ribose) polymerase (PARP) inhibitors have been used to achieve synthetic lethality in homology directed repair (HDR) deficient cancers. However, most cancers lack these predictive biomarkers. Treatment for the HDR proficient population represents an important unmet clinical need. There has been interest in the use of anti-angiogenic agents to promote tumor hypoxia and induce deficiency in a HDR proficient background. For example, the use of cediranib to inhibit PDGFR and downregulate enzymes of the HDR pathway can be used synergistically with a PARP inhibitor. This combination can improve therapeutic responses in HDR proficient cancers. Preclinical results and Phase II and III clinical trial data support the mechanistic rationale for the efficacy of these agents in combination. Future investigations should explore the effectiveness of cediranib and other anti-angiogenic agents with a PARP inhibitor to elicit an antitumor response and sensitize cancers to immunotherapy.</p></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"98 ","pages":"Pages 11-18"},"PeriodicalIF":14.5,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044579X23001487/pdfft?md5=1ff9eb0103e1003f4185e3378e11f463&pid=1-s2.0-S1044579X23001487-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138462424","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}

{"title":"Mathematical modeling of cardio-oncology: Modeling the systemic effects of cancer therapeutics on the cardiovascular system","authors":"Camara L. Casson ,&nbsp;Sofia A. John ,&nbsp;Meghan C. Ferrall-Fairbanks","doi":"10.1016/j.semcancer.2023.11.004","DOIUrl":"10.1016/j.semcancer.2023.11.004","url":null,"abstract":"<div><p>Cardiotoxicity is a common side-effect of many cancer therapeutics; however, to-date there has been very little push to understand the mechanisms underlying this group of pathologies. This has led to the emergence of cardio-oncology, a field of medicine focused on understanding the effects of cancer and its treatment on the human heart. Here, we describe how mechanistic modeling approaches have been applied to study open questions in the cardiovascular system and how these approaches are being increasingly applied to advance knowledge of the underlying effects of cancer treatments on the human heart. A variety of mechanistic, mathematical modeling techniques have been applied to explore the link between common cancer treatments, such as chemotherapy, radiation, targeted therapy, and immunotherapy, and cardiotoxicity, nevertheless there is limited coverage in the different types of cardiac dysfunction that may be associated with these treatments. Moreover, cardiac modeling has a rich heritage of mathematical modeling and is well suited for the further development of novel approaches for understanding the cardiotoxicities associated with cancer therapeutics. There are many opportunities to combine mechanistic, bottom-up approaches with data-driven, top-down approaches to improve personalized, precision oncology to better understand, and ultimately mitigate, cardiac dysfunction in cancer patients.</p></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"97 ","pages":"Pages 30-41"},"PeriodicalIF":14.5,"publicationDate":"2023-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044579X23001438/pdfft?md5=93f6da9919c765701550a9f17dbddd8a&pid=1-s2.0-S1044579X23001438-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138047838","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}

{"title":"Application of artificial intelligence in oncology","authors":"Xuelei Ma,&nbsp;Qi Zhao","doi":"10.1016/j.semcancer.2023.11.005","DOIUrl":"10.1016/j.semcancer.2023.11.005","url":null,"abstract":"","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"97 ","pages":"Pages 68-69"},"PeriodicalIF":14.5,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136399021","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}

{"title":"Thinking small to win big? A critical review on the potential application of extracellular vesicles for biomarker discovery and new therapeutic approaches in pancreatic cancer","authors":"Mahrou Vahabi ,&nbsp;Annalisa Comandatore ,&nbsp;Chiara Centra ,&nbsp;Giovanni Blandino ,&nbsp;Luca Morelli ,&nbsp;Elisa Giovannetti","doi":"10.1016/j.semcancer.2023.11.003","DOIUrl":"10.1016/j.semcancer.2023.11.003","url":null,"abstract":"<div><p>Pancreatic ductal adenocarcinoma (PDAC) is an extremely deadly form of cancer, with limited progress in 5-year survival rates despite significant research efforts. The main challenges in treating PDAC include difficulties in early detection, and resistance to current therapeutic approaches due to aggressive molecular and microenvironment features. These challenges emphasize the importance of identifying clinically validated biomarkers for early detection and clinical management. Extracellular vesicles (EVs), particularly exosomes, have emerged as crucial mediators of intercellular communication by transporting molecular cargo. Recent research has unveiled their role in initiation, metastasis, and chemoresistance of PDAC. Consequently, utilizing EVs in liquid biopsies holds promise for the identification of biomarkers for early detection, prognosis, and monitoring of drug efficacy. However, numerous limitations, including challenges in isolation and characterization of homogeneous EVs populations, as well as the absence of standardized protocols, can affect the reliability of studies involving EVs as biomarkers, underscoring the necessity for a prudent approach. EVs have also garnered considerable attention as a promising drug delivery system and novel therapy for tumors. The loading of biomolecules or chemical drugs into exosomes and their subsequent delivery to target cells can effectively impede tumor progression. Nevertheless, there are obstacles that must be overcome to ensure the accuracy and efficacy of therapies relying on EVs for the treatment of tumors. In this review, we examine both recent advancements and remaining obstacles, exploring the potential of utilizing EVs in biomarker discovery as well as for the development of drug delivery vehicles.</p></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"97 ","pages":"Pages 50-67"},"PeriodicalIF":14.5,"publicationDate":"2023-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044579X23001360/pdfft?md5=173c9cc7a0850568e37008eead652550&pid=1-s2.0-S1044579X23001360-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135664613","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}