Pub Date : 2024-11-01DOI: 10.1016/j.bbcan.2024.189206
Lingwei Li , Litong Yao , Mozhi Wang , Xiang Zhou , Yingying Xu
Phase separation, a process in which biomolecules segregate into distinct liquid-like compartments within cells, has recently been identified as a crucial regulator of various cellular functions, including the DNA damage response (DDR). Dysregulation of phase separation may contribute to genomic instability, oncogenesis, and tumor progression. However, the specific roles and mechanisms underlying phase separation remain largely elusive. This comprehensive review aims to elucidate the complex relationship between phase separation and the DDR in the context of cancer biology. We focus on the molecular mechanisms underlying phase separation and its role in orchestrating DDR signaling and repair processes. Additionally, we discuss how the dysregulation of phase separation in cancer cells impacts genome stability, tumorigenesis, and therapeutic responses. By leveraging the unique properties of phase separation in the DDR, researchers can potentially advance basic research and develop personalized cancer therapies targeting the dysregulated biomolecular condensates that drive tumorigenesis.
相分离是生物大分子在细胞内分离成不同液态区室的过程，最近已被确定为各种细胞功能（包括 DNA 损伤反应）的关键调节因子。相分离失调可能会导致基因组不稳定、肿瘤发生和肿瘤进展。然而，相分离的具体作用和机制在很大程度上仍然难以捉摸。本综述旨在阐明癌症生物学背景下相位分离与 DDR 之间的复杂关系。我们将重点关注相分离的分子机制及其在协调 DDR 信号传导和修复过程中的作用。此外，我们还讨论了癌细胞中的相分离失调如何影响基因组稳定性、肿瘤发生和治疗反应。通过利用 DDR 中相位分离的独特特性，研究人员有可能推进基础研究，并开发出针对导致肿瘤发生的失调生物分子凝聚物的个性化癌症疗法。
{"title":"Phase separation in DNA damage response: New insights into cancer development and therapy","authors":"Lingwei Li , Litong Yao , Mozhi Wang , Xiang Zhou , Yingying Xu","doi":"10.1016/j.bbcan.2024.189206","DOIUrl":"10.1016/j.bbcan.2024.189206","url":null,"abstract":"<div><div>Phase separation, a process in which biomolecules segregate into distinct liquid-like compartments within cells, has recently been identified as a crucial regulator of various cellular functions, including the DNA damage response (DDR). Dysregulation of phase separation may contribute to genomic instability, oncogenesis, and tumor progression. However, the specific roles and mechanisms underlying phase separation remain largely elusive. This comprehensive review aims to elucidate the complex relationship between phase separation and the DDR in the context of cancer biology. We focus on the molecular mechanisms underlying phase separation and its role in orchestrating DDR signaling and repair processes. Additionally, we discuss how the dysregulation of phase separation in cancer cells impacts genome stability, tumorigenesis, and therapeutic responses. By leveraging the unique properties of phase separation in the DDR, researchers can potentially advance basic research and develop personalized cancer therapies targeting the dysregulated biomolecular condensates that drive tumorigenesis.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1879 6","pages":"Article 189206"},"PeriodicalIF":9.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634338","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.bbcan.2024.189213
Luyi Tan , Chenyu Zhu , Xinyu Zhang , Jiaqi Fu , Tingting Huang , Wenji Zhang , Wenjuan Zhang
Mitochondria have a complete and independent genetic system with necessary biological energy for cancer occurrence and persistence. Mitochondrial RNA (mt-RNA) methylation, as a frontier in epigenetics, has linked to cancer progression with growing evidences. This review has comprehensively summarized detailed mechanisms of mt-RNA methylation in regulating cancer proliferation, metastasis, and immune infiltration from the mt-RNA methylation sites, biological significance, and its methyltransferases. The mt-RNA methylation also plays a very significant role via epigenetic crosstalk between nucleus and mitochondria. Importantly, the unique structures and functional characteristics of mt-RNA methyltransferases and the potential targeting treatment drugs for cancer are also analyzed. Revealing human mt-RNA methylation regulatory system and the relationship with cancer will contribute to identifying potential biomarkers and therapeutic targets for precise prevention, detection, intervention and treatment in the future.
{"title":"Mitochondrial RNA methylation in cancer","authors":"Luyi Tan , Chenyu Zhu , Xinyu Zhang , Jiaqi Fu , Tingting Huang , Wenji Zhang , Wenjuan Zhang","doi":"10.1016/j.bbcan.2024.189213","DOIUrl":"10.1016/j.bbcan.2024.189213","url":null,"abstract":"<div><div>Mitochondria have a complete and independent genetic system with necessary biological energy for cancer occurrence and persistence. Mitochondrial RNA (mt-RNA) methylation, as a frontier in epigenetics, has linked to cancer progression with growing evidences. This review has comprehensively summarized detailed mechanisms of mt-RNA methylation in regulating cancer proliferation, metastasis, and immune infiltration from the mt-RNA methylation sites, biological significance, and its methyltransferases. The mt-RNA methylation also plays a very significant role <em>via</em> epigenetic crosstalk between nucleus and mitochondria. Importantly, the unique structures and functional characteristics of mt-RNA methyltransferases and the potential targeting treatment drugs for cancer are also analyzed. Revealing human mt-RNA methylation regulatory system and the relationship with cancer will contribute to identifying potential biomarkers and therapeutic targets for precise prevention, detection, intervention and treatment in the future.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1879 6","pages":"Article 189213"},"PeriodicalIF":9.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634336","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 : 2024-10-24DOI: 10.1016/j.bbcan.2024.189203
Paola Sanese , Candida Fasano , Martina Lepore Signorile , Katia De Marco , Giovanna Forte , Vittoria Disciglio , Valentina Grossi , Cristiano Simone
Drug resistance is a significant challenge in oncology and is driven by various mechanisms, among which a crucial role is played by enhanced DNA repair. Thus, targeting DNA damage response (DDR) factors with specific inhibitors is emerging as a promising therapeutic strategy. An important process involved in the modulation of DNA repair pathways, and hence in drug resistance, is post-translational modification (PTM). PTMs such as methylation affect protein function and are critical in cancer biology. Methylation is catalyzed by specific enzymes called protein methyltransferases. In recent years, the SET domain-containing N-lysine methyltransferase SMYD3 has emerged as a significant oncogenic driver. It is overexpressed in several tumor types and plays a signal-dependent role in promoting gastrointestinal cancer formation and development. Recent evidence indicates that SMYD3 is involved in the maintenance of cancer genome integrity and contributes to drug resistance in response to genotoxic stress by regulating DDR mechanisms. Several potential SMYD3 interactors implicated in DNA repair, especially in the homologous recombination and non-homologous end-joining pathways, have been identified by in silico analyses and confirmed by experimental validation, showing that SMYD3 promotes DDR protein interactions and enzymatic activity, thereby sustaining cancer cell survival. Targeting SMYD3, in combination with standard or targeted therapy, shows promise in overcoming drug resistance in colorectal, gastric, pancreatic, breast, endometrial, and lung cancer models, supporting the integration of SMYD3 inhibition into cancer treatment regimens. In this review, we describe the role played by SMYD3 in drug resistance and analyze its potential as a molecular target to sensitize cancer cells to treatment.
耐药性是肿瘤学面临的一项重大挑战，其驱动机制多种多样，其中 DNA 修复能力的增强发挥了至关重要的作用。因此，以 DNA 损伤应答（DDR）因子为靶点的特异性抑制剂正成为一种前景广阔的治疗策略。DNA 修复途径的一个重要调节过程是翻译后修饰 (PTM)，这也是导致耐药性的一个重要原因。甲基化等 PTM 会影响蛋白质的功能，在癌症生物学中至关重要。甲基化由称为蛋白质甲基转移酶的特定酶催化。近年来，含 SET 结构域的 N-赖氨酸甲基转移酶 SMYD3 已成为一种重要的致癌驱动因子。它在几种肿瘤类型中过度表达，并在促进胃肠癌的形成和发展中发挥着信号依赖性作用。最近的证据表明，SMYD3 参与了癌症基因组完整性的维护，并通过调节 DDR 机制在应对基因毒性压力时产生抗药性。一些潜在的 SMYD3 与 DNA 修复（尤其是同源重组和非同源末端连接途径）有关的相互作用因子已通过硅学分析确定，并通过实验验证得到证实，表明 SMYD3 促进了 DDR 蛋白相互作用和酶活性，从而维持了癌细胞的存活。在结直肠癌、胃癌、胰腺癌、乳腺癌、子宫内膜癌和肺癌模型中，靶向 SMYD3 与标准疗法或靶向疗法相结合，有望克服耐药性，支持将 SMYD3 抑制纳入癌症治疗方案。在这篇综述中，我们描述了 SMYD3 在耐药性中扮演的角色，并分析了其作为分子靶点使癌细胞对治疗敏感的潜力。
{"title":"Methyltransferases in cancer drug resistance: Unlocking the potential of targeting SMYD3 to sensitize cancer cells","authors":"Paola Sanese , Candida Fasano , Martina Lepore Signorile , Katia De Marco , Giovanna Forte , Vittoria Disciglio , Valentina Grossi , Cristiano Simone","doi":"10.1016/j.bbcan.2024.189203","DOIUrl":"10.1016/j.bbcan.2024.189203","url":null,"abstract":"<div><div>Drug resistance is a significant challenge in oncology and is driven by various mechanisms, among which a crucial role is played by enhanced DNA repair. Thus, targeting DNA damage response (DDR) factors with specific inhibitors is emerging as a promising therapeutic strategy. An important process involved in the modulation of DNA repair pathways, and hence in drug resistance, is post-translational modification (PTM). PTMs such as methylation affect protein function and are critical in cancer biology. Methylation is catalyzed by specific enzymes called protein methyltransferases. In recent years, the SET domain-containing N-lysine methyltransferase SMYD3 has emerged as a significant oncogenic driver. It is overexpressed in several tumor types and plays a signal-dependent role in promoting gastrointestinal cancer formation and development. Recent evidence indicates that SMYD3 is involved in the maintenance of cancer genome integrity and contributes to drug resistance in response to genotoxic stress by regulating DDR mechanisms. Several potential SMYD3 interactors implicated in DNA repair, especially in the homologous recombination and non-homologous end-joining pathways, have been identified by <em>in silico</em> analyses and confirmed by experimental validation, showing that SMYD3 promotes DDR protein interactions and enzymatic activity, thereby sustaining cancer cell survival. Targeting SMYD3, in combination with standard or targeted therapy, shows promise in overcoming drug resistance in colorectal, gastric, pancreatic, breast, endometrial, and lung cancer models, supporting the integration of SMYD3 inhibition into cancer treatment regimens. In this review, we describe the role played by SMYD3 in drug resistance and analyze its potential as a molecular target to sensitize cancer cells to treatment.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1879 6","pages":"Article 189203"},"PeriodicalIF":9.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514566","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 : 2024-10-18DOI: 10.1016/j.bbcan.2024.189196
Ziyue Yuan , Jiani He , Zhijia Li , Bo Fan , Lan Zhang , Xiaojun Man
The urological system, including kidneys, ureters, bladder, urethra and prostate is known to be vital for blood filtration, waste elimination and electrolyte balance. Notably, urological system cancers represent a significant portion of global cancer diagnoses and mortalities. The current therapeutic strategies for early-stage cancer primarily involve resection surgery, which significantly affects the quality of life of patients, whereas advanced-stage cancer often relies on less effective chemo- or radiotherapy. Recently, accumulating evidence has revealed that autophagy, a crucial process in which excess organelles or inclusions within cells are removed to maintain cell homeostasis, has numerous links to urological system cancers. In this review, we focus on summarizing the underlying two-sided mechanisms of autophagy in urological system cancers. We also review the current clinical drugs targeting autophagy, which demonstrate significant potential in improving treatment outcomes for urological system cancers. In addition, we provide an overview of the research status of novel small molecule compounds targeting autophagy that are in the preclinical stages of investigation. Furthermore, drug combinations based on autophagy modulation strategies in urological system cancers are systematically summarized and discussed. These findings provide comprehensive new insight for the future discovery of more autophagy-related drug candidates.
{"title":"Targeting autophagy in urological system cancers: From underlying mechanisms to therapeutic implications","authors":"Ziyue Yuan , Jiani He , Zhijia Li , Bo Fan , Lan Zhang , Xiaojun Man","doi":"10.1016/j.bbcan.2024.189196","DOIUrl":"10.1016/j.bbcan.2024.189196","url":null,"abstract":"<div><div>The urological system, including kidneys, ureters, bladder, urethra and prostate is known to be vital for blood filtration, waste elimination and electrolyte balance. Notably, urological system cancers represent a significant portion of global cancer diagnoses and mortalities. The current therapeutic strategies for early-stage cancer primarily involve resection surgery, which significantly affects the quality of life of patients, whereas advanced-stage cancer often relies on less effective chemo- or radiotherapy. Recently, accumulating evidence has revealed that autophagy, a crucial process in which excess organelles or inclusions within cells are removed to maintain cell homeostasis, has numerous links to urological system cancers. In this review, we focus on summarizing the underlying two-sided mechanisms of autophagy in urological system cancers. We also review the current clinical drugs targeting autophagy, which demonstrate significant potential in improving treatment outcomes for urological system cancers. In addition, we provide an overview of the research status of novel small molecule compounds targeting autophagy that are in the preclinical stages of investigation. Furthermore, drug combinations based on autophagy modulation strategies in urological system cancers are systematically summarized and discussed. These findings provide comprehensive new insight for the future discovery of more autophagy-related drug candidates.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1879 6","pages":"Article 189196"},"PeriodicalIF":9.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482911","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.bbcan.2024.189200
Xiaoyu Li , Meng Tian , Liuchunyang Yu , JinXiu Qian , Jue Yang , Xiangpeng Wang , Cheng Lu , Cheng Xiao , Yuanyan Liu
Tumour metastasis is a crucial factor in determining clinically challenging tumours. In this respect, the lymphatic system may act as potential entry portals for tumour metastasis, whilst, clinical detection of tumour-infiltrated lymph nodes also indicates poorer prognosis and higher metastatic risk. Whether tumour cells gain ferroptosis resistance in lymph that make them exhibit a stronger propensity for lymphatic dissemination compared to hematogenous spread might be a breakthrough for elucidating lymph-associated tumour metastasis. This review discusses how the lymphatic system endows tumour cells with ferroptosis resistance character, which makes them more propensity for lymph node pre-metastasis and distant metastasis through lymphatic circulation. Comprehensively considering the distinct structure and property of lymph and the unique metabolic characteristics of tumours, all of the lymphatic vessels, intestinal lymph and lymph nodes collectively manipulate an intricate interaction with the hematogenous system and afford substances exchange with tumour cells and extracellular vesicles, upon which make a ferroptosis resistant microenvironment for subsequent metastasis in distant organs and lymph nodes.
{"title":"The role of ferroptosis resistance in lymph-associated tumour metastasis","authors":"Xiaoyu Li , Meng Tian , Liuchunyang Yu , JinXiu Qian , Jue Yang , Xiangpeng Wang , Cheng Lu , Cheng Xiao , Yuanyan Liu","doi":"10.1016/j.bbcan.2024.189200","DOIUrl":"10.1016/j.bbcan.2024.189200","url":null,"abstract":"<div><div>Tumour metastasis is a crucial factor in determining clinically challenging tumours. In this respect, the lymphatic system may act as potential entry portals for tumour metastasis, whilst, clinical detection of tumour-infiltrated lymph nodes also indicates poorer prognosis and higher metastatic risk. Whether tumour cells gain ferroptosis resistance in lymph that make them exhibit a stronger propensity for lymphatic dissemination compared to hematogenous spread might be a breakthrough for elucidating lymph-associated tumour metastasis. This review discusses how the lymphatic system endows tumour cells with ferroptosis resistance character, which makes them more propensity for lymph node pre-metastasis and distant metastasis through lymphatic circulation. Comprehensively considering the distinct structure and property of lymph and the unique metabolic characteristics of tumours, all of the lymphatic vessels, intestinal lymph and lymph nodes collectively manipulate an intricate interaction with the hematogenous system and afford substances exchange with tumour cells and extracellular vesicles, upon which make a ferroptosis resistant microenvironment for subsequent metastasis in distant organs and lymph nodes.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1879 6","pages":"Article 189200"},"PeriodicalIF":9.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482915","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.bbcan.2024.189201
Yang Yang, Surong Dong, Benshuai You, Chenglin Zhou
Human endogenous retroviruses (HERVs) are a class of transposable elements formed by the integration of ancient retroviruses into the germline genome. They are inherited in a Mendelian manner and approximately constitute 8 % of the human genome. HERVs were considered as “junk DNA” for decades, but increasing evidence suggests that they play significant roles in pathological inflammation, neural differentiation, and oncogenesis. Specifically, HERVs expression has been implicated in several oncogenic processes and the formation of the tumor microenvironment. Indeed, the dual roles of HERVs in cancer, serving as both promoters of oncogenesis and forerunners of the innate antitumor immune response, remain a subject of debate. In this review, we will discuss how HERVs participate in cancer progression and how they are regulated. Our aim is to provide a comprehensive understanding of the fundamental properties and potential function of HERVs in propagating oncogenesis and activating the antitumor immune response. We hope that updated knowledge will reshape our understanding of the critical roles played by HERVs in human evolution and cancer progression.
{"title":"Dual roles of human endogenous retroviruses in cancer progression and antitumor immune response","authors":"Yang Yang, Surong Dong, Benshuai You, Chenglin Zhou","doi":"10.1016/j.bbcan.2024.189201","DOIUrl":"10.1016/j.bbcan.2024.189201","url":null,"abstract":"<div><div>Human endogenous retroviruses (HERVs) are a class of transposable elements formed by the integration of ancient retroviruses into the germline genome. They are inherited in a Mendelian manner and approximately constitute 8 % of the human genome. HERVs were considered as “junk DNA” for decades, but increasing evidence suggests that they play significant roles in pathological inflammation, neural differentiation, and oncogenesis. Specifically, HERVs expression has been implicated in several oncogenic processes and the formation of the tumor microenvironment. Indeed, the dual roles of HERVs in cancer, serving as both promoters of oncogenesis and forerunners of the innate antitumor immune response, remain a subject of debate. In this review, we will discuss how HERVs participate in cancer progression and how they are regulated. Our aim is to provide a comprehensive understanding of the fundamental properties and potential function of HERVs in propagating oncogenesis and activating the antitumor immune response. We hope that updated knowledge will reshape our understanding of the critical roles played by HERVs in human evolution and cancer progression.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1879 6","pages":"Article 189201"},"PeriodicalIF":9.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482909","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 : 2024-10-15DOI: 10.1016/j.bbcan.2024.189193
Dandan Feng , Dongqing Pu , Jinlu Ren , Ming Liu , Zhen Zhang , Zhiyong Liu , Jingwei Li
CD8+ T-cell exhaustion has been identified as a significant contributor to immunosuppression and immune escape in triple-negative breast cancer (TNBC). Dysfunction due to cell exhaustion is characterized by reduced effector capacity and sustained expression of inhibitory receptors (IRs). The factors contributing to CD8+ T-cell exhaustion are multifaceted, encompassing external influences such as the upregulation of IRs, reduction of effector cytokines, and internal changes within the immune cell, including transcriptomic alterations, epigenetic landscape remodeling, and metabolomic shifts. The impact of the altered TNBC tumor microenvironment (TME) on Tex is also a critical consideration. The production of exhausted CD8+ T-cells (CD8+ Tex) is positively correlated with poor prognosis and reduced response rates to immunotherapy in TNBC patients, underscoring the urgent need for the development of novel TNBC immunotherapeutic strategies that target the mechanisms of CD8+ T-cell exhaustion. This review delineates the dynamic trajectory of CD8+ T-cell exhaustion development in TNBC, provides an update on the latest research advancements in understanding its pathogenesis, and offers insights into potential immunotherapeutic strategies.
{"title":"CD8+ T-cell exhaustion: Impediment to triple-negative breast cancer (TNBC) immunotherapy","authors":"Dandan Feng , Dongqing Pu , Jinlu Ren , Ming Liu , Zhen Zhang , Zhiyong Liu , Jingwei Li","doi":"10.1016/j.bbcan.2024.189193","DOIUrl":"10.1016/j.bbcan.2024.189193","url":null,"abstract":"<div><div>CD8<sup>+</sup> T-cell exhaustion has been identified as a significant contributor to immunosuppression and immune escape in triple-negative breast cancer (TNBC). Dysfunction due to cell exhaustion is characterized by reduced effector capacity and sustained expression of inhibitory receptors (IRs). The factors contributing to CD8<sup>+</sup> T-cell exhaustion are multifaceted, encompassing external influences such as the upregulation of IRs, reduction of effector cytokines, and internal changes within the immune cell, including transcriptomic alterations, epigenetic landscape remodeling, and metabolomic shifts. The impact of the altered TNBC tumor microenvironment (TME) on Tex is also a critical consideration. The production of exhausted CD8<sup>+</sup> T-cells (CD8<sup>+</sup> Tex) is positively correlated with poor prognosis and reduced response rates to immunotherapy in TNBC patients, underscoring the urgent need for the development of novel TNBC immunotherapeutic strategies that target the mechanisms of CD8<sup>+</sup> T-cell exhaustion. This review delineates the dynamic trajectory of CD8<sup>+</sup> T-cell exhaustion development in TNBC, provides an update on the latest research advancements in understanding its pathogenesis, and offers insights into potential immunotherapeutic strategies.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1879 6","pages":"Article 189193"},"PeriodicalIF":9.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482913","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 : 2024-10-15DOI: 10.1016/j.bbcan.2024.189199
Zikai Guo , Zhichao Li , Jia Wang , Hongxiao Jiang , Xu Wang , Yangyang Sun , Weiren Huang
Bladder cancer (BCa) is the most common malignant tumor of the urinary system. Current treatments often have poor efficacy and carry a high risk of recurrence and progression due to the lack of consideration of tumor heterogeneity. Patient-derived organoids (PDOs) are three-dimensional tissue cultures that preserve tumor heterogeneity and clinical relevance better than cancer cell lines. Moreover, PDOs are more cost-effective and efficient to cultivate compared to patient-derived tumor xenografts, while closely mirroring the tissue and genetic characteristics of their source tissues. The development of PDOs involves critical steps such as sample selection and processing, culture medium optimization, matrix selection, and improvements in culture methods. This review summarizes the methodologies for generating PDOs from patients with BCa and discusses the current advancements in drug sensitivity testing, immunotherapy, living biobanks, drug screening, and mechanistic studies, highlighting their role in advancing personalized medicine.
{"title":"Modeling bladder cancer in the laboratory: Insights from patient-derived organoids","authors":"Zikai Guo , Zhichao Li , Jia Wang , Hongxiao Jiang , Xu Wang , Yangyang Sun , Weiren Huang","doi":"10.1016/j.bbcan.2024.189199","DOIUrl":"10.1016/j.bbcan.2024.189199","url":null,"abstract":"<div><div>Bladder cancer (BCa) is the most common malignant tumor of the urinary system. Current treatments often have poor efficacy and carry a high risk of recurrence and progression due to the lack of consideration of tumor heterogeneity. Patient-derived organoids (PDOs) are three-dimensional tissue cultures that preserve tumor heterogeneity and clinical relevance better than cancer cell lines. Moreover, PDOs are more cost-effective and efficient to cultivate compared to patient-derived tumor xenografts, while closely mirroring the tissue and genetic characteristics of their source tissues. The development of PDOs involves critical steps such as sample selection and processing, culture medium optimization, matrix selection, and improvements in culture methods. This review summarizes the methodologies for generating PDOs from patients with BCa and discusses the current advancements in drug sensitivity testing, immunotherapy, living biobanks, drug screening, and mechanistic studies, highlighting their role in advancing personalized medicine.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1879 6","pages":"Article 189199"},"PeriodicalIF":9.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482914","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 : 2024-10-15DOI: 10.1016/j.bbcan.2024.189198
Engeng Chen , Zhiru Zeng , Wei Zhou
Increased matrix stiffness within the colorectal cancer (CRC) tumor microenvironment (TME) has emerged as a pivotal determinant of immunotherapy outcomes. This review discusses the role of aberrant extracellular matrix (ECM) deposition and cross-linking in augmenting matrix stiffness, a phenomenon that not only scaffolds the tumor architecture but also contributes to tumorigenicity and immunologic evasion. Herein, we critically appraise the influence of matrix stiffness on the immunotherapeutic landscape of CRC, focusing on its capacity to impede therapeutic efficacy by modulating immune cell infiltration, activation, and functional performance. The review explores the molecular dynamics whereby matrix stiffness prompts tumor evolution, highlighting the integral role of integrin signaling, cancer-associated fibroblasts (CAFs), and the process of epithelial-mesenchymal transition (EMT). We bring to the fore the paradoxical impact of an indurated ECM on immune effector cells, chiefly T cells and macrophages, which are indispensable for immune surveillance and the execution of immunotherapeutic strategies, yet are markedly restrained by a fibrotic matrix. Furthermore, we examine how matrix stiffness modulates immune checkpoint molecule expression, thereby exacerbating the immunosuppressive milieu within the TME and attenuating immunotherapeutic potency. Emergent therapeutic regimens targeting matrix stiffness—including matrix modulators, inhibitors of mechanotransduction signaling pathways, and advanced biomaterials that mimic the ECM—proffer novel modalities to potentiate immunotherapy responsiveness. By refining the ECM's biomechanical attributes, the mechanical barriers posed by the tumor stroma can be improved, facilitating robust immune cell penetration and activity, and thereby bolstering the tumor's susceptibility to immunotherapy. Ongoing clinical trials are evaluating these innovative treatments, particularly in combination with immunotherapies, with the aim of enhancing clinical outcomes for CRC patients afflicted by pronounced matrix stiffness.
{"title":"The key role of matrix stiffness in colorectal cancer immunotherapy: mechanisms and therapeutic strategies","authors":"Engeng Chen , Zhiru Zeng , Wei Zhou","doi":"10.1016/j.bbcan.2024.189198","DOIUrl":"10.1016/j.bbcan.2024.189198","url":null,"abstract":"<div><div>Increased matrix stiffness within the colorectal cancer (CRC) tumor microenvironment (TME) has emerged as a pivotal determinant of immunotherapy outcomes. This review discusses the role of aberrant extracellular matrix (ECM) deposition and cross-linking in augmenting matrix stiffness, a phenomenon that not only scaffolds the tumor architecture but also contributes to tumorigenicity and immunologic evasion. Herein, we critically appraise the influence of matrix stiffness on the immunotherapeutic landscape of CRC, focusing on its capacity to impede therapeutic efficacy by modulating immune cell infiltration, activation, and functional performance. The review explores the molecular dynamics whereby matrix stiffness prompts tumor evolution, highlighting the integral role of integrin signaling, cancer-associated fibroblasts (CAFs), and the process of epithelial-mesenchymal transition (EMT). We bring to the fore the paradoxical impact of an indurated ECM on immune effector cells, chiefly T cells and macrophages, which are indispensable for immune surveillance and the execution of immunotherapeutic strategies, yet are markedly restrained by a fibrotic matrix. Furthermore, we examine how matrix stiffness modulates immune checkpoint molecule expression, thereby exacerbating the immunosuppressive milieu within the TME and attenuating immunotherapeutic potency. Emergent therapeutic regimens targeting matrix stiffness—including matrix modulators, inhibitors of mechanotransduction signaling pathways, and advanced biomaterials that mimic the ECM—proffer novel modalities to potentiate immunotherapy responsiveness. By refining the ECM's biomechanical attributes, the mechanical barriers posed by the tumor stroma can be improved, facilitating robust immune cell penetration and activity, and thereby bolstering the tumor's susceptibility to immunotherapy. Ongoing clinical trials are evaluating these innovative treatments, particularly in combination with immunotherapies, with the aim of enhancing clinical outcomes for CRC patients afflicted by pronounced matrix stiffness.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1879 6","pages":"Article 189198"},"PeriodicalIF":9.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445946","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}
The WNT/β-catenin is among one of the most extensively studied cellular signaling pathways involved in the initiation and progression of several deadly cancers. It is now understood that the WNT/β-catenin signaling, during tumor progression operates in a very complex fashion beyond the earlier assumed simple WNT ‘On’ or ‘Off’ mode as it recruits numerous WNT ligands, receptors, transcriptional factors and also cross-talks with other signaling molecules including the noncanonical WNT regulators. WNT/β-catenin signaling molecules are often mutated in different cancers which makes them very challenging to inhibit and sometimes ranks them among the undruggable targets. Furthermore, due to the evolutionary conservation of this pathway, inhibiting WNT/β-catenin has caused significant toxicity in normal cells. These challenges are reflected in clinical trial data, where the use of WNT/β-catenin inhibitors as standalone treatments remains limited. In this review, we have highlighted the crucial functional associations of diverse WNT/β-catenin signaling regulators with cancer progression and the phenotypic switching of tumor cells. Next, we have shed light on the roles of WNT/β-catenin signaling in drug resistance, clonal evolution, tumor heterogeneity, and immune evasion. The present review also focuses on various classes of routine and novel WNT/β-catenin therapeutic regimes while addressing the challenges associated with targeting the regulators of this complex pathway. In the light of multiple case studies on WNT/β-catenin inhibitors, we also highlighted the challenges and opportunities for future clinical trial strategies involving these treatments. Additionally, we have proposed strategies for future WNT/β-catenin-based drug discovery trials, emphasizing the potential of combination therapies and AI/ML-driven prediction approaches. Overall, here we showcased the opportunities, possibilities, and potentialities of WNT/β-catenin signaling modulatory therapeutic regimes as promising precision cancer medicines for the future.
{"title":"Belling the “cat”: Wnt/β-catenin signaling and its significance in future cancer therapies","authors":"Akansha Goyal , Satyajit Laxman Murkute , Sujoy Bhowmik , Chandra Prakash Prasad , Purusottam Mohapatra","doi":"10.1016/j.bbcan.2024.189195","DOIUrl":"10.1016/j.bbcan.2024.189195","url":null,"abstract":"<div><div>The WNT/β-catenin is among one of the most extensively studied cellular signaling pathways involved in the initiation and progression of several deadly cancers. It is now understood that the WNT/β-catenin signaling, during tumor progression operates in a very complex fashion beyond the earlier assumed simple WNT ‘On’ or ‘Off’ mode as it recruits numerous WNT ligands, receptors, transcriptional factors and also cross-talks with other signaling molecules including the noncanonical WNT regulators. WNT/β-catenin signaling molecules are often mutated in different cancers which makes them very challenging to inhibit and sometimes ranks them among the undruggable targets. Furthermore, due to the evolutionary conservation of this pathway, inhibiting WNT/β-catenin has caused significant toxicity in normal cells. These challenges are reflected in clinical trial data, where the use of WNT/β-catenin inhibitors as standalone treatments remains limited. In this review, we have highlighted the crucial functional associations of diverse WNT/β-catenin signaling regulators with cancer progression and the phenotypic switching of tumor cells. Next, we have shed light on the roles of WNT/β-catenin signaling in drug resistance, clonal evolution, tumor heterogeneity, and immune evasion. The present review also focuses on various classes of routine and novel WNT/β-catenin therapeutic regimes while addressing the challenges associated with targeting the regulators of this complex pathway. In the light of multiple case studies on WNT/β-catenin inhibitors, we also highlighted the challenges and opportunities for future clinical trial strategies involving these treatments. Additionally, we have proposed strategies for future WNT/β-catenin-based drug discovery trials, emphasizing the potential of combination therapies and AI/ML-driven prediction approaches. Overall, here we showcased the opportunities, possibilities, and potentialities of WNT/β-catenin signaling modulatory therapeutic regimes as promising precision cancer medicines for the future.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1879 6","pages":"Article 189195"},"PeriodicalIF":9.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445947","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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