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1
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Chiang ZC, Xu S, Zhao X, Liu M, Lin J, Chen Q. Generation and characterization of 7DC-DM1: a non-cleavable CD47-targeting antibody-drug conjugates with antitumor effects. Int J Biol Macromol 2025; 310:142844. [PMID: 40187444 DOI: 10.1016/j.ijbiomac.2025.142844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 03/30/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
Colorectal cancer is the second leading cause of cancer-related deaths following lung cancer in recent years. Therefore, lung or colorectal cancer therapy is very important for reducing mortality. In this study, we developed and characterized CD47-specific antibody-drug conjugates, namely 7DC-DM1 ADCs, to evaluate their therapeutic effects on lung and colorectal cancer. Both 7DC2-DM1 and 7DC4-DM1 demonstrated good binding affinities of 0.56 nM and 0.49 nM, respectively, and exhibited significant cytotoxicity, though they displayed different penetration effects. These findings suggest that the binding complexes of 7DC2-DM1 and 7DC4-DM1 with CD47 receptors adopt different conformations, leading to variations in their cellular internalized efficiencies. Molecular docking simulations revealed that 7DC2 and 7DC4 bind to CD47 molecules in distinct orientations and epitopes, differing between conserved and non-conserved regions. Furthermore, treatments with 7DC2-DM1 and 7DC4-DM1 displayed notable differences in antitumor effects in murine syngeneic tumor models derived from the MC38 cell line in C57BL/6 mice. In the tumor model treated with 7DC4-DM1, immunofluorescence staining analysis revealed a large area of necrosis in the tumor stroma, accompanied by a significant infiltration of CD11b-expressing immune cells. In summary, these results indicate that 7DC4-DM1 holds promise as a therapeutic agent for colorectal cancer treatment.
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Affiliation(s)
- Zu-Chian Chiang
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China; College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, China.
| | - Shan Xu
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
| | - Xiangqian Zhao
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China
| | - Min Liu
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China.
| | - Jizhen Lin
- The Cancer Center, Union Hospital, Fujian Medical University, Fuzhou, Fujian, China.
| | - Qi Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, Fujian, China.
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2
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Shang T, Jia Z, Li J, Cao H, Xu H, Cong L, Ma D, Wang X, Liu J. Unraveling the triad of hypoxia, cancer cell stemness, and drug resistance. J Hematol Oncol 2025; 18:32. [PMID: 40102937 PMCID: PMC11921735 DOI: 10.1186/s13045-025-01684-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 03/05/2025] [Indexed: 03/20/2025] Open
Abstract
In the domain of addressing cancer resistance, challenges such as limited effectiveness and treatment resistance remain persistent. Hypoxia is a key feature of solid tumors and is strongly associated with poor prognosis in cancer patients. Another significant portion of the development of acquired drug resistance is attributed to tumor stemness. Cancer stem cells (CSCs), a small tumor cell subset with self-renewal and proliferative abilities, are crucial for tumor initiation, metastasis, and intra-tumoral heterogeneity. Studies have shown a significant association between hypoxia and CSCs in the context of tumor resistance. Recent studies reveal a strong link between hypoxia and tumor stemness, which together promote tumor survival and progression during treatment. This review elucidates the interplay between hypoxia and CSCs, as well as their correlation with resistance to therapeutic drugs. Targeting pivotal genes associated with hypoxia and stemness holds promise for the development of novel therapeutics to combat tumor resistance.
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Affiliation(s)
- Tongxuan Shang
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Ziqi Jia
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiayi Li
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China
| | - Heng Cao
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hengyi Xu
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lin Cong
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- School of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Dongxu Ma
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiang Wang
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jiaqi Liu
- Department of Breast Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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3
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Zhang S, Dong H, Jin X, Sun J, Li Y. The multifaceted roles of macrophages in the transition from hepatitis to hepatocellular carcinoma: From mechanisms to therapeutic strategies. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167676. [PMID: 39828046 DOI: 10.1016/j.bbadis.2025.167676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/06/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
Macrophages are central to the progression from hepatitis to hepatocellular carcinoma (HCC), with their remarkable plasticity and ability to adapt to the changing liver microenvironment. Chronic inflammation, fibrosis, and ultimately tumorigenesis are driven by macrophage activation, making them key regulators of liver disease progression. This review explores the diverse roles of macrophages in the transition from hepatitis to HCC. In the early stages of hepatitis, macrophages are essential for pathogen clearance and tissue repair. However, chronic activation leads to prolonged inflammation, which exacerbates liver damage and promotes fibrosis. As the disease progresses to liver fibrosis, macrophages interact with hepatic stellate cells, fostering a pro-tumorigenic microenvironment that supports HCC development. In hepatocarcinogenesis, macrophages contribute to tumor initiation, growth, metastasis, immune evasion, cancer stem cell maintenance, and angiogenesis. Their functional plasticity enables them to adapt to the tumor microenvironment, thereby promoting tumor progression and resistance to therapy. Targeting macrophages represents a promising strategy for preventing and treating HCC. Therapeutic approaches, including reprogramming macrophage phenotypes to enhance anti-tumor immunity, blocking macrophage recruitment and activation, and utilizing nanoparticle-based drug delivery systems, may provide new avenues for combating HCC by modulating macrophage functions and tumor microenvironment dynamics.
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Affiliation(s)
- Shuairan Zhang
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China
| | - Hang Dong
- Phase I Clinical Trials Center, The People's Hospital of China Medical University, Shenyang, PR China
| | - Xiuli Jin
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China
| | - Jing Sun
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China
| | - Yiling Li
- Department of Gastroenterology, The First Hospital of China Medical University, Shenyang, PR China.
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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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Hemida AS, Tantawy MS. Implication of TRPM8, CD47, and CDK4 expressions in hepatocellular carcinoma progression. J Immunoassay Immunochem 2025; 46:245-261. [PMID: 39957041 DOI: 10.1080/15321819.2025.2464718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2025]
Abstract
Participation of TRPM8 in hepatocellular carcinoma (HCC) development was not precisely declared. CD47 mediates immune escape and macrophage phagocytosis of tumors. CDK4 mediates oncogenesis. Synergistic implications of TRPM8, CD47, and CDK4 in HCC were not declared. This research aims to demonstrate the expressions of TRPM8, CD47and CDK4 in HCC and to declare correlations and significance. Paraffin blocks from 101 hCC and 82 adjacent non-tumorous liver were immunostained using TRPM8, CD47 and CDK4 antibodies. HCC showed highly significant increased TRPM8, CD47, and CDK4 expressions than control liver tissue (p < 0.001) for all. TRPM8, CD47, and CDK4 were significantly associated with poor prognostic criteria as high tumor grade, advanced stage, microvascular invasion, and necrosis. There was a significant association between cirrhotic and non-cirrhotic adjacent liver regarding positive TRPM8 (p < 0.02) and high CDK4 expressions (p < 0.045). There were significant direct relationships between each immunohistochemical antibody and the other two. Prolonged overall survival was significantly associated with low CDK4 (p = 0.019). In conclusion, TRPM8, CD47, and CDK4 may regulate synergistic functions in HCC oncogenesis and accomplish unfavorable prognostic significance. TRPM8 and CDK4 might share in development of HCC from cirrhosis. TRPM8, CD47, and CDK4 could be therapeutic targets in HCC.
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Affiliation(s)
- Aiat Shaban Hemida
- Pathology Department, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
| | - Mona Saeed Tantawy
- Pathology Department, National Liver Institute- Menoufia University, Shebin El Kom, Egypt
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6
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Verona F, Di Bella S, Schirano R, Manfredi C, Angeloro F, Bozzari G, Todaro M, Giannini G, Stassi G, Veschi V. Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction. Front Immunol 2025; 16:1529847. [PMID: 39981232 PMCID: PMC11839637 DOI: 10.3389/fimmu.2025.1529847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 01/17/2025] [Indexed: 02/22/2025] Open
Abstract
Cancer stem cells (CSCs) are a small subset within the tumor mass significantly contributing to cancer progression through dysregulation of various oncogenic pathways, driving tumor growth, chemoresistance and metastasis formation. The aggressive behavior of CSCs is guided by several intracellular signaling pathways such as WNT, NF-kappa-B, NOTCH, Hedgehog, JAK-STAT, PI3K/AKT1/MTOR, TGF/SMAD, PPAR and MAPK kinases, as well as extracellular vesicles such as exosomes, and extracellular signaling molecules such as cytokines, chemokines, pro-angiogenetic and growth factors, which finely regulate CSC phenotype. In this scenario, tumor microenvironment (TME) is a key player in the establishment of a permissive tumor niche, where CSCs engage in intricate communications with diverse immune cells. The "oncogenic" immune cells are mainly represented by B and T lymphocytes, NK cells, and dendritic cells. Among immune cells, macrophages exhibit a more plastic and adaptable phenotype due to their different subpopulations, which are characterized by both immunosuppressive and inflammatory phenotypes. Specifically, tumor-associated macrophages (TAMs) create an immunosuppressive milieu through the production of a plethora of paracrine factors (IL-6, IL-12, TNF-alpha, TGF-beta, CCL1, CCL18) promoting the acquisition by CSCs of a stem-like, invasive and metastatic phenotype. TAMs have demonstrated the ability to communicate with CSCs via direct ligand/receptor (such as CD90/CD11b, LSECtin/BTN3A3, EPHA4/Ephrin) interaction. On the other hand, CSCs exhibited their capacity to influence immune cells, creating a favorable microenvironment for cancer progression. Interestingly, the bidirectional influence of CSCs and TME leads to an epigenetic reprogramming which sustains malignant transformation. Nowadays, the integration of biological and computational data obtained by cutting-edge technologies (single-cell RNA sequencing, spatial transcriptomics, trajectory analysis) has significantly improved the comprehension of the biunivocal multicellular dialogue, providing a comprehensive view of the heterogeneity and dynamics of CSCs, and uncovering alternative mechanisms of immune evasion and therapeutic resistance. Moreover, the combination of biology and computational data will lead to the development of innovative target therapies dampening CSC-TME interaction. Here, we aim to elucidate the most recent insights on CSCs biology and their complex interactions with TME immune cells, specifically TAMs, tracing an exhaustive scenario from the primary tumor to metastasis formation.
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Affiliation(s)
- Francesco Verona
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Sebastiano Di Bella
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Roberto Schirano
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Camilla Manfredi
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Francesca Angeloro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Giulia Bozzari
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Matilde Todaro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
- Azienda Ospedaliera Universitaria Policlinico “Paolo Giaccone” (AOUP), Palermo, Italy
| | - Giuseppe Giannini
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
- Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Giorgio Stassi
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Veronica Veschi
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
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7
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Che Z, Wang W, Zhang L, Lin Z. Therapeutic strategies targeting CD47-SIRPα signaling pathway in gastrointestinal cancers treatment. J Pharm Anal 2025; 15:101099. [PMID: 39881799 PMCID: PMC11772969 DOI: 10.1016/j.jpha.2024.101099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 09/04/2024] [Accepted: 09/07/2024] [Indexed: 01/31/2025] Open
Abstract
Gastrointestinal (GI) cancers are prevalent globally, with leading incidence and mortality rates among malignant tumors. Despite notable advancements in surgical resection, radiotherapy, and chemotherapy, the overall survival rates remain low. Hence, it is imperative to explore alternative approaches that enhance patient outcomes. Cluster of differentiation 47 (CD47), serving as an early diagnostic marker, is predominantly overexpressed in GI cancers and associated with poor prognosis. Targeting the CD47-signal regulatory protein alpha (SIRPα) signaling pathway may provide a novel strategy for GI cancers treatment. This study summarizes current knowledge of the structure and function of CD47 and SIRPα, their roles in signaling pathways, the prognostic significance of CD47, therapeutic strategies targeting the CD47-SIRPα signaling pathway in GI cancer, and highlights key issues for future investigations.
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Affiliation(s)
- Zhengping Che
- School of Life Sciences, Chongqing University, Chongqing, 401331, China
| | - Wei Wang
- Department of Cancer Center, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Chongqing, 404000, China
| | - Lin Zhang
- Department of Gastroenterology, Chongqing University Jiangjin Hospital, Chongqing, 402260, China
| | - Zhenghong Lin
- School of Life Sciences, Chongqing University, Chongqing, 401331, China
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8
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Arafat Hossain M. A comprehensive review of immune checkpoint inhibitors for cancer treatment. Int Immunopharmacol 2024; 143:113365. [PMID: 39447408 DOI: 10.1016/j.intimp.2024.113365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 09/28/2024] [Accepted: 10/05/2024] [Indexed: 10/26/2024]
Abstract
Immunology-based therapies are emerging as an effective cancer treatment, using the body's immune system to target tumors. Immune checkpoints, which regulate immune responses to prevent tissue damage and autoimmunity, are often exploited by cancer cells to avoid destruction. The discovery of checkpoint proteins like PD-1/PD-L1 and CTLA-4 was pivotal in developing cancer immunotherapy. Immune checkpoint inhibitors (ICIs) have shown great success, with FDA-approved drugs like PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and CTLA-4 inhibitors (Ipilimumab, Tremelimumab), alongside LAG-3 inhibitor Relatlimab. Research continues on new checkpoints like TIM-3, VISTA, B7-H3, BTLA, and TIGIT. Biomarkers like PDL-1 expression, tumor mutation burden, interferon-γ presence, microbiome composition, and extracellular matrix characteristics play a crucial role in predicting responses to immunotherapy with checkpoint inhibitors. Despite their effectiveness, not all patients experience the same level of benefit, and organ-specific immune-related adverse events (irAEs) such as rash or itching, colitis, diarrhea, hyperthyroidism, and hypothyroidism may occur. Given the rapid advancements in this field and the variability in patient outcomes, there is an urgent need for a comprehensive review that consolidates the latest findings on immune checkpoint inhibitors, covering their clinical status, biomarkers, resistance mechanisms, strategies to overcome resistance, and associated adverse effects. This review aims to fill this gap by providing an analysis of the current clinical status of ICIs, emerging biomarkers, mechanisms of resistance, strategies to enhance therapeutic efficacy, and assessment of adverse effects. This review is crucial to furthering our understanding of ICIs and optimizing their application in cancer therapy.
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Affiliation(s)
- Md Arafat Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh.
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9
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Li X, Han H, Yang K, Li S, Ma L, Yang Z, Zhao YX. Crosstalk between thyroid CSCs and immune cells: basic principles and clinical implications. Front Immunol 2024; 15:1476427. [PMID: 39776907 PMCID: PMC11703838 DOI: 10.3389/fimmu.2024.1476427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025] Open
Abstract
Thyroid cancer has become the most common endocrine malignancy. Although the majority of differentiated thyroid cancers have a favorable prognosis, advanced thyroid cancers, iodine-refractory thyroid cancers, and highly malignant undifferentiated carcinomas still face a serious challenge of poor prognosis and even death. Cancer stem cells are recognized as one of the central drivers of tumor evolution, recurrence and treatment resistance. A fresh viewpoint on the oncological aspects of thyroid cancer, including proliferation, invasion, recurrence, metastasis, and therapeutic resistance, has been made possible by the recent thorough understanding of the defining and developing features as well as the plasticity of thyroid cancer stem cells (TCSCs). The above characteristics of TCSCs are complicated and regulated by cell-intrinsic mechanisms (including activation of key stem signaling pathways, somatic cell dedifferentiation, etc.) and cell-extrinsic mechanisms. The complex communication between TCSCs and the infiltrating immune cell populations in the tumor microenvironment (TME) is a paradigm for cell-extrinsic regulators. This review introduces the current advances in the studies of TCSCs, including the origin of TCSCs, the intrinsic signaling pathways regulating the stemness of TCSCs, and emerging biomarkers; We further highlight the underlying principles of bidirectional crosstalk between TCSCs and immune cell populations driving thyroid cancer progression, recurrence, or metastasis, including the specific mechanisms by which immune cells maintain the stemness and other properties of TCSCs and how TCSCs reshape the immune microenvironmental landscape to create an immune evasive and pro-tumorigenic ecological niche. Finally, we outline promising strategies and challenges for targeting key programs in the TCSCs-immune cell crosstalk process to treat thyroid cancer.
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Affiliation(s)
- Xiaoxiao Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Hengtong Han
- The Seventh Department of General Surgery, Department of Thyroid Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Kaili Yang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Shouhua Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Libin Ma
- The Seventh Department of General Surgery, Department of Thyroid Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ze Yang
- The Seventh Department of General Surgery, Department of Thyroid Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yong-xun Zhao
- The Seventh Department of General Surgery, Department of Thyroid Surgery, The First Hospital of Lanzhou University, Lanzhou, China
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10
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Polara R, Ganesan R, Pitson SM, Robinson N. Cell autonomous functions of CD47 in regulating cellular plasticity and metabolic plasticity. Cell Death Differ 2024; 31:1255-1266. [PMID: 39039207 PMCID: PMC11445524 DOI: 10.1038/s41418-024-01347-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/09/2024] [Accepted: 07/11/2024] [Indexed: 07/24/2024] Open
Abstract
CD47 is a ubiquitously expressed cell surface receptor, which is widely known for preventing macrophage-mediated phagocytosis by interacting with signal regulatory protein α (SIRPα) on the surface of macrophages. In addition to its role in phagocytosis, emerging studies have reported numerous noncanonical functions of CD47 that include regulation of various cellular processes such as proliferation, migration, apoptosis, differentiation, stress responses, and metabolism. Despite lacking an extensive cytoplasmic signaling domain, CD47 binds to several cytoplasmic proteins, particularly upon engaging with its secreted matricellular ligand, thrombospondin 1. Indeed, the regulatory functions of CD47 are greatly influenced by its interacting partners. These interactions are often cell- and context-specific, adding a further level of complexity. This review addresses the downstream cell-intrinsic signaling pathways regulated by CD47 in various cell types and environments. Some of the key pathways modulated by this receptor include the PI3K/AKT, MAPK/ERK, and nitric oxide signaling pathways, as well as those implicated in glucose, lipid, and mitochondrial metabolism. These pathways play vital roles in maintaining tissue homeostasis, highlighting the importance of understanding the phagocytosis-independent functions of CD47. Given that CD47 expression is dysregulated in a variety of cancers, improving our understanding of the cell-intrinsic signals regulated by this molecule will help advance the development of CD47-targeted therapies.
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Affiliation(s)
- Ruhi Polara
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
| | - Raja Ganesan
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
- Institute for Molecular Immunology, CECAD Research Center, University Hospital Cologne, Cologne, Germany
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
- School of Biological Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Nirmal Robinson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.
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11
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Tsui YM, Tian L, Lu J, Ma H, Ng IOL. Interplay among extracellular vesicles, cancer stemness and immune regulation in driving hepatocellular carcinoma progression. Cancer Lett 2024; 597:217084. [PMID: 38925362 DOI: 10.1016/j.canlet.2024.217084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 06/20/2024] [Accepted: 06/23/2024] [Indexed: 06/28/2024]
Abstract
The intricate interplay among extracellular vesicles, cancer stemness properties, and the immune system significantly impacts hepatocellular carcinoma (HCC) progression, treatment response, and patient prognosis. Extracellular vesicles (EVs), which are membrane-bound structures, play a pivotal role in conveying proteins, lipids, and nucleic acids between cells, thereby serving as essential mediators of intercellular communication. Since a lot of current research focuses on small extracellular vesicles (sEVs), with diameters ranging from 30 nm to 200 nm, this review emphasizes the role of sEVs in the context of interactions between HCC stemness-bearing cells and the immune cells. sEVs offer promising opportunities for the clinical application of innovative diagnostic and prognostic biomarkers in HCC. By specifically targeting sEVs, novel therapeutics aimed at cancer stemness can be developed. Ongoing investigations into the roles of sEVs in cancer stemness and immune regulation in HCC will broaden our understanding and ultimately pave the way for groundbreaking therapeutic interventions.
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Affiliation(s)
- Yu-Man Tsui
- Department of Pathology, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Lu Tian
- Department of Pathology, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Jingyi Lu
- Department of Pathology, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Huanhuan Ma
- Department of Pathology, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.
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Guo DZ, Zhang X, Zhang SQ, Zhang SY, Zhang XY, Yan JY, Dong SY, Zhu K, Yang XR, Fan J, Zhou J, Huang A. Single-cell tumor heterogeneity landscape of hepatocellular carcinoma: unraveling the pro-metastatic subtype and its interaction loop with fibroblasts. Mol Cancer 2024; 23:157. [PMID: 39095854 PMCID: PMC11295380 DOI: 10.1186/s12943-024-02062-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 07/05/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Tumor heterogeneity presents a formidable challenge in understanding the mechanisms driving tumor progression and metastasis. The heterogeneity of hepatocellular carcinoma (HCC) in cellular level is not clear. METHODS Integration analysis of single-cell RNA sequencing data and spatial transcriptomics data was performed. Multiple methods were applied to investigate the subtype of HCC tumor cells. The functional characteristics, translation factors, clinical implications and microenvironment associations of different subtypes of tumor cells were analyzed. The interaction of subtype and fibroblasts were analyzed. RESULTS We established a heterogeneity landscape of HCC malignant cells by integrated 52 single-cell RNA sequencing data and 5 spatial transcriptomics data. We identified three subtypes in tumor cells, including ARG1+ metabolism subtype (Metab-subtype), TOP2A+ proliferation phenotype (Prol-phenotype), and S100A6+ pro-metastatic subtype (EMT-subtype). Enrichment analysis found that the three subtypes harbored different features, that is metabolism, proliferating, and epithelial-mesenchymal transition. Trajectory analysis revealed that both Metab-subtype and EMT-subtype originated from the Prol-phenotype. Translation factor analysis found that EMT-subtype showed exclusive activation of SMAD3 and TGF-β signaling pathway. HCC dominated by EMT-subtype cells harbored an unfavorable prognosis and a deserted microenvironment. We uncovered a positive loop between tumor cells and fibroblasts mediated by SPP1-CD44 and CCN2/TGF-β-TGFBR1 interaction pairs. Inhibiting CCN2 disrupted the loop, mitigated the transformation to EMT-subtype, and suppressed metastasis. CONCLUSION By establishing a heterogeneity landscape of malignant cells, we identified a three-subtype classification in HCC. Among them, S100A6+ tumor cells play a crucial role in metastasis. Targeting the feedback loop between tumor cells and fibroblasts is a promising anti-metastatic strategy.
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Affiliation(s)
- De-Zhen Guo
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xin Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Sen-Quan Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Shi-Yu Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiang-Yu Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jia-Yan Yan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - San-Yuan Dong
- Department of Radiology, Zhongshan Hospital, Shanghai Institute of Medical Imaging, Fudan University, Shanghai, 200032, China
| | - Kai Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xin-Rong Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China.
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
| | - Ao Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, China.
- Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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13
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Saw PE, Liu Q, Wong PP, Song E. Cancer stem cell mimicry for immune evasion and therapeutic resistance. Cell Stem Cell 2024; 31:1101-1112. [PMID: 38925125 DOI: 10.1016/j.stem.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 03/11/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024]
Abstract
Cancer stem cells (CSCs) are heterogeneous, possess self-renewal attributes, and orchestrate important crosstalk in tumors. We propose that the CSC state represents "mimicry" by cancer cells that leads to phenotypic plasticity. CSC mimicry is suggested as CSCs can impersonate immune cells, vasculo-endothelia, or lymphangiogenic cells to support cancer growth. CSCs facilitate both paracrine and juxtracrine signaling to prime tumor-associated immune and stromal cells to adopt pro-tumoral phenotypes, driving therapeutic resistance. Here, we outline the ingenuity of CSCs' mimicry in their quest to evade immune detection, which leads to immunotherapeutic resistance, and highlight CSC-mimicry-targeted therapeutic strategies for robust immunotherapy.
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Affiliation(s)
- Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan, China
| | - Qiang Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ping-Pui Wong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan, China
| | - Erwei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan, China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Zenith Institute of Medical Sciences, Guangzhou 510120, China.
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14
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Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z, Zhai Z, Tanzhu G, Yang J, Zhou R. Cancer stem cells: advances in knowledge and implications for cancer therapy. Signal Transduct Target Ther 2024; 9:170. [PMID: 38965243 PMCID: PMC11224386 DOI: 10.1038/s41392-024-01851-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 03/27/2024] [Accepted: 04/28/2024] [Indexed: 07/06/2024] Open
Abstract
Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.
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Affiliation(s)
- Xianjing Chu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wentao Tian
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaoyang Ning
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Gang Xiao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yunqi Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ziqi Wang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuofan Zhai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guilong Tanzhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jie Yang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
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15
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Ma Y, Lv H, Xing F, Xiang W, Wu Z, Feng Q, Wang H, Yang W. Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression. Front Med 2024; 18:430-445. [PMID: 38600350 DOI: 10.1007/s11684-023-1049-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/15/2023] [Indexed: 04/12/2024]
Abstract
Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.
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Affiliation(s)
- Yue Ma
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongwei Lv
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China
| | - Fuxue Xing
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Wei Xiang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Zixin Wu
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Qiyu Feng
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongyang Wang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
| | - Wen Yang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
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Zhao Z, Deng Y, Han J, Ma L, Zhu Y, Zhang H, He Z, Song Y. CircMALAT1 promotes cancer stem-like properties and chemoresistance via regulating Musashi-2/c-Myc axis in esophageal squamous cell carcinoma. MedComm (Beijing) 2024; 5:e612. [PMID: 38881674 PMCID: PMC11176741 DOI: 10.1002/mco2.612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 06/18/2024] Open
Abstract
The primary challenge in treating esophageal squamous cell carcinoma (ESCC) is resistance to chemotherapy. Cancer stem cell (CSC) is the root cause of tumor drug resistance. Therefore, targeting CSCs has been considered promising therapeutic strategy for tumor treatment. Here, we report that circMALAT1 was significantly upregulated in ESCC CSC-like cells and primary tumors from ESCC patients. Clinically, there was a positive correlation between circMALAT1 expression and ESCC stage and lymph node metastasis, as well as poor prognosis for ESCC patients. In vitro and in vivo functional studies revealed that circMALAT1 promoted CSC-like cells expansion, tumor growth, lung metastasis and drug resistance of ESCC. Mechanistically, circMALAT1 directly interacted with CSC-functional protein Musashi RNA Binding Protein 2 (MSI2). CircMALAT1 inhibited MSI2 ubiquitination by preventing it from interacting with β-transducin repeat containing protein (BTRC) E3 ubiquitin ligase. Also, circMALAT1 knockdown inhibited the expression of MSI2-regulating CSC-markers c-Myc in ESCC. Collectively, circMALAT1 modulated the ubiquitination and degradation of the MSI2 protein signaling with ESCC CSCs and accelerated malignant progression of ESCC. CircMALAT1 has the potential to serve as a biomarker for drug resistance and as a target for therapy in CSCs within ESCC.
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Affiliation(s)
- Zitong Zhao
- Key Laboratory of Cancer and Microbiome State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Yingni Deng
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine Zunyi Medical University Zunyi China
| | - Jing Han
- Department of Oncology The Fourth Hospital of Hebei Medical University Shijiazhuang Hebei China
| | - Liying Ma
- Key Laboratory of Cancer and Microbiome State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Yumeng Zhu
- Key Laboratory of Cancer and Microbiome State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
- Beijing No.4 High School International Campus Beijing China
| | - Hua Zhang
- School of Continuing Education Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China
| | - Zhixu He
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine Zunyi Medical University Zunyi China
| | - Yongmei Song
- Key Laboratory of Cancer and Microbiome State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
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17
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Tsui YM, Ho DWH, Sze KMF, Lee JMF, Lee E, Zhang Q, Cheung GCH, Tang CN, Tang VWL, Cheung ETY, Lo ILO, Chan ACY, Cheung TT, Ng IOL. Sorted-Cell Sequencing on HCC Specimens Reveals EPS8L3 as a Key Player in CD24/CD13/EpCAM-Triple Positive, Stemness-Related HCC Cells. Cell Mol Gastroenterol Hepatol 2024; 18:101358. [PMID: 38750898 PMCID: PMC11238133 DOI: 10.1016/j.jcmgh.2024.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 05/07/2024] [Accepted: 05/07/2024] [Indexed: 06/02/2024]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a heterogeneous cancer with varying levels of liver tumor initiating or cancer stem cells in the tumors. We aimed to investigate the expression of different liver cancer stem cell (LCSC) markers in human HCCs and identify their regulatory mechanisms in stemness-related cells. METHODS We used an unbiased, single-marker sorting approach by flow cytometry, fluorescence-activated cell sorting, and transcriptomic analyses on HCC patients' resected specimens. Knockdown approach was used, and relevant functional assays were conducted on the identified targets of interest. RESULTS Flow cytometry on a total of 60 HCC resected specimens showed significant heterogeneity in the expression of LCSC markers, with CD24, CD13, and EpCAM mainly contributing to this heterogeneity. Concomitant expression of CD24, CD13, and EpCAM was detected in 32 HCC samples, and this was associated with advanced tumor stages. Transcriptomic sequencing on the HCC cells sorted for these individual markers identified epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3) as a common gene associated with the 3 markers and was functionally validated in HCC cells. Knocking down EPS8L3 suppressed the expression of all 3 markers. To search for the upstream regulation of EPS8L3, we found SP1 bound to EPS8L3 promoter to drive EPS8L3 expression. Furthermore, using Akt inhibitor MK2206, we showed that Akt signaling-driven SP1 drove the expression of the 3 LCSC markers. CONCLUSIONS Our findings suggest that Akt signaling-driven SP1 promotes EPS8L3 expression, which is critical in maintaining the downstream expression of CD24, CD13, and EpCAM. The findings provide insight into potential LCSC-targeting therapeutic strategies.
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Affiliation(s)
- Yu-Man Tsui
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Daniel Wai-Hung Ho
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Karen Man-Fong Sze
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Joyce Man-Fong Lee
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Eva Lee
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Qingyang Zhang
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Gary Cheuk-Hang Cheung
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | | | | | | | | | - Albert Chi-Yan Chan
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong; Department of Surgery, The University of Hong Kong, Hong Kong
| | - Tan-To Cheung
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong; Department of Surgery, The University of Hong Kong, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.
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18
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Zhao H, Ling Y, He J, Dong J, Mo Q, Wang Y, Zhang Y, Yu H, Tang C. Potential targets and therapeutics for cancer stem cell-based therapy against drug resistance in hepatocellular carcinoma. Drug Resist Updat 2024; 74:101084. [PMID: 38640592 DOI: 10.1016/j.drup.2024.101084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/22/2024] [Accepted: 04/06/2024] [Indexed: 04/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common digestive malignancyin the world, which is frequently diagnosed at late stage with a poor prognosis. For most patients with advanced HCC, the therapeutic options arelimiteddue to cancer occurrence of drug resistance. Hepatic cancer stem cells (CSCs) account for a small subset of tumor cells with the ability of self-renewal and differentiationin HCC. It is widely recognized that the presence of CSCs contributes to primary and acquired drug resistance. Therefore, hepatic CSCs-targeted therapy is considered as a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. In this article, we review drug resistance in HCC and provide a summary of potential targets for CSCs-based therapy. In addition, the development of CSCs-targeted therapeuticsagainst drug resistance in HCC is summarized in both preclinical and clinical trials. The in-depth understanding of CSCs-related drug resistance in HCC will favor optimization of the current therapeutic strategies and gain encouraging therapeutic outcomes.
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Affiliation(s)
- Hongxing Zhao
- Department of Radiology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yuhang Ling
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jie He
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jinling Dong
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Qinliang Mo
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yao Wang
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Ying Zhang
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Hongbin Yu
- Department of General Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Chengwu Tang
- Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China.
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19
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Kaur S, Reginauld B, Razjooyan S, Phi T, Singh SP, Meyer TJ, Cam MC, Roberts DD. Effects of a humanized CD47 antibody and recombinant SIRPα proteins on triple negative breast carcinoma stem cells. Front Cell Dev Biol 2024; 12:1356421. [PMID: 38495618 PMCID: PMC10940465 DOI: 10.3389/fcell.2024.1356421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/12/2024] [Indexed: 03/19/2024] Open
Abstract
Signal regulatory protein-α (SIRPα, SHPS-1, CD172a) expressed on myeloid cells transmits inhibitory signals when it engages its counter-receptor CD47 on an adjacent cell. Elevated CD47 expression on some cancer cells thereby serves as an innate immune checkpoint that limits phagocytic clearance of tumor cells by macrophages and antigen presentation to T cells. Antibodies and recombinant SIRPα constructs that block the CD47-SIRPα interaction on macrophages exhibit anti-tumor activities in mouse models and are in ongoing clinical trials for treating several human cancers. Based on prior evidence that engaging SIRPα can also alter CD47 signaling in some nonmalignant cells, we compared direct effects of recombinant SIRPα-Fc and a humanized CD47 antibody that inhibits CD47-SIRPα interaction (CC-90002) on CD47 signaling in cancer stem cells derived from the MDA-MB- 231 triple-negative breast carcinoma cell line. Treatment with SIRPα-Fc significantly increased the formation of mammospheres by breast cancer stem cells as compared to CC-90002 treatment or controls. Furthermore, SIRPα-Fc treatment upregulated mRNA and protein expression of ALDH1 and altered the expression of genes involved in epithelial/mesenchymal transition pathways that are associated with a poor prognosis and enhanced metastatic activity. This indicates that SIRPα-Fc has CD47-mediated agonist activities in breast cancer stem cells affecting proliferation and metastasis pathways that differ from those of CC-90002. This SIRPα-induced CD47 signaling in breast carcinoma cells may limit the efficacy of SIRPα decoy therapeutics intended to stimulate innate antitumor immune responses.
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Affiliation(s)
- Sukhbir Kaur
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Bianca Reginauld
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Sam Razjooyan
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Trung Phi
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Satya P. Singh
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Thomas J. Meyer
- CCR Collaborative Bioinformatics, Resource, Office of Science and Technology Resources, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Margaret C. Cam
- CCR Collaborative Bioinformatics, Resource, Office of Science and Technology Resources, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - David D. Roberts
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
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20
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Yang K, Yi T. Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy. Front Mol Biosci 2024; 10:1297611. [PMID: 38455361 PMCID: PMC10918437 DOI: 10.3389/fmolb.2023.1297611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/14/2023] [Indexed: 03/09/2024] Open
Abstract
The cancer stem cells are a rare group of self-renewable cancer cells capable of the initiation, progression, metastasis and recurrence of tumors, and also a key contributor to the therapeutic resistance. Thus, understanding the molecular mechanism of tumor stemness regulation, especially in the gastrointestinal (GI) cancers, is of great importance for targeting CSC and designing novel therapeutic strategies. This review aims to elucidate current advancements in the understanding of CSC regulation, including CSC biomarkers, signaling pathways, and non-coding RNAs. We will also provide a comprehensive view on how the tumor microenvironment (TME) display an overall tumor-promoting effect, including the recruitment and impact of cancer-associated fibroblasts (CAFs), the establishment of an immunosuppressive milieu, and the induction of angiogenesis and hypoxia. Lastly, this review consolidates mainstream novel therapeutic interventions targeting CSC stemness regulation.
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Affiliation(s)
- Kangqi Yang
- School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Tuo Yi
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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21
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Khan SU, Fatima K, Aisha S, Malik F. Unveiling the mechanisms and challenges of cancer drug resistance. Cell Commun Signal 2024; 22:109. [PMID: 38347575 PMCID: PMC10860306 DOI: 10.1186/s12964-023-01302-1] [Citation(s) in RCA: 64] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 08/30/2023] [Indexed: 02/15/2024] Open
Abstract
Cancer treatment faces many hurdles and resistance is one among them. Anti-cancer treatment strategies are evolving due to innate and acquired resistance capacity, governed by genetic, epigenetic, proteomic, metabolic, or microenvironmental cues that ultimately enable selected cancer cells to survive and progress under unfavorable conditions. Although the mechanism of drug resistance is being widely studied to generate new target-based drugs with better potency than existing ones. However, due to the broader flexibility in acquired drug resistance, advanced therapeutic options with better efficacy need to be explored. Combination therapy is an alternative with a better success rate though the risk of amplified side effects is commonplace. Moreover, recent groundbreaking precision immune therapy is one of the ways to overcome drug resistance and has revolutionized anticancer therapy to a greater extent with the only limitation of being individual-specific and needs further attention. This review will focus on the challenges and strategies opted by cancer cells to withstand the current therapies at the molecular level and also highlights the emerging therapeutic options -like immunological, and stem cell-based options that may prove to have better potential to challenge the existing problem of therapy resistance. Video Abstract.
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Affiliation(s)
- Sameer Ullah Khan
- Division of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Holcombe Blvd, Houston, TX, 77030, USA.
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar-190005, Jammu and Kashmir, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
| | - Kaneez Fatima
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar-190005, Jammu and Kashmir, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Shariqa Aisha
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar-190005, Jammu and Kashmir, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Fayaz Malik
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar-190005, Jammu and Kashmir, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
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22
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Huang H, Tsui YM, Ho DWH, Chung CYS, Sze KMF, Lee E, Cheung GCH, Zhang VX, Wang X, Lyu X, Ng IOL. LANCL1, a cell surface protein, promotes liver tumor initiation through FAM49B-Rac1 axis to suppress oxidative stress. Hepatology 2024; 79:323-340. [PMID: 37540188 PMCID: PMC10789379 DOI: 10.1097/hep.0000000000000523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/25/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND AND AIMS HCC is an aggressive cancer with a poor clinical outcome. Understanding the mechanisms that drive tumor initiation is important for improving treatment strategy. This study aimed to identify functional cell membrane proteins that promote HCC tumor initiation. APPROACH AND RESULTS Tailor-made siRNA library screening was performed for all membrane protein-encoding genes that are upregulated in human HCC (n = 134), with sphere formation as a surrogate readout for tumor initiation. Upon confirmation of membranous localization by immunofluorescence and tumor initiation ability by limiting dilution assay in vivo, LanC-like protein-1 (LANCL1) was selected for further characterization. LANCL1 suppressed intracellular reactive oxygen species (ROS) and promoted tumorigenicity both in vitro and in vivo. Mechanistically, with mass spectrometry, FAM49B was identified as a downstream binding partner of LANCL1. LANCL1 stabilized FAM49B by blocking the interaction of FAM49B with the specific E3 ubiquitin ligase TRIM21, thus protecting FAM49B from ubiquitin-proteasome degradation. The LANCL1-FAM49B axis suppressed the Rac1-NADPH oxidase-driven ROS production, but this suppression of ROS was independent of the glutathione transferase function of LANCL1. Clinically, HCCs with high co-expression of LANCL1 and FAM49B were associated with more advanced tumor stage, poorer overall survival, and disease-free survival. In addition, anti-LANCL1 antibodies targeting the extracellular N-terminal domain were able to suppress the self-renewal ability, as demonstrated by the sphere formation ability of HCC cells. CONCLUSIONS Our data showed that LANCL1 is a cell surface protein and a key contributor to HCC initiation. Targeting the LANCL1-FAM49B-Rac1-NADPH oxidase-ROS signaling axis may be a promising therapeutic strategy for HCC.
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Affiliation(s)
- Hongyang Huang
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Yu-Man Tsui
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Daniel Wai-Hung Ho
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Clive Yik-Sham Chung
- Department of Pathology, The University of Hong Kong, Hong Kong
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Karen Man-Fong Sze
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Eva Lee
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Gary Cheuk-Hang Cheung
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Vanilla Xin Zhang
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Xia Wang
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Xueying Lyu
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
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23
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Mahanti K, Bhattacharyya S. Rough neighborhood: Intricacies of cancer stem cells and infiltrating immune cell interaction in tumor microenvironment and potential in therapeutic targeting. Transl Res 2023; 265:S1931-5244(23)00176-7. [PMID: 39491179 DOI: 10.1016/j.trsl.2023.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/25/2023] [Accepted: 10/25/2023] [Indexed: 11/05/2024]
Abstract
Ongoing research on cellular heterogeneity of Cancer stem cells (CSCs) and its synergistic involvement with tumor milieu reveals enormous complexity, resulting in diverse hindrance in immune therapy. CSCs has captured attention for their contribution in shaping of tumor microenvironment and as target for therapeutic intervention. Recent studies have highlighted cell-extrinsic and intrinsic mechanisms of reciprocal interaction between tumor stroma constituents and CSCs. Therapeutic targeting requires an in-depth understanding of the underlying mechanisms involved with the rate limiting factors in tumor aggressiveness and pinpoint role of CSCs. Some of the major constituents of tumor microenvironment includes resident and infiltrating immune cell, both innate and adaptive. Some of these immune cells play crucial role as adjustors of tumor immune response. Tumor-adjustor immune cell interaction confer plasticity and features enabling tumor growth and metastasis in one hand and on the other hand blunts anti-tumor immunity. Detail understanding of CSC and TME resident immune cells interaction can shape new avenues for cancer immune therapy. In this review, we have tried to summarize the development of knowledge on cellular, molecular and functional interaction between CSCs and tumor microenvironment immune cells, highlighting immune-mediated therapeutic strategies aimed at CSCs. We also discussed developing a potential CSC and TME targeted therapeutic avenue.
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Affiliation(s)
- Krishna Mahanti
- Immunobiology and Translational medicine laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia, 723104, West Bengal India
| | - Sankar Bhattacharyya
- Immunobiology and Translational medicine laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia, 723104, West Bengal India.
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24
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Ye ZH, Yu WB, Huang MY, Chen J, Lu JJ. Building on the backbone of CD47-based therapy in cancer: Combination strategies, mechanisms, and future perspectives. Acta Pharm Sin B 2023; 13:1467-1487. [PMID: 37139405 PMCID: PMC10149906 DOI: 10.1016/j.apsb.2022.12.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 10/10/2022] [Accepted: 11/18/2022] [Indexed: 12/27/2022] Open
Abstract
Described as a "don't eat me" signal, CD47 becomes a vital immune checkpoint in cancer. Its interaction with signal regulatory protein alpha (SIRPα) prevents macrophage phagocytosis. In recent years, a growing body of evidences have unveiled that CD47-based combination therapy exhibits a superior anti-cancer effect. Latest clinical trials about CD47 have adopted the regimen of collaborating with other therapies or developing CD47-directed bispecific antibodies, indicating the combination strategy as a general trend of the future. In this review, clinical and preclinical cases about the current combination strategies targeting CD47 are collected, their underlying mechanisms of action are discussed, and ideas from future perspectives are shared.
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Affiliation(s)
- Zi-Han Ye
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Wei-Bang Yu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Mu-Yang Huang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Jun Chen
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Jin-Jian Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao 999078, China
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao 999078, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, University of Macau, Macao 999078, China
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25
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Kim M, Jo KW, Kim H, Han ME, Oh SO. Genetic heterogeneity of liver cancer stem cells. Anat Cell Biol 2023; 56:94-108. [PMID: 36384888 PMCID: PMC9989795 DOI: 10.5115/acb.22.161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 11/19/2022] Open
Abstract
Cancer cell heterogeneity is a serious problem in the control of tumor progression because it can cause chemoresistance and metastasis. Heterogeneity can be generated by various mechanisms, including genetic evolution of cancer cells, cancer stem cells (CSCs), and niche heterogeneity. Because the genetic heterogeneity of CSCs has been poorly characterized, the genetic mutation status of CSCs was examined using Exome-Seq and RNA-Seq data of liver cancer. Here we show that different surface markers for liver cancer stem cells (LCSCs) showed a unique propensity for genetic mutations. Cluster of differentiation 133 (CD133)-positive cells showed frequent mutations in the IRF2, BAP1, and ERBB3 genes. However, leucine-rich repeat-containing G protein-coupled receptor 5-positive cells showed frequent mutations in the CTNNB1, RELN, and ROBO1 genes. In addition, some genetic mutations were frequently observed irrespective of the surface markers for LCSCs. BAP1 mutations was frequently observed in CD133-, CD24-, CD13-, CD90-, epithelial cell adhesion molecule-, or keratin 19-positive LCSCs. ASXL2, ERBB3, IRF2, TLX3, CPS1, and NFATC2 mutations were observed in more than three types of LCSCs, suggesting that common mechanisms for the development of these LCSCs. The present study provides genetic heterogeneity depending on the surface markers for LCSCs. The genetic heterogeneity of LCSCs should be considered in the development of LCSC-targeting therapeutics.
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Affiliation(s)
- Minjeong Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Kwang-Woo Jo
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Hyojin Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Myoung-Eun Han
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Sae-Ock Oh
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
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26
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Yan H, Huang W, Chen C, Zhang X, Zhu K, Yuan J. MiR-133a/CD47 axis is a novel prognostic biomarker to promote triple negative breast cancer progression. Pathol Res Pract 2023; 244:154400. [PMID: 36893709 DOI: 10.1016/j.prp.2023.154400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/07/2023]
Abstract
Cluster of differentiation 47 (CD47) acts as an anti-engulfment signal on tumor cells, and its overexpression is correlated with poor prognosis of various malignant tumors. However, the role and mechanism of CD47 in tumor cell proliferation, migration and apoptosis remain unclarified. Emerging evidence indicates that microRNAs (miRNAs) are potential regulators to mediate CD47 generation. In this study, we found that CD47 was up-regulated while miR-133a was down-regulated in triple-negative breast cancer (TNBC) in vitro and in vivo. Moreover, we demonstrated for the first time that CD47 was a direct target of miR-133a in TNBC cells, and provided direct evidence of the inverse correlation between miR-133a and CD47 expression in TNBC. Besides, miR-133a functioned as a tumor suppressor to inhibit proliferation and migration, and promote apoptosis of TNBC cells by targeting CD47. Furthermore, overexpression of miR-133a inhibited the tumor growth of TNBC in an in vivo xenograft animal model by targeting CD47. Thus, miR-133a/CD47 axis provides new insight into the mechanism of TNBC progression and could be a promising candidate in the diagnosis and treatment of TNBC.
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Affiliation(s)
- Honglin Yan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China
| | - Wenxian Huang
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China
| | - Chuang Chen
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China
| | - Xiuyun Zhang
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China
| | - Kaimei Zhu
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China.
| | - Jingping Yuan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China.
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27
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Yan ZJ, Chen L, Wang HY. To be or not to be: The double-edged sword roles of liver progenitor cells. Biochim Biophys Acta Rev Cancer 2023; 1878:188870. [PMID: 36842766 DOI: 10.1016/j.bbcan.2023.188870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/11/2023] [Accepted: 01/28/2023] [Indexed: 02/28/2023]
Abstract
Given the liver's remarkable and unique regenerative capacity, researchers have long focused on liver progenitor cells (LPCs) and liver cancer stem cells (LCSCs). LPCs can differentiate into both hepatocytes and cholangiocytes. However, the mechanism underlying cell conversion and its distinct contribution to liver homeostasis and tumorigenesis remain unclear. In this review, we discuss the complicated conversions involving LPCs and LCSCs. As the critical intermediate state in malignant transformation, LPCs play double-edged sword roles. LPCs are not only involved in hepatic wound-healing responses by supplementing liver cells and bile duct cells in the damaged liver but may transform into LCSCs under dysregulation of key signaling pathways, resulting in refractory malignant liver tumors. Because LPC lineages are temporally and spatially dynamic, we discuss crucial LPC subgroups and summarize regulatory factors correlating with the trajectories of LPCs and LCSCs in the liver tumor microenvironment. This review elaborates on the double-edged sword roles of LPCs to help understand the liver's regenerative potential and tumor heterogeneity. Understanding the sources and transformations of LPCs is essential in determining how to exploit their regenerative capacity in the future.
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Affiliation(s)
- Zi-Jun Yan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China
| | - Lei Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China.
| | - Hong-Yang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China.
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28
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Wu B, Shi X, Jiang M, Liu H. Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment. Mol Cancer 2023; 22:38. [PMID: 36810098 PMCID: PMC9942413 DOI: 10.1186/s12943-023-01748-4] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Ongoing research has revealed that the existence of cancer stem cells (CSCs) is one of the biggest obstacles in the current cancer therapy. CSCs make an influential function in tumor progression, recurrence and chemoresistance due to their typical stemness characteristics. CSCs are preferentially distributed in niches, and those niche sites exhibit characteristics typical of the tumor microenvironment (TME). The complex interactions between CSCs and TME illustrate these synergistic effects. The phenotypic heterogeneity within CSCs and the spatial interactions with the surrounding tumor microenvironment led to increased therapeutic challenges. CSCs interact with immune cells to protect themselves against immune clearance by exploiting the immunosuppressive function of multiple immune checkpoint molecules. CSCs also can protect themselves against immune surveillance by excreting extracellular vesicles (EVs), growth factors, metabolites and cytokines into the TME, thereby modulating the composition of the TME. Therefore, these interactions are also being considered for the therapeutic development of anti-tumor agents. We discuss here the immune molecular mechanisms of CSCs and comprehensively review the interplay between CSCs and the immune system. Thus, studies on this topic seem to provide novel ideas for reinvigorating therapeutic approaches to cancer.
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Affiliation(s)
- Bo Wu
- grid.459742.90000 0004 1798 5889Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042 China
| | - Xiang Shi
- grid.459742.90000 0004 1798 5889Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042 China
| | - Meixi Jiang
- grid.412644.10000 0004 5909 0696Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032 China
| | - Hongxu Liu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China.
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29
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Zhou XH, Li JR, Zheng TH, Chen H, Cai C, Ye SL, Gao B, Xue TC. Portal vein tumor thrombosis in hepatocellular carcinoma: molecular mechanism and therapy. Clin Exp Metastasis 2023; 40:5-32. [PMID: 36318440 DOI: 10.1007/s10585-022-10188-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/04/2022] [Indexed: 11/05/2022]
Abstract
Portal vein tumor thrombosis (PVTT), a common complication of advanced hepatocellular carcinoma (HCC), remains the bottleneck of the treatments. Liver cancer cells potentially experienced multi-steps during PVTT process, including cancer cells leave from cancer nest, migrate in extracellular matrix, invade the vascular barrier, and colonize in the portal vein. Accumulated evidences have revealed numerous of molecular mechanisms including genetic and epigenetic regulation, cancer stem cells, immunosuppressive microenvironment, hypoxia, et al. contributed to the PVTT formation. In this review, we discuss state-of-the-art PVTT research on the potential molecular mechanisms and experimental models. In addition, we summarize PVTT-associated clinical trials and current treatments for PVTT and suppose perspectives exploring the molecular mechanisms and improving PVTT-related treatment for the future.
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Affiliation(s)
- Xing-Hao Zhou
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Jing-Ru Li
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Tang-Hui Zheng
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Department of Hepatic Oncology, Xiamen Branch, Fudan University, Zhongshan Hospital, Xiamen, 361015, China
| | - Hong Chen
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Department of Hepatic Oncology, Xiamen Branch, Fudan University, Zhongshan Hospital, Xiamen, 361015, China
| | - Chen Cai
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Sheng-Long Ye
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Bo Gao
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai Medical College, Shanghai, 200032, China.
| | - Tong-Chun Xue
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China. .,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China. .,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China.
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30
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Sipos F, Műzes G. Cancer Stem Cell Relationship with Pro-Tumoral Inflammatory Microenvironment. Biomedicines 2023; 11:189. [PMID: 36672697 PMCID: PMC9855358 DOI: 10.3390/biomedicines11010189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Inflammatory processes and cancer stem cells (CSCs) are increasingly recognized as factors in the development of tumors. Emerging evidence indicates that CSCs are associated with cancer properties such as metastasis, treatment resistance, and disease recurrence. However, the precise interaction between CSCs and the immune microenvironment remains unexplored. Although evasion of the immune system by CSCs has been extensively studied, new research demonstrates that CSCs can also control and even profit from the immune response. This review provides an overview of the reciprocal interplay between CSCs and tumor-infiltrating immune cells, collecting pertinent data about how CSCs stimulate leukocyte reprogramming, resulting in pro-tumor immune cells that promote metastasis, chemoresistance, tumorigenicity, and even a rise in the number of CSCs. Tumor-associated macrophages, neutrophils, Th17 and regulatory T cells, mesenchymal stem cells, and cancer-associated fibroblasts, as well as the signaling pathways involved in these pro-tumor activities, are among the immune cells studied. Although cytotoxic leukocytes have the potential to eliminate CSCs, immune evasion mechanisms in CSCs and their clinical implications are also known. We intended to compile experimental findings that provide direct evidence of interactions between CSCs and the immune system and CSCs and the inflammatory milieu. In addition, we aimed to summarize key concepts in order to comprehend the cross-talk between CSCs and the tumor microenvironment as a crucial process for the effective design of anti-CSC therapies.
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Affiliation(s)
| | - Györgyi Műzes
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, Hungary
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Chen Y, Klingen TA, Aas H, Wik E, Akslen LA. CD47 and CD68 expression in breast cancer is associated with tumor-infiltrating lymphocytes, blood vessel invasion, detection mode, and prognosis. J Pathol Clin Res 2023; 9:151-164. [PMID: 36598153 PMCID: PMC10073931 DOI: 10.1002/cjp2.309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 12/16/2022] [Accepted: 12/23/2022] [Indexed: 01/05/2023]
Abstract
CD47 expressed on tumor cells binds to signal regulatory protein alpha on macrophages, initiating inhibition of phagocytosis. We investigated the relationships between tumor expression of CD47 and CD68 macrophage content, subsets of tumor-infiltrating lymphocytes (TILs), and vascular invasion in breast cancer. A population-based series of 282 cases (200 screen detected and 82 interval patients) from the Norwegian Breast Cancer Screening Program was examined. Immunohistochemical staining for CD47 and CD68 was evaluated on tissue microarray (TMA) slides. For CD47 evaluation, a staining index was used. CD68 tumor-associated macrophages were counted and dichotomized. TIL subsets (CD45, CD3, CD4, CD8, and FOXP3) were counted and dichotomized using immunohistochemistry on TMA slides. Vascular invasion (both lymphatic and blood vessel) was determined on whole tissue slides. High CD47 tumor cell expression or high counts of CD68 macrophages were significantly associated with elevated levels of all TIL subsets (p < 0.02), CD163 macrophages (p < 0.001), blood vessel invasion (CD31 positive) (p < 0.01), and high tumor cell Ki67 (p < 0.004). High CD47 expression was associated with ER negativity (p < 0.001), HER2 positive status (p = 0.03), and interval-detected tumors (p = 0.03). Combined high expression of CD47-CD68 was associated with a shorter recurrence-free survival (RFS) by multivariate analysis (hazard ratio [HR]: 2.37, p = 0.018), adjusting for tumor diameter, histologic grade, lymph node status, and molecular subtype. Patients with luminal A tumors showed a shorter RFS for CD47-CD68 high cases by multivariate assessment (HR: 5.73, p = 0.004). This study demonstrates an association of concurrent high CD47 tumor cell expression and high CD68 macrophage counts with various TIL subsets, blood vessel invasion (CD31 positive), other aggressive tumor features, and interval-presenting breast cancer. Our findings suggest a link between CD47, tumor immune response, and blood vessel invasion (CD31 positive). Combined high expression of CD47-CD68 was an independent prognostic factor associated with poor prognosis in all cases, as well as in the luminal A category.
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Affiliation(s)
- Ying Chen
- Centre for Cancer Biomarkers CCBIO, Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of PathologyVestfold HospitalTønsbergNorway
- Department of PathologyOslo University HospitalOsloNorway
- Fürst Medical LaboratoryOsloNorway
| | - Tor Audun Klingen
- Centre for Cancer Biomarkers CCBIO, Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of PathologyVestfold HospitalTønsbergNorway
| | - Hans Aas
- Department of SurgeryVestfold HospitalTønsbergNorway
| | - Elisabeth Wik
- Centre for Cancer Biomarkers CCBIO, Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of PathologyHaukeland University HospitalBergenNorway
| | - Lars A Akslen
- Centre for Cancer Biomarkers CCBIO, Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of PathologyHaukeland University HospitalBergenNorway
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An J, Hu X, Liu F. Current understanding of cancer stem cells: Immune evasion and targeted immunotherapy in gastrointestinal malignancies. Front Oncol 2023; 13:1114621. [PMID: 36910604 PMCID: PMC9996315 DOI: 10.3389/fonc.2023.1114621] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
As a relatively rare population of cancer cells existing in the tumor microenvironment, cancer stem cells (CSCs) possess properties of immune privilege to evade the attack of immune system, regulated by the microenvironment of CSCs, the so-called CSCs niche. The bidirectional interaction of CSCs with tumor microenvironment (TME) components favors an immunosuppressive shelter for CSCs' survival and maintenance. Gastrointestinal cancer stem cells (GCSCs) are broadly regarded to be intimately involved in tumor initiation, progression, metastasis and recurrence, with elevated tumor resistance to conventional therapies, which pose a major hindrance to the clinical efficacy for treated patients with gastrointestinal malignancies. Thus, a multitude of efforts have been made to combat and eradicate GCSCs within the tumor mass. Among diverse methods of targeting CSCs in gastrointestinal malignancies, immunotherapy represents a promising strategy. And the better understanding of GCSCs immunomodulation and immunoresistance mechanisms is beneficial to guide and design novel GCSCs-specific immunotherapies with enhanced immune response and clinical efficacy. In this review, we have gathered available and updated information to present an overview of the immunoevasion features harbored by cancer stem cells, and we focus on the description of immune escape strategies utilized by CSCs and microenvironmental regulations underlying CSCs immuno-suppression in the context of gastrointestinal malignancies. Importantly, this review offers deep insights into recent advances of CSC-targeting immunotherapeutic approaches in gastrointestinal cancers.
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Affiliation(s)
- Junyi An
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaohua Hu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Liu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Peach CJ, Edgington-Mitchell LE, Bunnett NW, Schmidt BL. Protease-activated receptors in health and disease. Physiol Rev 2023; 103:717-785. [PMID: 35901239 PMCID: PMC9662810 DOI: 10.1152/physrev.00044.2021] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 07/08/2022] [Accepted: 07/10/2022] [Indexed: 11/22/2022] Open
Abstract
Proteases are signaling molecules that specifically control cellular functions by cleaving protease-activated receptors (PARs). The four known PARs are members of the large family of G protein-coupled receptors. These transmembrane receptors control most physiological and pathological processes and are the target of a large proportion of therapeutic drugs. Signaling proteases include enzymes from the circulation; from immune, inflammatory epithelial, and cancer cells; as well as from commensal and pathogenic bacteria. Advances in our understanding of the structure and function of PARs provide insights into how diverse proteases activate these receptors to regulate physiological and pathological processes in most tissues and organ systems. The realization that proteases and PARs are key mediators of disease, coupled with advances in understanding the atomic level structure of PARs and their mechanisms of signaling in subcellular microdomains, has spurred the development of antagonists, some of which have advanced to the clinic. Herein we review the discovery, structure, and function of this receptor system, highlight the contribution of PARs to homeostatic control, and discuss the potential of PAR antagonists for the treatment of major diseases.
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Affiliation(s)
- Chloe J Peach
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
- Department of Neuroscience and Physiology and Neuroscience Institute, Grossman School of Medicine, New York University, New York, New York
| | - Laura E Edgington-Mitchell
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
- Bluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, New York
| | - Nigel W Bunnett
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
- Department of Neuroscience and Physiology and Neuroscience Institute, Grossman School of Medicine, New York University, New York, New York
| | - Brian L Schmidt
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
- Bluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, New York
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Li L, Xun C, Yu CH. Role of microRNA-regulated cancer stem cells in recurrent hepatocellular carcinoma. World J Hepatol 2022; 14:1985-1996. [PMID: 36618329 PMCID: PMC9813843 DOI: 10.4254/wjh.v14.i12.1985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/24/2022] [Accepted: 11/22/2022] [Indexed: 12/23/2022] Open
Abstract
Among the most common cancers, hepatocellular carcinoma (HCC) has a high rate of tumor recurrence, tumor dormancy, and drug resistance after initial successful chemotherapy or radiotherapy. A small subset of cancer cells, cancer stem cells (CSCs), exhibit stem cell characteristics and are present in various cancers, including HCC. The dysregulation of microRNAs (miRNAs) often accompanies the occurrence and development of HCC. miRNAs can influence tumorigenesis, progression, recurrence, and drug resistance by regulating CSCs properties, which supports their clinical utility in managing and treating HCC. This review summarizes the regulatory effects of miRNAs on CSCs in HCC with a special focus on their impact on HCC recurrence.
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Affiliation(s)
- Lei Li
- Department of Pathology, University of Otago, Dunedin 9016, New Zealand
| | - Chen Xun
- Department of Hepatobiliary Surgery, Zhuzhou Central Hospital, Zhuzhou 412000, Hunan Province, China
| | - Chun-Hong Yu
- School of Engineering Medicine, Beihang University, Beijing 100191, China.
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The Role of Cancer Stem Cells and Their Extracellular Vesicles in the Modulation of the Antitumor Immunity. Int J Mol Sci 2022; 24:ijms24010395. [PMID: 36613838 PMCID: PMC9820747 DOI: 10.3390/ijms24010395] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
Cancer stem cells (CSCs) are a population of tumor cells that share similar properties to normal stem cells. CSCs are able to promote tumor progression and recurrence due to their resistance to chemotherapy and ability to stimulate angiogenesis and differentiate into non-CSCs. Cancer stem cells can also create a significant immunosuppressive environment around themselves by suppressing the activity of effector immune cells and recruiting cells that support tumor escape from immune response. The immunosuppressive effect of CSCs can be mediated by receptors located on their surface, as well as by secreted molecules, which transfer immunosuppressive signals to the cells of tumor microenvironment. In this article, the ability of CSCs to regulate the antitumor immune response and a contribution of CSC-derived EVs into the avoidance of the immune response are discussed.
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Smyth P, Sasiwachirangkul J, Williams R, Scott CJ. Cathepsin S (CTSS) activity in health and disease - A treasure trove of untapped clinical potential. Mol Aspects Med 2022; 88:101106. [PMID: 35868042 DOI: 10.1016/j.mam.2022.101106] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 06/24/2022] [Accepted: 07/11/2022] [Indexed: 12/14/2022]
Abstract
Amongst the lysosomal cysteine cathepsin family of proteases, cathepsin S (CTSS) holds particular interest due to distinctive properties including a normal restricted expression profile, inducible upregulation and activity at a broad pH range. Consequently, while CTSS is well-established as a member of the proteolytic cocktail within the lysosome, degrading unwanted and damaged proteins, it has increasingly been shown to mediate a number of distinct, more selective roles including antigen processing and antigen presentation, and cleavage of substrates both intra and extracellularly. Increasingly, aberrant CTSS expression has been demonstrated in a variety of conditions and disease states, marking it out as both a biomarker and potential therapeutic target. This review seeks to contextualise CTSS within the cysteine cathepsin family before providing an overview of the broad range of pathologies in which roles for CTSS have been identified. Additionally, current clinical progress towards specific inhibitors is detailed, updating the position of the field in exploiting this most unique of proteases.
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Affiliation(s)
- Peter Smyth
- The Patrick G Johnston Centre for Cancer Research, Queen's University, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Jutharat Sasiwachirangkul
- The Patrick G Johnston Centre for Cancer Research, Queen's University, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Rich Williams
- The Patrick G Johnston Centre for Cancer Research, Queen's University, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Christopher J Scott
- The Patrick G Johnston Centre for Cancer Research, Queen's University, 97 Lisburn Road, Belfast, BT9 7AE, UK.
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CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer. Front Med 2022; 17:105-118. [PMID: 36414917 DOI: 10.1007/s11684-022-0934-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 04/21/2022] [Indexed: 11/24/2022]
Abstract
The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of "eat me" signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.
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Cancer Stem Cells in Hepatocellular Carcinoma: Intrinsic and Extrinsic Molecular Mechanisms in Stemness Regulation. Int J Mol Sci 2022; 23:ijms232012327. [PMID: 36293184 PMCID: PMC9604119 DOI: 10.3390/ijms232012327] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/18/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains the most predominant type of liver cancer with an extremely poor prognosis due to its late diagnosis and high recurrence rate. One of the culprits for HCC recurrence and metastasis is the existence of cancer stem cells (CSCs), which are a small subset of cancer cells possessing robust stem cell properties within tumors. CSCs play crucial roles in tumor heterogeneity constitution, tumorigenesis, tumor relapse, metastasis, and resistance to anti-cancer therapies. Elucidation of how these CSCs maintain their stemness features is essential for the development of CSCs-based therapy. In this review, we summarize the present knowledge of intrinsic molecules and signaling pathways involved in hepatic CSCs, especially the CSC surface markers and associated signaling in regulating the stemness characteristics and the heterogeneous subpopulations within the CSC pool. In addition, we recapitulate the effects of crucial extrinsic cellular components in the tumor microenvironment, including stromal cells and immune cells, on the modulation of hepatic CSCs. Finally, we synopsize the currently valuable CSCs-targeted therapy strategies based on intervention in these intrinsic and extrinsic molecular mechanisms, in the hope of shedding light on better clinical management of HCC patients.
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Chen B, Yang Z, Lang Z, Tao Q, Zhang R, Zhan Y, Xu X, Zhu K, Zheng J, Yu Z, Yu S. M6A-related lncRNAs predict clinical outcome and regulate the tumor immune microenvironment in hepatocellular carcinoma. BMC Cancer 2022; 22:867. [PMID: 35941582 PMCID: PMC9361634 DOI: 10.1186/s12885-022-09925-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 07/20/2022] [Indexed: 02/06/2023] Open
Abstract
LncRNA N6-methylandenosine (m6A) modification has been shown to be associated with the constitution of the tumor microenvironment (TME) and tumorigenesis. It's essential to understand the mechanisms of lncRNA m6A modification in hepatocellular carcinoma (HCC) and identify relative prognostic predictors to guide therapy and explore potential therapeutic targets. Pearson correlation analysis was performed to identify m6A-related lncRNAs in 374 patients with HCC. Unsupervised cluster analysis of the potential m6A-related lncRNA-based HCC subtypes was conducted, followed by the concurrent analysis of their relationship with TME characteristics, immune checkpoints, immune features, and prognosis through single sample gene set enrichment analysis and ESTIMATE algorithm. Cox regression analyses were performed to screen prognostic m6A-related lncRNA, construct an m6A-related lncRNA signature (m6A-RLRS), and establish an integrated nomogram for the prognosis of patients with HCC. We identified 61 m6A-related lncRNAs and two HCC subtypes defined by consensus cluster of m6A-related lncRNAs with distinct clinical features. Progression-free survival (PFS), three TME-related scores, 15 immune-associated gene sets, and two immune checkpoints expression were found to be significantly different among the two subtypes. Twenty-five prognostic m6A-related lncRNAs were determined, four of which were included to establish an m6A-RLRS with favorable discrimination, and the signature was validated in the validation set and an independent FAHWMU cohort (n = 60). Furthermore, a novel nomogram combining signature and clinical predictors was generated with a C-index of 0.703, and an original ceRNA regulatory network consisting of 9 lncRNAs, 28 miRNAs, and 75 target mRNAs was constructed. Finally, the differential expression of four m6A-related lncRNA was verified by qRT-PCR. In conclusion, m6A-related lncRNA prognostic signature and molecular subtype contributes to accurately predict the prognosis of HCC and provide potential novel therapeutic targets.
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Affiliation(s)
- Bo Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, No.2 fuxue lane, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Zhan Yang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhichao Lang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Qiqi Tao
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Rongrong Zhang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Yating Zhan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xuantong Xu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Kai Zhu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jianjian Zheng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhengping Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, No.2 fuxue lane, Wenzhou, 325000, Zhejiang, People's Republic of China.
| | - Suhui Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, No.2 fuxue lane, Wenzhou, 325000, Zhejiang, People's Republic of China.
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Wang S, Wu Q, Chen T, Su R, Pan C, Qian J, Huang H, Yin S, Xie H, Zhou L, Zheng S. Blocking CD47 promotes antitumour immunity through CD103 + dendritic cell-NK cell axis in murine hepatocellular carcinoma model. J Hepatol 2022; 77:467-478. [PMID: 35367532 DOI: 10.1016/j.jhep.2022.03.011] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 02/23/2022] [Accepted: 03/02/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS The CD47-signal regulatory protein α (SIRPα) axis inhibits dendritic cell (DC) phagocytosis and contributes to immune evasion. However, the behaviour of DCs and the potential crosstalk between DCs and natural killer (NK) cells in the hepatocellular carcinoma (HCC) microenvironment after CD47 blockade remain unclear. METHODS The infiltration of CD103+ DCs and NK cells were analysed by immunohistochemistry and immunofluorescence in both human and murine HCC specimens. An orthotopic liver tumour model was used to evaluate the function of the CD103+ DC-NK cell axis after CD47 blockade in vivo in wild-type, Rag1-/-, Batf3-/-, and STING1-/- mice. Phagocytosis assays were performed in CD103+ DC and HCC cell lines. CD103+ DC-derived cytokines were analysed by chemokine array. Spleen-derived NK cells in C57BL/6J mice were used to evaluate cytotoxic functions in vitro. RESULTS Higher CD47 expression was associated with worse prognosis in patients with HCC. CD47 blockade enhanced antitumour efficacy by stimulating the CD103+ DC-NK cell axis. The hypoxic microenvironment promoted CD47 blockade-induced tumour DNA phagocytosis by CD103+ DCs. By releasing IL-12 and CXCL9, activated CD103+ DCs induced the recruitment of NK cells with upregulated expression of granzyme B, NKG2D, interferon-γ, and tumour necrosis factor-α and downregulated expression of NKG2A. The antitumour effects of CD47 blockade could be abolished by cyclic GMP-AMP synthase (cGAS)-STING pathway inhibition. CONCLUSIONS In addition to the classical DC-T cell axis, CD47 blockade significantly enhanced the ability of CD103+ DCs to take up tumour DNA, resulting in the stimulation of the cGAS-STING pathway, which promoted the infiltration and activation of NK cells in liver cancer. LAY SUMMARY Hypoxia (low oxygen levels) is prevalent in the hepatocellular carcinoma microenvironment and promotes the phagocytosis (ingestion and elimination) of tumour DNA by CD103+ dendritic cells (a type of immune cell). Blockade of the cell surface protein CD47 resulted in activation of CD103+ dendritic cells which led to the recruitment and activation of natural killer cells (a different immune cell). When activated, these cells exhibit an antitumour effect.
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Affiliation(s)
- Shuai Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, China
| | - Qinchuan Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, China
| | - Tianchi Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, China
| | - Rong Su
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, China
| | - Caixu Pan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, China
| | - Junjie Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, China
| | - Hechen Huang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, China
| | - Shengyong Yin
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, China
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, China.
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China; Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences, Hangzhou, China; Key Laboratory of Organ Transplantation, Hangzhou, China.
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Mechanisms of resistance to tyrosine kinase inhibitors in liver cancer stem cells and potential therapeutic approaches. Essays Biochem 2022; 66:371-386. [PMID: 35818992 DOI: 10.1042/ebc20220001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/13/2022] [Accepted: 06/17/2022] [Indexed: 12/24/2022]
Abstract
The administration of tyrosine kinase inhibitors (TKIs) for the treatment of advanced-stage patients is common in hepatocellular carcinoma (HCC). However, therapy resistance is often encountered, and its emergence eventually curtails long-term clinical benefits. Cancer stem cells (CSCs) are essential drivers of tumor recurrence and therapy resistance; thus, the elucidation of key hallmarks of resistance mechanisms of liver CSC-driven HCC may help improve patient outcomes and reduce relapse. The present review provides a comprehensive summary of the intrinsic and extrinsic mechanisms of TKI resistance in liver CSCs, which mediate treatment failure, and discusses potential strategies to overcome TKI resistance from a preclinical perspective.
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Chen C, Wang R, Chen X, Hou Y, Jiang J. Targeting CD47 as a Novel Immunotherapy for Breast Cancer. Front Oncol 2022; 12:924740. [PMID: 35860564 PMCID: PMC9289165 DOI: 10.3389/fonc.2022.924740] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/07/2022] [Indexed: 11/23/2022] Open
Abstract
Nowadays, breast cancer has become the most common cancer worldwide with a high mortality rate. Immune checkpoint blockade holds great promise in tumor‐targeted therapy, and CD47 blockade as one immune therapy is undergoing various preclinical studies and clinical trials to demonstrate its safety and efficacy in breast cancer. In this review, we summarized different therapeutic mechanisms targeting CD47 and its prognostic role and therapeutic value in breast cancer.
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Affiliation(s)
- Can Chen
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Runlu Wang
- Respiratory Division, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xi Chen
- Department of Dermatology, First People’s Hospital, Huzhou, China
| | - Yulong Hou
- Department of Surgery, Huzhou Central Hospital, Huzhou, China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
- *Correspondence: Jingting Jiang,
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43
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Mok EHK, Leung CON, Zhou L, Lei MML, Leung HW, Tong M, Wong TL, Lau EYT, Ng IOL, Ding J, Yun JP, Yu J, Zhu HL, Lin CH, Lindholm D, Leung KS, Cybulski JD, Baker DM, Ma S, Lee TKW. Caspase-3-induced activation of SREBP2 drives drug resistance via promotion of cholesterol biosynthesis in hepatocellular carcinoma. Cancer Res 2022; 82:3102-3115. [PMID: 35767704 DOI: 10.1158/0008-5472.can-21-2934] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 02/14/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022]
Abstract
Accumulating evidence has demonstrated that drug resistance can be acquired in cancer through the repopulation of tumors by cancer stem cell (CSC) expansion. Here, we investigated mechanisms driving resistance and CSC repopulation in hepatocellular carcinoma (HCC) as a cancer model using two drug-resistant, patient-derived tumor xenografts that mimicked the development of acquired resistance to sorafenib or lenvatinib treatment observed in HCC patients. RNA sequencing analysis revealed that cholesterol biosynthesis was most commonly enriched in the drug-resistant xenografts. Comparison of the genetic profiles of CD133+ stem cells and CD133- bulk cells from liver regeneration and HCC mouse models showed that the cholesterol pathway was preferentially upregulated in liver CSCs compared to normal liver stem cells. Consistently, SREBP2-mediated cholesterol biosynthesis was crucial for the augmentation of liver CSCs, and loss of SREBP2 conferred sensitivity to tyrosine kinase inhibitors, suggesting a role in regulation of acquired drug resistance in HCC. Similarly, exogenous cholesterol-treated HCC cells showed enhanced cancer stemness abilities and drug resistance. Mechanistically, caspase-3 (CASP3)-mediated cleavage of SREBP2 from the endoplasmic reticulum to promote cholesterol biosynthesis, which consequently caused resistance to sorafenib/lenvatinib treatment by driving activation of the sonic hedgehog signaling pathway. Simvastatin, an FDA-approved cholesterol-lowering drug, not only suppressed HCC tumor growth but also sensitized HCC cells to sorafenib. These findings demonstrate that CSC populations in HCC expand via CASP3-dependent, SREBP2-mediated cholesterol biosynthesis in response to tyrosine kinase inhibitor therapy and that targeting cholesterol biosynthesis can overcome acquired drug resistance.
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Affiliation(s)
- Etienne Ho Kit Mok
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
| | - Carmen Oi Ning Leung
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
| | - Lei Zhou
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Martina Mang Leng Lei
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
| | - Hoi Wing Leung
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
| | - Man Tong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Tin Lok Wong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | | | - Irene Oi Lin Ng
- Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Jin Ding
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Jing Ping Yun
- Department of Pathology, Sun Yat Sen University Cancer Center, Guangzhou, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Hui Lian Zhu
- School of Public Health, Sun Yat Sen University, Guangzhou, China
| | - Chi Ho Lin
- Centre for PanorOmic Science, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Dan Lindholm
- Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Kit Sum Leung
- School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong
| | - Jonathan D Cybulski
- School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong
| | - David M Baker
- School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong
| | - Stephanie Ma
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
- State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong
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44
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Li J, Sun Z, Cui Y, Qin L, Wu F, Li Y, Du N, Li X. Knockdown of LMNB1 Inhibits the Proliferation of Lung Adenocarcinoma Cells by Inducing DNA Damage and Cell Senescence. Front Oncol 2022; 12:913740. [PMID: 35712471 PMCID: PMC9194513 DOI: 10.3389/fonc.2022.913740] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 04/19/2022] [Indexed: 12/15/2022] Open
Abstract
Background Lung cancer has considerably high mortality and morbidity rate. Lung adenocarcinoma (LUAD) tissues highly express lamin B1 (LMNB1), compared with normal tissues. In this study, we knocked down LMNB1 in LUAD cells A549 and NCI-1299 to explore the effect of its inhibition on the proliferation of cells and the potential mechanism. Methods Using bioinformatics methods, we analyzed the specificity of LMNB1 mRNA expression level in LUAD and its effect on prognosis from TCGA data. SiRNAs were used to knock down LMNB1 in the A549 cell line, and the knockdown effect was identified by western blotting and qRT-PCR. Through CCK8 cell proliferation assay, wound healing assay, TRAP, cloning formation Assay, DNase I-TUNEL assay, ATAC-seq, immunofluorescence, FISH, in vivo mouse xenograft studies, etc, we evaluated the influence and mechanism of LMNB1 on LUAD cell line proliferation in vitro and in vivo. Results According to bioinformatics analysis, LMNB1 is substantially abundant in LUAD tissues and is associated with tumor stage and patient survival (P < 0.05). After silencing LMNB1, the rate of cell growth, wound healing, the number of transwells, and the number of cell colonies all decreased significantly (P < 0.01). With the decreased LMNB1 expression, H3K9me3 protein expression decreases, chromosome accessibility increases, P53, P21, P16 and γ-H2AX protein expression increases, and the number of senescence staining positive cells increases. At the same time, in vivo mouse xenograft experiments showed that the tumor volume of the LMNB1-silenced group was significantly reduced, compared to that of the control group (P < 0.01), and the proliferation biomarker Ki-67 level (P < 0.01) was considerably reduced. Conclusions Overexpression of LMNB1 in LUAD cells is significant, which has excellent potential to be an indicator for evaluating the clinical prognosis of LUAD patients and a target for precise treatment.
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Affiliation(s)
- Jiangbo Li
- Department of Biology, Beijing Institute of Biotechnology, Beijing, China
| | - Zhijia Sun
- Medical School of Chinese People's Liberation Army (PLA), Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yingshu Cui
- Medical School of Chinese People's Liberation Army (PLA), Chinese People's Liberation Army General Hospital, Beijing, China
| | - Lingmei Qin
- Department of Biology, Beijing Institute of Biotechnology, Beijing, China
| | - Fengyun Wu
- College of Life Sciences, Capital Normal University, Beijing, China
| | - Yufang Li
- College of Life Sciences, Capital Normal University, Beijing, China
| | - Nan Du
- Department of Oncology, Fourth Medical Center of Chinese PLA General Hospital, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Xiaosong Li
- Department of Oncology, Fourth Medical Center of Chinese PLA General Hospital, Chinese People's Liberation Army General Hospital, Beijing, China.,Department of Oncology, Seventh Medical Center of Chinese PLA General Hospital, Chinese People's Liberation Army General Hospital, Beijing, China
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45
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Chiang ZC, Fang S, Shen YK, Cui D, Weng H, Wang D, Zhao Y, Lin J, Chen Q. Development of Novel CD47-Specific ADCs Possessing High Potency Against Non-Small Cell Lung Cancer in vitro and in vivo. Front Oncol 2022; 12:857927. [PMID: 35646646 PMCID: PMC9133542 DOI: 10.3389/fonc.2022.857927] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/13/2022] [Indexed: 12/18/2022] Open
Abstract
Targeted therapies hold promise for efficiently and accurately delivering cytotoxic drugs directly to tumor tissue to exert anticancer effects. CD47 is a membrane protein expressed in a variety of malignant tumors and hematopoietic cells, which plays a key role in immune escape and tumor progression. Although CD47 immunocheckpoint therapy has been developed in recent years, many patients cannot benefit from it because of its low efficiency. To strengthen and extend the therapeutic efficacy of anti-CD47 monoclonal antibody (mAb), we used the newly developed 7DC2 and 7DC4 mAbs as the targeting payload adaptor and VCMMAE as the toxin payload to construct novel CD47-specific immunotoxin (7DC-VCMMAE) by engineering cysteine residues. These CD47-specific ADCs have the better cell penetration, excellent DAR, similar payload distribution and good antigen-binding affinity. In vitro, 7DC-VCMMAE treatment induced death of non-small cell lung cancer (NSCLC) cell lines 95D and SPC-A1, but not A549 that express low levels of CD47 on the cell membrane. This finding suggests that 7DC-VCMMAE may possess greater therapeutic effect on NSCLC tumors expressing a high level of CD47 antigen; however, 7DC-VCMMAE treatment also promoted phagocytosis of A549 cells by macrophages. In vivo, 7DC-VCMMAE treatment had remarkable antitumor effects in a NSCLC cell line-derived xenograft (CDX) mouse model based on nonobese diabetic/severe combined immunodeficient (NOD/SCID). In summary, this study combined VCMMAE with anti-CD47 mAbs, emphasizing a novel and promising immunotherapy method for direct killing of NSCLC, which provides a valuable new way to meet the needs of the cancer therapy field.
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Affiliation(s)
- Zu-Chian Chiang
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China.,The Cancer Center, Union Hospital, Fujian Medical University, Fuzhou, China.,College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, China
| | - Shubin Fang
- The Cancer Center, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Yang-Kun Shen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China
| | - Dongya Cui
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China
| | - Huanjiao Weng
- The Cancer Center, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Dawei Wang
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China
| | - Yuxiang Zhao
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China
| | - Jizhen Lin
- The Cancer Center, Union Hospital, Fujian Medical University, Fuzhou, China.,The Department of Otolaryngology, Head and Neck Surgery, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Qi Chen
- Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University, Fuzhou, China
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46
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Qu T, Li B, Wang Y. Targeting CD47/SIRPα as a therapeutic strategy, where we are and where we are headed. Biomark Res 2022; 10:20. [PMID: 35418166 PMCID: PMC9009010 DOI: 10.1186/s40364-022-00373-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/31/2022] [Indexed: 02/08/2023] Open
Abstract
Immunotherapy using PD-1 and CTLA4 inhibitors to stimulate T cell immunity has achieved significant clinical success. However, only a portion of patients benefit from T cell-based immunotherapy. Macrophages, the most abundant type of innate immune cells in the body, play an important role in eliminating tumor cells and infectious microbes. The phagocytic check point protein CD47 inhibits the phagocytic activity of macrophages through binding to SIRPα expressed on macrophages. Blockade of the interaction between CD47 and SIRPα could restore phagocytic activity and eliminate tumor cells in vitro and in vivo. In this manuscript, we review the mechanism of action and development status of agents (antibodies targeting CD47 and SIRPα, SIRPα-Fc fusion proteins, and bi-specific antibodies) that block CD47/SIRPα interaction in preclinical studies and in the clinical setting. In addition, small molecules, mRNA, and CAR-T/M that target the CD47/SIRPα axis are also reviewed in this article.
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Affiliation(s)
- Tailong Qu
- College of life Science and Technology, Jinan University, No.601, West Huangpu Avenue, Guangzhou, Guangdong 510632 People’s Republic of China
- Department of Antibody Discovery, Akeso Biopharma, No.6 of Shennong Road, Torch Development District, Zhongshan, 528437 People’s Republic of China
| | - Baiyong Li
- Department of Antibody Discovery, Akeso Biopharma, No.6 of Shennong Road, Torch Development District, Zhongshan, 528437 People’s Republic of China
| | - Yifei Wang
- College of life Science and Technology, Jinan University, No.601, West Huangpu Avenue, Guangzhou, Guangdong 510632 People’s Republic of China
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47
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Dianat-Moghadam H, Mahari A, Salahlou R, Khalili M, Azizi M, Sadeghzadeh H. Immune evader cancer stem cells direct the perspective approaches to cancer immunotherapy. Stem Cell Res Ther 2022; 13:150. [PMID: 35395787 PMCID: PMC8994338 DOI: 10.1186/s13287-022-02829-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/22/2022] [Indexed: 12/12/2022] Open
Abstract
Exploration of tumor immunity leads to the development of immune checkpoint inhibitors and cell-based immunotherapies which improve the clinical outcomes in several tumor types. However, the poor clinical efficacy of these treatments observed for other tumors could be attributed to the inherent complex tumor microenvironment (TME), cellular heterogeneity, and stemness driven by cancer stem cells (CSCs). CSC-specific characteristics provide the bulk tumor surveillance and resistance to entire eradication upon conventional therapies. CSCs-immune cells crosstalk creates an immunosuppressive TME that reshapes the stemness in tumor cells, resulting in tumor formation and progression. Thus, identifying the immunological features of CSCs could introduce the therapeutic targets with powerful antitumor responses. In this review, we summarized the role of immune cells providing CSCs to evade tumor immunity, and then discussed the intrinsic mechanisms represented by CSCs to promote tumors' resistance to immunotherapies. Then, we outlined potent immunotherapeutic interventions followed by a perspective outlook on the use of nanomedicine-based drug delivery systems for controlled modulation of the immune system.
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Affiliation(s)
- Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Amir Mahari
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA
| | - Reza Salahlou
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mostafa Khalili
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Mehdi Azizi
- Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hadi Sadeghzadeh
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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48
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Geh D, Leslie J, Rumney R, Reeves HL, Bird TG, Mann DA. Neutrophils as potential therapeutic targets in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2022; 19:257-273. [PMID: 35022608 DOI: 10.1038/s41575-021-00568-5] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/06/2021] [Indexed: 12/13/2022]
Abstract
The success of atezolizumab plus bevacizumab treatment contributed to a shift in systemic therapies for hepatocellular carcinoma (HCC) towards combinations that include cancer immunotherapeutic agents. Thus far, the principal focus of cancer immunotherapy has been on interrupting immune checkpoints that suppress antitumour lymphocytes. As well as lymphocytes, the HCC environment includes numerous other immune cell types, among which neutrophils are emerging as an important contributor to the pathogenesis of HCC. A growing body of evidence supports neutrophils as key mediators of the immunosuppressive environment in which some cancers develop, as well as drivers of tumour progression. If neutrophils have a similar role in HCC, approaches that target or manipulate neutrophils might have therapeutic benefits, potentially including sensitization of tumours to conventional immunotherapy. Several neutrophil-directed therapies for patients with HCC (and other cancers) are now entering clinical trials. This Review outlines the evidence in support of neutrophils as drivers of HCC and details their mechanistic roles in development, progression and metastasis, highlighting the reasons that neutrophils are well worth investigating despite the challenges associated with studying them. Neutrophil-modulating anticancer therapies entering clinical trials are also summarized.
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Affiliation(s)
- Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Rob Rumney
- School of Pharmacy, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
- Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Thomas G Bird
- Cancer Research UK Beatson Institute, Glasgow, UK
- MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
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49
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Liu S, Bu X, Kan A, Luo L, Xu Y, Chen H, Lin X, Lai Z, Wen D, Huang L, Shi M. SP1-induced lncRNA DUBR promotes stemness and oxaliplatin resistance of hepatocellular carcinoma via E2F1-CIP2A feedback. Cancer Lett 2022; 528:16-30. [PMID: 34958891 DOI: 10.1016/j.canlet.2021.12.026] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/20/2022]
Abstract
Oxaliplatin-based chemotherapy is widely used to treat advanced hepatocellular carcinoma (HCC), but many patients develop drug resistance that leads to tumor recurrence. Cancer stem cells (CSCs) are known to contribute to chemoresistance, the underlying mechanism, however, remains largely unknown. In this study, we discovered a specificity protein 1 (SP1)-induced long noncoding RNA--DPPA2 upstream binding RNA (DUBR) and its high expression in HCC tissues and liver CSCs. DUBR was associated with HCC progression and poor chemotherapy response. Moreover, DUBR facilitated the stemness and oxaliplatin resistance of HCC in vitro and in vivo. Mechanistically, DUBR upregulated cancerous inhibitor of protein phosphatase 2A (CIP2A) expression through E2F1-mediated transcription regulation. DUBR also exerted function by binding microRNA (miR)-520d-5p as a competing endogenous RNA to upregulate CIP2A at mRNA level. CIP2A, in turn, stabilized E2F1 protein and activated the Notch1 signaling pathway, thereby increasing the stemness feature of HCC and leading to chemoresistance. In conclusion, we identified SP1/DUBR/E2F1-CIP2A as a critical axis to activate the Notch1 signaling pathway and promote stemness and chemoresistance of HCC. Therefore, DUBR could be a potential target in HCC treatment.
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Affiliation(s)
- S Liu
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xy Bu
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Anna Kan
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - L Luo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yj Xu
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Hl Chen
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xj Lin
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zc Lai
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ds Wen
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Lc Huang
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - M Shi
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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50
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Wilczyński JR, Wilczyński M, Paradowska E. Cancer Stem Cells in Ovarian Cancer-A Source of Tumor Success and a Challenging Target for Novel Therapies. Int J Mol Sci 2022; 23:ijms23052496. [PMID: 35269636 PMCID: PMC8910575 DOI: 10.3390/ijms23052496] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 02/20/2022] [Accepted: 02/22/2022] [Indexed: 02/04/2023] Open
Abstract
Ovarian cancer is the most lethal neoplasm of the female genital organs. Despite indisputable progress in the treatment of ovarian cancer, the problems of chemo-resistance and recurrent disease are the main obstacles for successful therapy. One of the main reasons for this is the presence of a specific cell population of cancer stem cells. The aim of this review is to show the most contemporary knowledge concerning the biology of ovarian cancer stem cells (OCSCs) and their impact on chemo-resistance and prognosis in ovarian cancer patients, as well as to present the treatment options targeted exclusively on the OCSCs. The review presents data concerning the role of cancer stem cells in general and then concentrates on OCSCs. The surface and intracellular OCSCs markers and their meaning both for cancer biology and clinical prognosis, signaling pathways specifically activated in OCSCs, the genetic and epigenetic regulation of OCSCs function including the recent studies on the non-coding RNA regulation, cooperation between OCSCs and the tumor microenvironment (ovarian cancer niche) including very specific environment such as ascites fluid, the role of shear stress, autophagy and metabolic changes for the function of OCSCs, and finally mechanisms of OCSCs escape from immune surveillance, are described and discussed extensively. The possibilities of anti-OCSCs therapy both in experimental settings and in clinical trials are presented, including the recent II phase clinical trials and immunotherapy. OCSCs are a unique population of cancer cells showing a great plasticity, self-renewal potential and resistance against anti-cancer treatment. They are responsible for the progression and recurrence of the tumor. Several completed and ongoing clinical trials have tested different anti-OCSCs drugs which, however, have shown unsatisfactory efficacy in most cases. We propose a novel approach to ovarian cancer diagnosis and therapy.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecological Surgery and Gynecological Oncology, Medical University of Lodz, 4 Kosciuszki Str., 90-419 Lodz, Poland
- Correspondence:
| | - Miłosz Wilczyński
- Department of Gynecological, Endoscopic and Oncological Surgery, Polish Mother’s Health Center—Research Institute, 281/289 Rzgowska Str., 93-338 Lodz, Poland;
- Department of Surgical and Endoscopic Gynecology, Medical University of Lodz, 4 Kosciuszki Str., 90-419 Lodz, Poland
| | - Edyta Paradowska
- Laboratory of Virology, Institute of Medical Biology of the Polish Academy of Sciences, 106 Lodowa Str., 93-232 Lodz, Poland;
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