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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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2
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Akagi S, Ando H, Matsuo CNA, Tajima K, Takata H, Matsushima T, Kusano T, Ishida T. A 3D Cell-Culture System That Uses Nano-Fibrillated Bacterial Cellulose to Prepare a Spherical Formulation of Culture Cells. Biol Pharm Bull 2025; 48:23-32. [PMID: 39864853 DOI: 10.1248/bpb.b24-00804] [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: 01/28/2025]
Abstract
A 3-dimensional (3D) cell culture is now being actively pursued to accomplish the in vivo-like cellular morphology and biological functions in cell culture. We recently obtained nano-fibrillated bacterial cellulose (NFBC). In this study, we developed a novel NFBC-based 3D cell-culture system, the OnGel method, and the Suspension method. HepG2 human liver cancer cells were cultured via these methods and formed spherical formulations in the optimized condition, 1.0% (w/v) of NFBC in the OnGel method, and 0.06-0.10% (w/v) of NFBC in the Suspension method. Non-cancerous cells such as human-induced pluripotent stem (iPS) cells and human mesenchymal stem cells (MSCs) also formed spherical formulations. It is noteworthy that both the size and cell viability of spheroids prepared via these methods were comparable to those cultured using commercially available 3D cell-culture systems. Both OnGel and Suspension methods are less complicated than the existing 3D cell-culture systems, which is an invaluable advantage for the preparation of cancer spheroids. The NFBC-based 3D cell-culture systems introduced here show great promise as a tool to prepare cultures for cell-derived spheroids for the progress of both in vitro and in vivo studies of the biological functioning of cells.
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Affiliation(s)
- Shunsuke Akagi
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | - Hidenori Ando
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
- Innovative Research Center for Drug Delivery System, Institute of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | - Cristina Nana Amorim Matsuo
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | - Kenji Tajima
- Faculty of Engineering, Hokkaido University, Sapporo 060-8628, Japan
| | - Haruka Takata
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
- Innovative Research Center for Drug Delivery System, Institute of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | | | | | - Tatsuhiro Ishida
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
- Innovative Research Center for Drug Delivery System, Institute of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
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3
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Ma X, Zhou K, Yan T, Hu L, Xie S, Zheng H, Tong Y, Zhang H, Wang Y, Gong Z, Chen C, Tian Y, Guo L, Lu R. Calpain 2 promotes Lenvatinib resistance and cancer stem cell traits via both proteolysis-dependent and independent approach in hepatocellular carcinoma. MOLECULAR BIOMEDICINE 2024; 5:74. [PMID: 39739077 PMCID: PMC11688263 DOI: 10.1186/s43556-024-00242-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 11/22/2024] [Accepted: 12/06/2024] [Indexed: 01/02/2025] Open
Abstract
Lenvatinib, an approved first-line regimen, has been widely applied in hepatocellular carcinoma (HCC). However, clinical response towards Lenvatinib was limited, emphasizing the importance of understanding the underlying mechanism of its resistance. Herein, we employed integrated bioinformatic analysis to identify calpain-2 (CAPN2) as a novel key regulator for Lenvatinib resistance in HCC, and its expression greatly increased in both Lenvatinib-resistant HCC cell lines and clinical samples. Further in vitro and in vivo experiments indicated that knocking down CAPN2 greatly sensitized HCC cells to Lenvatinib treatment, while overexpression of CAPN2 achieved opposite effects in a Lenvatinib-sensitive HCC cell line. Interestingly, we observed a close relationship between CAPN2 expression and cancer stem cell (CSC) traits in HCC cells, evidenced by impaired sphere-forming and CSC-related marker expressions after CAPN2 knockdown, and verse vice. Mechanistically, we strikingly discovered that CAPN2 exerted its function by both enzyme-dependent and enzyme-independent manner simultaneously: activating β-Catenin signaling through its enzyme activity, and preventing GLI1/GLI2 degradation through direct binding to YWHAE in an enzyme-independent manner, which disrupting the association between YWHAE and GLI1/GLI2 to inhibit YWHAE-induced degradation of GLIs. Notably, further co-immunoprecipitation assays revealed that YWHAE could promote the protein stability of CAPN2 via recruiting a deubiquitinase COPS5 to prevent ubiquitination-induced degradation of CAPN2. In summary, our data demonstrated that CAPN2 promoted Lenvatinib resistance via both catalytic activity-dependent and -independent approaches. Reducing CAPN2 protein rather than inhibiting its activity might be a promising strategy to improve Lenvatinib treatment efficiency in HCC.
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Affiliation(s)
- Xiaolu Ma
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Kaixia Zhou
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Tianqing Yan
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Ling Hu
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Suhong Xie
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Hui Zheng
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Ying Tong
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Heng Zhang
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Yanchun Wang
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Zhiyun Gong
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Cuncun Chen
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Yanan Tian
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Lin Guo
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China.
| | - Renquan Lu
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
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Yang C, Geng H, Yang X, Ji S, Liu Z, Feng H, Li Q, Zhang T, Zhang S, Ma X, Zhu C, Xu N, Xia Y, Li Y, Wang H, Yu C, Du S, Miao B, Xu L, Wang H, Cao Y, Li B, Zhu L, Tang X, Zhang H, Zhu C, Huang Z, Leng C, Hu H, Chen X, Yuan S, Jin G, Bernards R, Sun C, Zheng Q, Qin W, Gao Q, Wang C. Targeting the immune privilege of tumor-initiating cells to enhance cancer immunotherapy. Cancer Cell 2024; 42:2064-2081.e19. [PMID: 39515328 DOI: 10.1016/j.ccell.2024.10.008] [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: 05/02/2024] [Revised: 09/09/2024] [Accepted: 10/11/2024] [Indexed: 11/16/2024]
Abstract
Tumor-initiating cells (TICs) possess the ability to evade anti-tumor immunity, potentially explaining many failures of cancer immunotherapy. Here, we identify CD49f as a prominent marker for discerning TICs in hepatocellular carcinoma (HCC), outperforming other commonly used TIC markers. CD49f-high TICs specifically recruit tumor-promoting neutrophils via the CXCL2-CXCR2 axis and create an immunosuppressive milieu in the tumor microenvironment (TME). Reciprocally, the neutrophils reprogram nearby tumor cells toward a TIC phenotype via secreting CCL4. These cells can evade CD8+ T cell-mediated killing through CCL4/STAT3-induced and CD49f-stabilized CD155 expression. Notably, while aberrant CD155 expression contributes to immune suppression, it also represents a TIC-specific vulnerability. We demonstrate that either CD155 deletion or antibody blockade significantly enhances sensitivity to anti-PD-1 therapy in preclinical HCC models. Our findings reveal a new mechanism of tumor immune evasion and provide a rationale for combining CD155 blockade with anti-PD-1/PD-L1 therapy in HCC.
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Affiliation(s)
- Chen Yang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Immune Regulation in Cancer Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Haigang Geng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xupeng Yang
- Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China
| | - Shuyi Ji
- Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China; Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhicheng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Feng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Li
- Department of Oncology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tangansu Zhang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sisi Zhang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuhui Ma
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuchen Zhu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Nuo Xu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuhan Xia
- Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Li
- Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Hongye Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chune Yu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shangce Du
- Immune Regulation in Cancer Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Beiping Miao
- Immune Regulation in Cancer Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lei Xu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Cao
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Botai Li
- Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lili Zhu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiangyu Tang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haoyu Zhang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunchao Zhu
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhao Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chao Leng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haiyan Hu
- Department of Oncology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shengxian Yuan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Guangzhi Jin
- Department of Interventional Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - René Bernards
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Chong Sun
- Immune Regulation in Cancer Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Quan Zheng
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan University, Shanghai, China.
| | - Cun Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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5
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Peñaherrera-Pazmiño AB, Isa-Jara RF, Hincapié-Arias E, Gómez S, Belgorosky D, Agüero EI, Tellado M, Eiján AM, Lerner B, Pérez M. AQSA-Algorithm for Automatic Quantification of Spheres Derived from Cancer Cells in Microfluidic Devices. J Imaging 2024; 10:295. [PMID: 39590759 PMCID: PMC11595607 DOI: 10.3390/jimaging10110295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 10/23/2024] [Accepted: 10/31/2024] [Indexed: 11/28/2024] Open
Abstract
Sphere formation assay is an accepted cancer stem cell (CSC) enrichment method. CSCs play a crucial role in chemoresistance and cancer recurrence. Therefore, CSC growth is studied in plates and microdevices to develop prediction chemotherapy assays in cancer. As counting spheres cultured in devices is laborious, time-consuming, and operator-dependent, a computational program called the Automatic Quantification of Spheres Algorithm (ASQA) that detects, identifies, counts, and measures spheres automatically was developed. The algorithm and manual counts were compared, and there was no statistically significant difference (p = 0.167). The performance of the AQSA is better when the input image has a uniform background, whereas, with a nonuniform background, artifacts can be interpreted as spheres according to image characteristics. The areas of spheres derived from LN229 cells and CSCs from primary cultures were measured. For images with one sphere, area measurements obtained with the AQSA and SpheroidJ were compared, and there was no statistically significant difference between them (p = 0.173). Notably, the AQSA detects more than one sphere, compared to other approaches available in the literature, and computes the sphere area automatically, which enables the observation of treatment response in the sphere derived from the human glioblastoma LN229 cell line. In addition, the algorithm identifies spheres with numbers to identify each one over time. The AQSA analyzes many images in 0.3 s per image with a low computational cost, enabling laboratories from developing countries to perform sphere counts and area measurements without needing a powerful computer. Consequently, it can be a useful tool for automated CSC quantification from cancer cell lines, and it can be adjusted to quantify CSCs from primary culture cells. CSC-derived sphere detection is highly relevant as it avoids expensive treatments and unnecessary toxicity.
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Affiliation(s)
- Ana Belén Peñaherrera-Pazmiño
- Centro de Investigación Biomédica (CENBIO), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito 170527, Ecuador;
- Special Coatings and Nanostructures Engineering (IREN), National Technological University, Buenos Aires 1706, Argentina; (R.F.I.-J.); (B.L.)
| | - Ramiro Fernando Isa-Jara
- Special Coatings and Nanostructures Engineering (IREN), National Technological University, Buenos Aires 1706, Argentina; (R.F.I.-J.); (B.L.)
- Facultad de Informática y Electrónica Escuela Superior Politécnica de Chimborazo (ESPOCH), Riobamba 060104, Ecuador
| | - Elsa Hincapié-Arias
- Facultad de Medicina, Universidad de Buenos Aires, Instituto de Oncología Ángel H. Roffo, Buenos Aires C1417, Argentina; (E.H.-A.); (S.G.); (D.B.); (E.I.A.); (A.M.E.)
- National Council for Scientific and Technical Research (CONICET), Buenos Aires C1414, Argentina
| | - Silvia Gómez
- Facultad de Medicina, Universidad de Buenos Aires, Instituto de Oncología Ángel H. Roffo, Buenos Aires C1417, Argentina; (E.H.-A.); (S.G.); (D.B.); (E.I.A.); (A.M.E.)
- Scientific and Technological Promotion National Agency, Buenos Aires C1425, Argentina
| | - Denise Belgorosky
- Facultad de Medicina, Universidad de Buenos Aires, Instituto de Oncología Ángel H. Roffo, Buenos Aires C1417, Argentina; (E.H.-A.); (S.G.); (D.B.); (E.I.A.); (A.M.E.)
| | - Eduardo Imanol Agüero
- Facultad de Medicina, Universidad de Buenos Aires, Instituto de Oncología Ángel H. Roffo, Buenos Aires C1417, Argentina; (E.H.-A.); (S.G.); (D.B.); (E.I.A.); (A.M.E.)
| | - Matías Tellado
- VetOncologia Cancer Clinic Buenos Aires, Buenos Aires C1408, Argentina;
| | - Ana María Eiján
- Facultad de Medicina, Universidad de Buenos Aires, Instituto de Oncología Ángel H. Roffo, Buenos Aires C1417, Argentina; (E.H.-A.); (S.G.); (D.B.); (E.I.A.); (A.M.E.)
- National Council for Scientific and Technical Research (CONICET), Buenos Aires C1414, Argentina
| | - Betiana Lerner
- Special Coatings and Nanostructures Engineering (IREN), National Technological University, Buenos Aires 1706, Argentina; (R.F.I.-J.); (B.L.)
- Collaborative Research Institute Intelligent Oncology (CRIION), Hermann-Herder-Straße 4, 79104 Freiburg im Breisgau, Germany
- Department of Electrical and Computer Engineering, Florida International University, Miami, FL 33174, USA
| | - Maximiliano Pérez
- Special Coatings and Nanostructures Engineering (IREN), National Technological University, Buenos Aires 1706, Argentina; (R.F.I.-J.); (B.L.)
- Collaborative Research Institute Intelligent Oncology (CRIION), Hermann-Herder-Straße 4, 79104 Freiburg im Breisgau, Germany
- Department of Electrical and Computer Engineering, Florida International University, Miami, FL 33174, USA
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Chen LY, Wu DS, Shen YA. Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies. J Lipid Res 2024; 65:100660. [PMID: 39332525 PMCID: PMC11539133 DOI: 10.1016/j.jlr.2024.100660] [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: 04/28/2024] [Revised: 09/17/2024] [Accepted: 09/19/2024] [Indexed: 09/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) poses significant treatment challenges due to high postoperative recurrence rates and the limited effectiveness of targeted medications. Researchers have identified the unique metabolic profiles of cancer stem cells (CSCs) as the primary drivers of cancer recurrence, metastasis, and drug resistance. Therefore, to address the therapeutic conundrum, this study focused on rewinding metabolic reprogramming of CSCs as a novel therapeutic strategy. HCC CSCs exhibited elevated fatty acid (FA) metabolism compared with parental cells. To specifically target FA metabolism in CSCs, we utilized cerulenin, a fatty acid synthase (FASN) inhibitor. Surprisingly, cerulenin can diminish CSC-like characteristics, including stemness gene expression, spherogenicity, tumorigenicity, and metastatic potential. In addition, sorafenib, a multikinase inhibitor used as targeted therapy for advanced HCC, was employed in combination with cerulenin, demonstrating a great synergistic effect, particularly in CSCs. Importantly, our RNA sequencing analysis disclosed that the amyloid protein precursor (APP) is a crucial downstream effector of FASN in regulating CSC properties. We found that APP plays a crucial role in CSCs' characteristics that can be inhibited by cerulenin. By focusing on FA metabolism, this study identified the FASN/APP axis as a viable target to develop a more potent therapy strategy for advanced HCC.
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Affiliation(s)
- Liang-Yun Chen
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Dao-Sian Wu
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yao-An Shen
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; International Master/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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7
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Singh MK, Han S, Kim S, Kang I. Targeting Lipid Metabolism in Cancer Stem Cells for Anticancer Treatment. Int J Mol Sci 2024; 25:11185. [PMID: 39456967 PMCID: PMC11508222 DOI: 10.3390/ijms252011185] [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: 09/06/2024] [Revised: 10/14/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
Cancer stem cells (CSCs), or tumor-initiating cells (TICs), are small subpopulations (0.0001-0.1%) of cancer cells that are crucial for cancer relapse and therapy resistance. The elimination of each CSC is essential for achieving long-term remission. Metabolic reprogramming, particularly lipids, has a significant impact on drug efficacy by influencing drug diffusion, altering membrane permeability, modifying mitochondrial function, and adjusting the lipid composition within CSCs. These changes contribute to the development of chemoresistance in various cancers. The intricate relationship between lipid metabolism and drug resistance in CSCs is an emerging area of research, as different lipid species play essential roles in multiple stages of autophagy. However, the link between autophagy and lipid metabolism in the context of CSC regulation remains unclear. Understanding the interplay between autophagy and lipid reprogramming in CSCs could lead to the development of new approaches for enhancing therapies and reducing tumorigenicity in these cells. In this review, we explore the latest findings on lipid metabolism in CSCs, including the role of key regulatory enzymes, inhibitors, and the contribution of autophagy in maintaining lipid homeostasis. These recent findings may provide critical insights for identifying novel pharmacological targets for effective anticancer treatment.
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Affiliation(s)
- Manish Kumar Singh
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sunhee Han
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sungsoo Kim
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Insug Kang
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
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8
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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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9
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Du J, Qin H. Lipid metabolism dynamics in cancer stem cells: potential targets for cancers. Front Pharmacol 2024; 15:1367981. [PMID: 38994204 PMCID: PMC11236562 DOI: 10.3389/fphar.2024.1367981] [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: 01/09/2024] [Accepted: 06/10/2024] [Indexed: 07/13/2024] Open
Abstract
Cancer stem cells (CSCs) represent a small subset of heterogeneous cells within tumors that possess the ability to self-renew and initiate tumorigenesis. They serve as potential drivers for tumor initiation, metastasis, recurrence, and drug resistance. Recent research has demonstrated that the stemness preservation of CSCs is heavily reliant on their unique lipid metabolism alterations, enabling them to maintain their own environmental homeostasis through various mechanisms. The primary objectives involve augmenting intracellular fatty acid (FA) content to bolster energy supply, promoting β-oxidation of FA to optimize energy utilization, and elevating the mevalonate (MVA) pathway for efficient cholesterol synthesis. Additionally, lipid droplets (LDs) can serve as alternative energy sources in the presence of glycolysis blockade in CSCs, thereby safeguarding FA from peroxidation. Furthermore, the interplay between autophagy and lipid metabolism facilitates rapid adaptation of CSCs to the harsh microenvironment induced by chemotherapy. In this review, we comprehensively review recent studies pertaining to lipid metabolism in CSCs and provide a concise overview of the indispensable role played by LDs, FA, cholesterol metabolism, and autophagy in maintaining the stemness of CSCs.
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Affiliation(s)
- Juan Du
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Hai Qin
- Department of Clinical Laboratory, Beijing Jishuitan Hospital Guizhou Hospital, Guiyang, China
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10
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Meroni M, Longo M, Dongiovanni P. Cardiometabolic risk factors in MASLD patients with HCC: the other side of the coin. Front Endocrinol (Lausanne) 2024; 15:1411706. [PMID: 38846491 PMCID: PMC11153718 DOI: 10.3389/fendo.2024.1411706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 05/10/2024] [Indexed: 06/09/2024] Open
Abstract
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) constitutes the commonest cause of chronic liver disorder worldwide, whereby affecting around one third of the global population. This clinical condition may evolve into Metabolic Dysfunction-Associated Steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC), in a predisposed subgroup of patients. The complex pathogenesis of MASLD is severely entangled with obesity, dyslipidemia and type 2 diabetes (T2D), so far so nutritional and lifestyle recommendations may be crucial in influencing the risk of HCC and modifying its prognosis. However, the causative association between HCC onset and the presence of metabolic comorbidities is not completely clarified. Therefore, the present review aimed to summarize the main literature findings that correlate the presence of inherited or acquired hyperlipidemia and metabolic risk factors with the increased predisposition towards liver cancer in MASLD patients. Here, we gathered the evidence underlining the relationship between circulating/hepatic lipids, cardiovascular events, metabolic comorbidities and hepatocarcinogenesis. In addition, we reported previous studies supporting the impact of triglyceride and/or cholesterol accumulation in generating aberrancies in the intracellular membranes of organelles, oxidative stress, ATP depletion and hepatocyte degeneration, influencing the risk of HCC and its response to therapeutic approaches. Finally, our pursuit was to emphasize the link between HCC and the presence of cardiometabolic abnormalities in our large cohort of histologically-characterized patients affected by MASLD (n=1538), of whom 86 had MASLD-HCC by including unpublished data.
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11
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Yuan Q, Wang R, Li X, Sun F, Lin J, Fu Z, Zhang J. DNMT1/miR-152-3p/SOS1 signaling axis promotes self-renewal and tumor growth of cancer stem-like cells derived from non-small cell lung cancer. Clin Epigenetics 2024; 16:55. [PMID: 38622665 PMCID: PMC11020669 DOI: 10.1186/s13148-024-01663-5] [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: 10/11/2023] [Accepted: 03/18/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND CSLCs(Cancer stem cell-like cells), which are central to tumorigenesis, are intrinsically influenced by epigenetic modifications. This study aimed to elucidate the underlying mechanism involving the DNMT1/miR-152-3p/SOS1 axis in regulating the self-renewal and tumor growth of LCSLCs (lung cancer stem-like cells). MATERIALS AND METHODS Target genes of miR-152-3p were predicted using TargetScan Human 8.0. Self-renewal and tumor growth of LCSLC were compared in suspension-cultured non-small cell lung cancer (NSCLC) cell lines H460 and A549 cell-derived globe cells. Functional effects of the DNMT1/miR-152-3p/SOS1 axis were assessed through gain-of-function experiments in vitro and in vivo. Additionally, luciferase reporter assays were employed to analyze the interaction among DNMT1, miR-152-3p, and SOS1. RESULTS Our findings highlight a negative interaction between DNMT1 and miR-152-3p, resulting in reduced miR-152-3p level. This, in turn, leads to the alleviation of the inhibitory effect of miR-152-3p on the target gene SOS1, ultimately activating SOS1 and playing an essential role in self-renewal and tumor growth of LCSLC. However, the alteration of SOS1 does not affect DNMT1/miR-152-3p regulation. Therefore, it is reasonable to infer that the DNMT1/miR-152-3p negative feedback loop critically sustains self-renewal and tumor growth of LCSLC through SOS1. CONCLUSIONS This study reveals a novel mechanism underpinning self-renewal and tumor growth of CSLC (cancer stem cell) in NSCLC and identifies potential therapeutic targets for NSCLC treatment.
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Affiliation(s)
- Qing Yuan
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha, 410013, China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013, China
| | - Rubo Wang
- Department of Pathology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Xiang Li
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha, 410013, China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013, China
| | - Fei Sun
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha, 410013, China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013, China
| | - Jiazhi Lin
- Department of Gynaecology and Obstetrics, Shenshan Medical Center, Memorial Hospital of Sun Yat-sen University, Shanwei, 516500, Guangdong, China
| | - Zhimin Fu
- Department of Thoracic Surgery, The Tenth Affiliated Dongguan Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523000, China.
| | - Jiansong Zhang
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha, 410013, China.
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013, China.
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12
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Cai X, Wang Z, Lin S, Chen H, Bu H. Ginsenoside Rg3 suppresses vasculogenic mimicry by impairing DVL3-maintained stemness via PAAD cell-derived exosomal miR-204 in pancreatic adenocarcinoma. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 126:155402. [PMID: 38350242 DOI: 10.1016/j.phymed.2024.155402] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 01/05/2024] [Accepted: 01/31/2024] [Indexed: 02/15/2024]
Abstract
BACKGROUND Vasculogenic mimicry (VM) is an angiogenesis-independent process that potentially contributes to the poor clinical outcome of anti-angiogenesis therapy in multiple malignant cancers, including pancreatic adenocarcinoma (PAAD). Several studies have shown that ginsenoside Rg3, a bioactive component of ginseng, holds considerable potential for cancer treatment. Our previous work has proved that Rg3 can inhibit VM formation in PAAD. However, its underlying mechanism remains unclear. PURPOSE To explore the underlying mechanism by which Rg3 affects VM formation in PAAD. METHODS We first investigated the effects of Rg3 on the cellular phenotypes of two PAAD cell lines (SW-1990 and PCI-35), and the expression of EMT- and stemness-related proteins. SW-1990 cells were adopted to construct xenograft models, and the anti-tumor effects of Rg3 in vivo were validated. Subsequently, we isolated the exosomes from the two PAAD cell lines with Rg3 treatment or not, and explored whether Rg3 regulated VM via PAAD cell-derived exosomes. MiRNA sequencing, clinical analysis, and rescue experiments were performed to investigate whether and which miRNA was involved. Subsequently, the target gene of miRNA was predicted using the miRDB website (https://mirdb.org/), and rescue experiments were further conducted to validate those in vitro and in vivo. RESULTS Rg3 indeed exhibited excellent anti-tumor effects both in vitro and in vivo, with inhibitory effects on EMT and stemness of PAAD cells. More interestingly, Rg3-treated PAAD cell-derived exosomes suppressed the tube-forming ability of HUVEC and PAAD cells, with a decrease in stemness-related protein expression, indicating that Rg3 inhibited both angiogenesis and VM processes. Subsequently, we found that Rg3 induced the up-regulation of miR-204 in PAAD cell-derived exosomes, and miR-204 alone inhibited tube and sphere formation abilities of PAAD cells like exosomes. Specifically, miR-204 down-regulated DVL3 expression, which was involved in regulating cancer cell stemness, and ultimately affected VM. The in vivo experiments further indicated that Rg3-treated SW-1990 cell-derived exosome-inhibited tumor growth, VM formation, and stemness-related protein expression can be abrogated by DVL3 overexpression. CONCLUSION Ginsenoside Rg3 increased the PAAD cell-derived exosomal miR-204 levels, which subsequently inhibited its target genes DVL3 expression in the receptor PAAD cells, and the down-regulated DVL3 broke stemness maintenance, ultimately suppressing VM formation of PAAD. Our findings revealed a novel mechanism by which Rg3 exerted its anti-tumor activity in PAAD via inhibiting VM, and provided a promising strategy to make up for the deficiency of anti-angiogenesis therapy in cancer.
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Affiliation(s)
- Xufan Cai
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China
| | - Zhaohong Wang
- Department of hepatobiliary and pancreatic surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Shengzhang Lin
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, #51 Huzhou Street, Gongshu District, Hangzhou, Zhejiang 310015, People's Republic of China.
| | - Hui Chen
- Department of hepatobiliary and pancreatic surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Heqi Bu
- Department of Surgery, Tongde Hospital of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang 310012, People's Republic of China
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13
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BharathwajChetty B, Sajeev A, Vishwa R, Aswani BS, Alqahtani MS, Abbas M, Kunnumakkara AB. Dynamic interplay of nuclear receptors in tumor cell plasticity and drug resistance: Shifting gears in malignant transformations and applications in cancer therapeutics. Cancer Metastasis Rev 2024; 43:321-362. [PMID: 38517618 DOI: 10.1007/s10555-024-10171-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/19/2024] [Indexed: 03/24/2024]
Abstract
Recent advances have brought forth the complex interplay between tumor cell plasticity and its consequential impact on drug resistance and tumor recurrence, both of which are critical determinants of neoplastic progression and therapeutic efficacy. Various forms of tumor cell plasticity, instrumental in facilitating neoplastic cells to develop drug resistance, include epithelial-mesenchymal transition (EMT) alternatively termed epithelial-mesenchymal plasticity, the acquisition of cancer stem cell (CSC) attributes, and transdifferentiation into diverse cell lineages. Nuclear receptors (NRs) are a superfamily of transcription factors (TFs) that play an essential role in regulating a multitude of cellular processes, including cell proliferation, differentiation, and apoptosis. NRs have been implicated to play a critical role in modulating gene expression associated with tumor cell plasticity and drug resistance. This review aims to provide a comprehensive overview of the current understanding of how NRs regulate these key aspects of cancer biology. We discuss the diverse mechanisms through which NRs influence tumor cell plasticity, including EMT, stemness, and metastasis. Further, we explore the intricate relationship between NRs and drug resistance, highlighting the impact of NR signaling on chemotherapy, radiotherapy and targeted therapies. We also discuss the emerging therapeutic strategies targeting NRs to overcome tumor cell plasticity and drug resistance. This review also provides valuable insights into the current clinical trials that involve agonists or antagonists of NRs modulating various aspects of tumor cell plasticity, thereby delineating the potential of NRs as therapeutic targets for improved cancer treatment outcomes.
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Affiliation(s)
- Bandari BharathwajChetty
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India.
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14
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Zhang Y, Xiao B, Liu Y, Wu S, Xiang Q, Xiao Y, Zhao J, Yuan R, Xie K, Li L. Roles of PPAR activation in cancer therapeutic resistance: Implications for combination therapy and drug development. Eur J Pharmacol 2024; 964:176304. [PMID: 38142851 DOI: 10.1016/j.ejphar.2023.176304] [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: 09/17/2023] [Revised: 12/09/2023] [Accepted: 12/21/2023] [Indexed: 12/26/2023]
Abstract
Therapeutic resistance is a major obstacle to successful treatment or effective containment of cancer. Peroxisome proliferator-activated receptors (PPARs) play an essential role in regulating energy homeostasis and determining cell fate. Despite of the pleiotropic roles of PPARs in cancer, numerous studies have suggested their intricate relationship with therapeutic resistance in cancer. In this review, we provided an overview of the roles of excessively activated PPARs in promoting resistance to modern anti-cancer treatments, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. The mechanisms through which activated PPARs contribute to therapeutic resistance in most cases include metabolic reprogramming, anti-oxidant defense, anti-apoptosis signaling, proliferation-promoting pathways, and induction of an immunosuppressive tumor microenvironment. In addition, we discussed the mechanisms through which activated PPARs lead to multidrug resistance in cancer, including drug efflux, epithelial-to-mesenchymal transition, and acquisition and maintenance of the cancer stem cell phenotype. Preliminary studies investigating the effect of combination therapies with PPAR antagonists have suggested the potential of these antagonists in reversing resistance and facilitating sustained cancer management. These findings will provide a valuable reference for further research on and clinical translation of PPAR-targeting treatment strategies.
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Affiliation(s)
- Yanxia Zhang
- School of Medicine, The South China University of Technology, Guangzhou, 510006, China; Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Bin Xiao
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Yunduo Liu
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Shunhong Wu
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Qin Xiang
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Yuhan Xiao
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Junxiu Zhao
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Ruanfei Yuan
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Keping Xie
- School of Medicine, The South China University of Technology, Guangzhou, 510006, China.
| | - Linhai Li
- Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China.
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15
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Liu W, Wang S, Lin L, Zou R, Sun H, Zeng K, Wu Y, Li Y, Shigeaki K, Wang X, Wang C, Zhao Y. BAP18 acting as a novel peroxisome proliferator-activated receptor α co-regulator contributes to hepatocellular carcinoma progression. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166974. [PMID: 38042310 DOI: 10.1016/j.bbadis.2023.166974] [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: 07/31/2023] [Revised: 11/16/2023] [Accepted: 11/26/2023] [Indexed: 12/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy worldwide with a poor prognosis. The therapeutic outcomes of HCC patients are urgently needed to be improved, and predictive biomarkers for the optimal treatment selection remains to be further defined. In the present study, our results showed that BPTF-associated protein of 18 KDa (BAP18) was highly expressed in HCC tissues. In cultured HCC cells, BAP18 regulated a subset of down-stream genes involved in different functions, particularly including peroxisome proliferator-activated receptor (PPAR) pathway and lipid metabolism. Furthermore, BAP18 co-activated PPARα-mediated transactivation and facilitated the recruitment of nucleosome acetyltransferase of H4 (NuA4)/tat interacting protein 60 (TIP60) complex, thereby increasing histone H4 acetylation on stearoyl-CoA desaturase 1 (SCD1) loci. In addition, BAP18 promoted HCC cell proliferation, increased intracellular lipid levels and enhanced cell survival under the metabolic stress conditions, such as glucose limitation or tyrosine kinase inhibitors (TKIs) treatment. Importantly, higher BAP18 expression was positively correlated with the postoperative recurrence and the poor disease-free survival in clinical patients receiving sorafenib treatment. Altogether, we discovered that BAP18 plays an oncogenic role in the survival and proliferation of HCC cells, and BAP18 may serve as a predictive biomarker for adjunct TKIs treatment in patients with HCC, and further facilitate the precise treatment.
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Affiliation(s)
- Wei Liu
- Department of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, and Key laboratory of Cell Biology, Ministry of Public Health, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China; Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang City, Liaoning Province 110004, China
| | - Shengli Wang
- Department of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, and Key laboratory of Cell Biology, Ministry of Public Health, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Lin Lin
- Department of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, and Key laboratory of Cell Biology, Ministry of Public Health, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Renlong Zou
- Department of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, and Key laboratory of Cell Biology, Ministry of Public Health, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Hongmiao Sun
- Department of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, and Key laboratory of Cell Biology, Ministry of Public Health, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Kai Zeng
- Department of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, and Key laboratory of Cell Biology, Ministry of Public Health, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China
| | - Yi Wu
- Department of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, and Key laboratory of Cell Biology, Ministry of Public Health, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China; Department of Pathogenic Biology, Shenyang Medical College, Shenyang City, Liaoning Province 110034, China
| | - Yiling Li
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang City, Liaoning Province 110001, China
| | - Kato Shigeaki
- Graduate School of Life Science and Engineering, Iryo Sosei University, Iino, Chuo-dai, Iwaki, Fukushima 9708551, Japan
| | - Xiuxia Wang
- Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang City, Liaoning Province 110004, China.
| | - Chunyu Wang
- Department of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, and Key laboratory of Cell Biology, Ministry of Public Health, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China.
| | - Yue Zhao
- Department of Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, and Key laboratory of Cell Biology, Ministry of Public Health, School of Life Sciences, China Medical University, Shenyang City, Liaoning Province 110122, China.
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16
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Liu M, Zhang Z, Chen Y, Feng T, Zhou Q, Tian X. Circadian clock and lipid metabolism disorders: a potential therapeutic strategy for cancer. Front Endocrinol (Lausanne) 2023; 14:1292011. [PMID: 38189049 PMCID: PMC10770836 DOI: 10.3389/fendo.2023.1292011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 11/30/2023] [Indexed: 01/09/2024] Open
Abstract
Recent research has emphasized the interaction between the circadian clock and lipid metabolism, particularly in relation to tumors. This review aims to explore how the circadian clock regulates lipid metabolism and its impact on carcinogenesis. Specifically, targeting key enzymes involved in fatty acid synthesis (SREBP, ACLY, ACC, FASN, and SCD) has been identified as a potential strategy for cancer therapy. By disrupting these enzymes, it may be possible to inhibit tumor growth by interfering with lipid metabolism. Transcription factors, like SREBP play a significant role in regulating fatty acid synthesis which is influenced by circadian clock genes such as BMAL1, REV-ERB and DEC. This suggests a strong connection between fatty acid synthesis and the circadian clock. Therefore, successful combination therapy should target fatty acid synthesis in addition to considering the timing and duration of drug use. Ultimately, personalized chronotherapy can enhance drug efficacy in cancer treatment and achieve treatment goals.
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Affiliation(s)
- Mengsi Liu
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Changsha, China
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention and Treatment, Hunan University of Chinese Medicine, Changsha, China
| | - Zhen Zhang
- Department of Oncology, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, China
| | - Yating Chen
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Changsha, China
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention and Treatment, Hunan University of Chinese Medicine, Changsha, China
| | - Ting Feng
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Changsha, China
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention and Treatment, Hunan University of Chinese Medicine, Changsha, China
| | - Qing Zhou
- Department of Andrology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Xuefei Tian
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Changsha, China
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention and Treatment, Hunan University of Chinese Medicine, Changsha, China
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17
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Liang K, Wang Q, Qiu L, Gong X, Chen Z, Zhang H, Ding K, Liu Y, Wei J, Lin S, Fu S, Du H. Combined Inhibition of UBE2C and PLK1 Reduce Cell Proliferation and Arrest Cell Cycle by Affecting ACLY in Pan-Cancer. Int J Mol Sci 2023; 24:15658. [PMID: 37958642 PMCID: PMC10650476 DOI: 10.3390/ijms242115658] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Various studies have shown that the cell-cycle-related regulatory proteins UBE2C, PLK1, and BIRC5 promote cell proliferation and migration in different types of cancer. However, there is a lack of in-depth and systematic research on the mechanism of these three as therapeutic targets. In this study, we found a positive correlation between the expression of UBE2C and PLK1/BIRC5 in the Cancer Genome Atlas (TCGA) database, revealing a potential combination therapy candidate for pan-cancer. Quantitative real-time PCR (qRT-PCR), Western blotting (WB), cell phenotype detection, and RNA-seq techniques were used to evidence the effectiveness of the combination candidate. We found that combined interference of UBE2C with PLK1 and UBE2C with BIRC5 affected metabolic pathways by significantly downregulating the mRNA expression of IDH1 and ACLY, which was related to the synthesis of acetyl-CoA. By combining the PLK1 inhibitor volasertib and the ACLY inhibitor bempedoic acid, it showed a higher synergistic inhibition of cell viability and higher synergy scores in seven cell lines, compared with those of other combination treatments. Our study reveals the potential mechanisms through which cell-cycle-related genes regulate metabolism and proposes a potential combined targeted therapy for patients with higher PLK1 and ACLY expression in pan-cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Hongli Du
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China; (K.L.); (Q.W.); (L.Q.); (X.G.); (Z.C.); (H.Z.); (K.D.); (Y.L.); (J.W.); (S.L.); (S.F.)
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18
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Liang J, Li L, Li L, Zhou X, Zhang Z, Huang Y, Xiao X. Lipid metabolism reprogramming in head and neck cancer. Front Oncol 2023; 13:1271505. [PMID: 37927468 PMCID: PMC10622980 DOI: 10.3389/fonc.2023.1271505] [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: 08/02/2023] [Accepted: 10/09/2023] [Indexed: 11/07/2023] Open
Abstract
Lipid metabolism reprogramming is one of the most prominent metabolic anomalies in cancer, wherein cancer cells undergo dysregulation of lipid metabolism to acquire adequate energy, cell membrane building blocks, as well as signaling molecules essential for cell proliferation, survival, invasion, and metastasis. These adaptations enable cancer cells to effectively respond to challenges posed by the tumor microenvironment, leading to cancer therapy resistance and poor cancer prognosis. Head and neck cancer, ranking as the seventh most prevalent cancer, exhibits numerous abnormalities in lipid metabolism. Nevertheless, the precise role of lipid metabolic rewiring in head and neck cancer remains unclear. In line with the LIPID MAPS Lipid Classification System and cancer risk factors, the present review delves into the dysregulated molecules and pathways participating in the process of lipid uptake, biosynthesis, transportation, and catabolism. We also present an overview of the latest advancements in understanding alterations in lipid metabolism and how they intersect with the carcinogenesis, development, treatment, and prognosis of head and neck cancer. By shedding light on the significance of metabolic therapy, we aspire to improve the overall prognosis and treatment outcomes of head and neck cancer patients.
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Affiliation(s)
- Jinfeng Liang
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lin Li
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Limei Li
- Department of Pediatric Dentistry, College & Hospital of Stomatology, Guangxi Medical University, Nanning, China
| | - Xiaoying Zhou
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, China
| | - Zhe Zhang
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, China
| | - Yi Huang
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xue Xiao
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, China
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19
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Roman V, Mihaila M, Radu N, Marineata S, Diaconu CC, Bostan M. Cell Culture Model Evolution and Its Impact on Improving Therapy Efficiency in Lung Cancer. Cancers (Basel) 2023; 15:4996. [PMID: 37894363 PMCID: PMC10605536 DOI: 10.3390/cancers15204996] [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: 08/15/2023] [Revised: 10/10/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Optimizing cell culture conditions is essential to ensure experimental reproducibility. To improve the accuracy of preclinical predictions about the response of tumor cells to different classes of drugs, researchers have used 2D or 3D cell cultures in vitro to mimic the cellular processes occurring in vivo. While 2D cell culture provides valuable information on how therapeutic agents act on tumor cells, it cannot quantify how the tumor microenvironment influences the response to therapy. This review presents the necessary strategies for transitioning from 2D to 3D cell cultures, which have facilitated the rapid evolution of bioengineering techniques, leading to the development of microfluidic technology, including organ-on-chip and tumor-on-chip devices. Additionally, the study aims to highlight the impact of the advent of 3D bioprinting and microfluidic technology and their implications for improving cancer treatment and approaching personalized therapy, especially for lung cancer. Furthermore, implementing microfluidic technology in cancer studies can generate a series of challenges and future perspectives that lead to the discovery of new predictive markers or targets for antitumor treatment.
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Affiliation(s)
- Viviana Roman
- Center of Immunology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (V.R.); (M.B.)
| | - Mirela Mihaila
- Center of Immunology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (V.R.); (M.B.)
| | - Nicoleta Radu
- Department of Biotechnology, University of Agronomic Sciences and Veterinary Medicine of Bucharest, 011464 Bucharest, Romania
- Biotechnology Department, National Institute for Chemistry and Petrochemistry R&D of Bucharest, 060021 Bucharest, Romania
| | - Stefania Marineata
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila, 050471 Bucharest, Romania;
| | - Carmen Cristina Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, 030304 Bucharest, Romania;
| | - Marinela Bostan
- Center of Immunology, Stefan S. Nicolau Institute of Virology, Romanian Academy, 030304 Bucharest, Romania; (V.R.); (M.B.)
- Department of Immunology, ‘Victor Babeș’ National Institute of Pathology, 050096 Bucharest, Romania
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20
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Wang F, Gao Y, Xue S, Zhao L, Jiang H, Zhang T, Li Y, Zhao C, Wu F, Siqin T, Liu Y, Wu J, Yan Y, Yuan J, Jiang JD, Li K. SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity. Nat Commun 2023; 14:5917. [PMID: 37739936 PMCID: PMC10517016 DOI: 10.1038/s41467-023-41593-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 09/11/2023] [Indexed: 09/24/2023] Open
Abstract
CSCs (Cancer stem cells) with distinct metabolic features are considered to cause HCC (hepatocellular carcinoma) initiation, metastasis and therapeutic resistance. Here, we perform a metabolic gene CRISPR/Cas9 knockout library screen in tumorspheres derived from HCC cells and find that deletion of SCARB2 suppresses the cancer stem cell-like properties of HCC cells. Knockout of Scarb2 in hepatocytes attenuates HCC initiation and progression in both MYC-driven and DEN (diethylnitrosamine)-induced HCC mouse models. Mechanistically, binding of SCARB2 with MYC promotes MYC acetylation by interfering with HDCA3-mediated MYC deacetylation on lysine 148 and subsequently enhances MYC transcriptional activity. Screening of a database of FDA (Food and Drug Administration)-approved drugs shows Polymyxin B displays high binding affinity for SCARB2 protein, disrupts the SCARB2-MYC interaction, decreases MYC activity, and reduces the tumor burden. Our study identifies SCARB2 as a functional driver of HCC and suggests Polymyxin B-based treatment as a targeted therapeutic option for HCC.
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Affiliation(s)
- Feng Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Yang Gao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Situ Xue
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Luyao Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Huimin Jiang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Tingting Zhang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Yunxuan Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Chenxi Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Fan Wu
- Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 100021, Beijing, China
| | - Tana Siqin
- Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 100021, Beijing, China
| | - Ying Liu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Jie Wu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Yechao Yan
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China
| | - Jian Yuan
- Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, 200120, China.
| | - Jian-Dong Jiang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China.
| | - Ke Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China.
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21
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Lama Tamang R, Kumar B, Patel SM, Thapa I, Ahmad A, Kumar V, Ahmad R, Becker DF, Bastola D(K, Dhawan P, Singh AB. Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Carcinogenesis by Modulating Microtubule-Associated Serine/Threonine Kinase-like/Wnt/β-Catenin Signaling. Cells 2023; 12:1883. [PMID: 37508547 PMCID: PMC10377831 DOI: 10.3390/cells12141883] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/03/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Despite significant progress in clinical management, colorectal cancer (CRC) remains the third most common cause of cancer-related deaths. A positive association between PYCR2 (pyrroline-5-carboxylate reductase-2), a terminal enzyme of proline metabolism, and CRC aggressiveness was recently reported. However, how PYCR2 promotes colon carcinogenesis remains ill understood. METHODS A comprehensive analysis was performed using publicly available cancer databases and CRC patient cohorts. Proteomics and biochemical evaluations were performed along with genetic manipulations and in vivo tumor growth assays to gain a mechanistic understanding. RESULTS PYCR2 expression was significantly upregulated in CRC and associated with poor patient survival, specifically among PYCR isoforms (PYCR1, 2, and 3). The genetic inhibition of PYCR2 inhibited the tumorigenic abilities of CRC cells and in vivo tumor growth. Coinciding with these observations was a significant decrease in cellular proline content. PYCR2 overexpression promoted the tumorigenic abilities of CRC cells. Proteomics (LC-MS/MS) analysis further demonstrated that PYCR2 loss of expression in CRC cells inhibits survival and cell cycle pathways. A subsequent biochemical analysis supported the causal role of PYCR2 in regulating CRC cell survival and the cell cycle, potentially by regulating the expression of MASTL, a cell-cycle-regulating protein upregulated in CRC. Further studies revealed that PYCR2 regulates Wnt/β-catenin-signaling in manners dependent on the expression of MASTL and the cancer stem cell niche. CONCLUSIONS PYCR2 promotes MASTL/Wnt/β-catenin signaling that, in turn, promotes cancer stem cell populations and, thus, colon carcinogenesis. Taken together, our data highlight the significance of PYCR2 as a novel therapeutic target for effectively treating aggressive colon cancer.
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Affiliation(s)
- Raju Lama Tamang
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Balawant Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Sagar M. Patel
- Department of Biochemistry and Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Ishwor Thapa
- School of Interdisciplinary Informatics, College of Information Science & Technology, University of Nebraska at Omaha, Omaha, NE 68182, USA
| | - Alshomrani Ahmad
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Vikas Kumar
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Rizwan Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Donald F. Becker
- Department of Biochemistry and Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Dundy (Kiran) Bastola
- School of Interdisciplinary Informatics, College of Information Science & Technology, University of Nebraska at Omaha, Omaha, NE 68182, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105-1850, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-65870, USA
| | - Amar B. Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105-1850, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-65870, USA
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22
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Groenewoud A, Yin J, Gelmi MC, Alsafadi S, Nemati F, Decaudin D, Roman-Roman S, Kalirai H, Coupland SE, Jochemsen AG, Jager MJ, Engel FB, Snaar-Jagalska BE. Patient-derived zebrafish xenografts of uveal melanoma reveal ferroptosis as a drug target. Cell Death Discov 2023; 9:183. [PMID: 37321991 DOI: 10.1038/s41420-023-01446-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 03/24/2023] [Accepted: 04/24/2023] [Indexed: 06/17/2023] Open
Abstract
Uveal melanoma (UM) has a high risk to progress to metastatic disease with a median survival of 3.9 months after metastases detection, as metastatic UM responds poorly to conventional and targeted chemotherapy and is largely refractory to immunotherapy. Here, we present a patient-derived zebrafish UM xenograft model mimicking metastatic UM. Cells isolated from Xmm66 spheroids derived from metastatic UM patient material were injected into 2 days-old zebrafish larvae resulting in micro-metastases in the liver and caudal hematopoietic tissue. Metastasis formation could be reduced by navitoclax and more efficiently by the combinations navitoclax/everolimus and flavopiridol/quisinostat. We obtained spheroid cultures from 14 metastatic and 10 primary UM tissues, which were used for xenografts with a success rate of 100%. Importantly, the ferroptosis-related genes GPX4 and SLC7A11 are negatively correlated with the survival of UM patients (TCGA: n = 80; Leiden University Medical Centre cohort: n = 64), ferroptosis susceptibility is correlated with loss of BAP1, one of the key prognosticators for metastatic UM, and ferroptosis induction greatly reduced metastasis formation in the UM xenograft model. Collectively, we have established a patient-derived animal model for metastatic UM and identified ferroptosis induction as a possible therapeutic strategy for the treatment of UM patients.
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Affiliation(s)
- Arwin Groenewoud
- Institute of Biology, Leiden University, Leiden, The Netherlands.
- Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
- Bavarian Cancer Research Center (BZKF), 91054, Erlangen, Germany.
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany.
| | - Jie Yin
- Institute of Biology, Leiden University, Leiden, The Netherlands
| | - Maria Chiara Gelmi
- Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
| | - Samar Alsafadi
- Uveal Melanoma Translational Group, Department of Translational Research, Institut Curie, PSL Research University, 75248 Paris, France
| | - Fariba Nemati
- Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL Research University, 75248 Paris, France
| | - Didier Decaudin
- Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL Research University, 75248 Paris, France
| | - Sergio Roman-Roman
- Uveal Melanoma Translational Group, Department of Translational Research, Institut Curie, PSL Research University, 75248 Paris, France
| | - Helen Kalirai
- Liverpool Ocular Oncology Research Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Sarah E Coupland
- Liverpool Ocular Oncology Research Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Aart G Jochemsen
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Martine J Jager
- Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
| | - Felix B Engel
- Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
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23
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Milan TM, Eskenazi APE, de Oliveira LD, da Silva G, Bighetti-Trevisan RL, Freitas GP, de Almeida LO. Interplay between EZH2/β-catenin in stemness of cisplatin-resistant HNSCC and their role as therapeutic targets. Cell Signal 2023:110773. [PMID: 37331417 DOI: 10.1016/j.cellsig.2023.110773] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/02/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023]
Abstract
The Wnt/β-catenin signaling pathway is associated with the regulation of cancer stem cells, and it can be driven by epigenetic modifications. Here, we aim to identify epigenetic modifications involved in the control of the Wnt/β-catenin signaling and investigate the role of this pathway in the accumulation of cancer stem cells (CSC) and chemoresistance of Head and Neck Squamous Cell Carcinoma (HNSCC). Quantitative-PCR, western blot, shRNA assay, viability assay, flow cytometry assay, spheres formation, xenograft model, and chromatin immunoprecipitation were employed to evaluate the Wnt/β-catenin pathway and EZH2 in wild-type and chemoresistant oral carcinoma cell lines, and in the populations of CSC and non-stem cells. We demonstrated that β-catenin and EZH2 were accumulated in cisplatin-resistant and CSC population. The upstream genes of the Wnt/β-catenin signaling (APC and GSK3β) were decreased, and the downstream gene MMP7 was increased in the chemoresistant cell lines. The inhibition of β-catenin and EZH2 combined effectively decreased the CSC population in vitro and reduced the tumor volume and CSC population in vivo. EZH2 inhibition increased APC and GSK3β, and the Wnt/β-catenin inhibition reduced MMP7 levels. In contrast, EZH2 overexpression decreased APC and GSK3β and increased MMP7. EZH2 and β-catenin inhibitors sensitized chemoresistant cells to cisplatin. EZH2 and H3K27me3 bounded the promoter of APC, leading to its repression. These results suggest that EZH2 regulates β-catenin by inhibiting the upstream gene APC contributing to the accumulation of cancer stem cells and chemoresistance. Moreover, the pharmacological inhibition of the Wnt/β-catenin combined with EZH2 can be an effective strategy for treating HNSCC.
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Affiliation(s)
- Thaís Moré Milan
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
| | - Ana Patrícia Espaladori Eskenazi
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
| | - Lucas Dias de Oliveira
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Gabriel da Silva
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
| | - Rayana Longo Bighetti-Trevisan
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
| | - Gileade Pereira Freitas
- Departament of Oral and Maxillofacial Surgery, School of Dentistry, Federal University of Goiás, Goiás, Brazil.
| | - Luciana Oliveira de Almeida
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
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24
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Min JY, Kim DH. Stearoyl-CoA Desaturase 1 as a Therapeutic Biomarker: Focusing on Cancer Stem Cells. Int J Mol Sci 2023; 24:ijms24108951. [PMID: 37240297 DOI: 10.3390/ijms24108951] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/06/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
The dysregulation of lipid metabolism and alterations in the ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) have been implicated in cancer progression and stemness. Stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in lipid desaturation, is crucial in regulating this ratio and has been identified as an important regulator of cancer cell survival and progression. SCD1 converts SFAs into MUFAs and is important for maintaining membrane fluidity, cellular signaling, and gene expression. Many malignancies, including cancer stem cells, have been reported to exhibit high expression of SCD1. Therefore, targeting SCD1 may provide a novel therapeutic strategy for cancer treatment. In addition, the involvement of SCD1 in cancer stem cells has been observed in various types of cancer. Some natural products have the potential to inhibit SCD1 expression/activity, thereby suppressing cancer cell survival and self-renewal activity.
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Affiliation(s)
- Jin-Young Min
- Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon 16227, Gyeonggi-do, Republic of Korea
| | - Do-Hee Kim
- Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon 16227, Gyeonggi-do, Republic of Korea
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25
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Sun J, Yu L, Qu X, Huang T. The role of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anticancer therapy. Front Pharmacol 2023; 14:1184794. [PMID: 37251321 PMCID: PMC10213337 DOI: 10.3389/fphar.2023.1184794] [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: 03/12/2023] [Accepted: 05/05/2023] [Indexed: 05/31/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for over 3 decades and consist of three isotypes, including PPARα, γ, and β/δ, that were originally considered key metabolic regulators controlling energy homeostasis in the body. Cancer has become a leading cause of human mortality worldwide, and the role of peroxisome proliferator-activated receptors in cancer is increasingly being investigated, especially the deep molecular mechanisms and effective cancer therapies. Peroxisome proliferator-activated receptors are an important class of lipid sensors and are involved in the regulation of multiple metabolic pathways and cell fate. They can regulate cancer progression in different tissues by activating endogenous or synthetic compounds. This review emphasizes the significance and knowledge of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anti-cancer treatment by summarizing recent research on peroxisome proliferator-activated receptors. In general, peroxisome proliferator-activated receptors either promote or suppress cancer in different types of tumor microenvironments. The emergence of this difference depends on various factors, including peroxisome proliferator-activated receptor type, cancer type, and tumor stage. Simultaneously, the effect of anti-cancer therapy based on drug-targeted PPARs differs or even opposes among the three peroxisome proliferator-activated receptor homotypes and different cancer types. Therefore, the current status and challenges of the use of peroxisome proliferator-activated receptors agonists and antagonists in cancer treatment are further explored in this review.
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Affiliation(s)
- Jiaao Sun
- Department of Urology, First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Liyan Yu
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China
| | - Xueling Qu
- Dalian Women and Children’s Medical Center(Group), Dalian, Liaoning, China
| | - Tao Huang
- Department of Urology, First Affiliated Hospital, Dalian Medical University, Dalian, China
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26
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Zhang Y, Wang Y, Zhao G, Orsulic S, Matei D. Metabolic dependencies and targets in ovarian cancer. Pharmacol Ther 2023; 245:108413. [PMID: 37059310 DOI: 10.1016/j.pharmthera.2023.108413] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 03/31/2023] [Accepted: 04/10/2023] [Indexed: 04/16/2023]
Abstract
Reprogramming of cellular metabolism is a hallmark of cancer. Cancer cells undergo metabolic adaptations to maintain tumorigenicity and survive under the attack of immune cells and chemotherapy in the tumor microenvironment. Metabolic alterations in ovarian cancer in part overlap with findings from other solid tumors and in part reflect unique traits. Altered metabolic pathways not only facilitate ovarian cancer cells' survival and proliferation but also endow them to metastasize, acquire resistance to chemotherapy, maintain cancer stem cell phenotype and escape the effects of anti-tumor immune defense. In this review, we comprehensively review the metabolic signatures of ovarian cancer and their impact on cancer initiation, progression, and resistance to treatment. We highlight novel therapeutic strategies targeting metabolic pathways under development.
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Affiliation(s)
- Yaqi Zhang
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Driskill Graduate Training Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Yinu Wang
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Guangyuan Zhao
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Driskill Graduate Training Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Sandra Orsulic
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
| | - Daniela Matei
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
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27
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Tseng CC, Hung CC, Shu CW, Lee CH, Chen CF, Kuo MS, Kao YY, Chen CL, Ger LP, Liu PF. The Clinical and Biological Effects of Receptor Expression-Enhancing Protein 6 in Tongue Squamous Cell Carcinoma. Biomedicines 2023; 11:biomedicines11051270. [PMID: 37238941 DOI: 10.3390/biomedicines11051270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/07/2023] [Accepted: 04/23/2023] [Indexed: 05/28/2023] Open
Abstract
There are currently no effective biomarkers for the diagnosis and treatment of tongue squamous cell carcinoma (TSCC), which causes a poor 5-year overall survival rate. Thus, it is crucial to identify more effective diagnostic/prognostic biomarkers and therapeutic targets for TSCC patients. The receptor expression-enhancing protein 6 (REEP6), a transmembrane endoplasmic reticulum resident protein, controls the expression or transport of a subset of proteins or receptors. Although it was reported that REEP6 plays a role in lung and colon cancers, its clinical impact and biological role in TSCC are still unknown. The present study aimed to identify a novel effective biomarker and therapeutic target for TSCC patients. Expression levels of REEP6 in specimens from TSCC patients were determined with immunohistochemistry. Gene knockdown was used to evaluate the effects of REEP6 in cancer malignancy (colony/tumorsphere formation, cell cycle regulation, migration, drug resistance and cancer stemness) of TSCC cells. The clinical impact of REEP6 expression and gene co-expression on prognosis were analyzed in oral cancer patients including TSCC patients from The Cancer Genome Atlas database. Tumor tissues had higher levels of REEP6 compared to normal tissues in TSCC patients. Higher REEP6 expression was related to shorter disease-free survival (DFS) in oral cancer patients with poorly differentiated tumor cells. REEP6-knocked-down TSCC cells showed diminished colony/tumorsphere formation, and they also caused G1 arrest and decreased migration, drug resistance and cancer stemness. A high co-expression of REEP6/epithelial-mesenchymal transition or cancer stemness markers also resulted in poor DFS in oral cancer patients. Thus, REEP6 is involved in the malignancy of TSCC and might serve as a potential diagnostic/prognostic biomarker and therapeutic target for TSCC patients.
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Affiliation(s)
- Chung-Chih Tseng
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
- Department of Dentistry, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 81342, Taiwan
| | - Chung-Ching Hung
- Department of Otolaryngology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 81342, Taiwan
| | - Chih-Wen Shu
- Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
| | - Cheng-Hsin Lee
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chun-Feng Chen
- Department of Stomatology, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Mei-Shu Kuo
- Department of Biotechnology, Chia Nan University, Tainan 71710, Taiwan
| | - Yu-Ying Kao
- Department of Biotechnology, Chia Nan University, Tainan 71710, Taiwan
| | - Chun-Lin Chen
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
| | - Luo-Ping Ger
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Pei-Feng Liu
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
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28
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Qian Z, Chen L, Liu J, Jiang Y, Zhang Y. The emerging role of PPAR-alpha in breast cancer. Biomed Pharmacother 2023; 161:114420. [PMID: 36812713 DOI: 10.1016/j.biopha.2023.114420] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/05/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Breast cancer has been confirmed to have lipid disorders in the tumour microenvironment. Peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcriptional factor that belongs to the family of nuclear receptors. PPARα regulates the expression of genes involved in fatty acid homeostasis and is a major regulator of lipid metabolism. Because of its effects on lipid metabolism, an increasing number of studies have investigated the relationship of PPARα with breast cancer. PPARα has been shown to impact the cell cycle and apoptosis in normal cells and tumoral cells through regulating genes of the lipogenic pathway, fatty acid oxidation, fatty acid activation, and uptake of exogenous fatty acids. Besides, PPARα is involved in the regulation of the tumour microenvironment (anti-inflammation and inhibition of angiogenesis) by modulating different signal pathways such as NF-κB and PI3K/AKT/mTOR. Some synthetic PPARα ligands are used in adjuvant therapy for breast cancer. PPARα agonists are reported to reduce the side effects of chemotherapy and endocrine therapy. In addition, PPARα agonists enhance the curative effects of targeted therapy and radiation therapy. Interestingly, with the emerging role of immunotherapy, attention has been focused on the tumour microenvironment. The dual functions of PPARα agonists in immunotherapy need further research. This review aims to consolidate the operations of PPARα in lipid-related and other ways, as well as discuss the current and potential applications of PPARα agonists in tackling breast cancer.
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Affiliation(s)
- Zhiwen Qian
- Department of Oncology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi 214002, China.
| | - Lingyan Chen
- Department of Oncology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi 214002, China.
| | - Jiayu Liu
- Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi 214000, China.
| | - Ying Jiang
- Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi 214000, China.
| | - Yan Zhang
- Department of Oncology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi 214002, China; Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi 214000, China.
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29
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Gómez-Gallegos AA, Ramírez-Vidal L, Becerril-Rico J, Pérez-Islas E, Hernandez-Peralta ZJ, Toledo-Guzmán ME, García-Carrancá A, Langley E, Hernández-Guerrero A, López-Casillas F, Herrera-Goepfert R, Oñate-Ocaña LF, Ortiz-Sánchez E. CD24+CD44+CD54+EpCAM+ gastric cancer stem cells predict tumor progression and metastasis: clinical and experimental evidence. Stem Cell Res Ther 2023; 14:16. [PMID: 36737794 PMCID: PMC9898964 DOI: 10.1186/s13287-023-03241-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 01/17/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. Specific and thorough identification of cancer cell subsets with higher tumorigenicity and chemoresistance, such as cancer stem cells (CSCs), could lead to the development of new and promising therapeutic targets. For better CSC identification, a complete or extended surface marker phenotype is needed to provide increased specificity for new cell targeting approaches. Our goal is to identify and characterize a putative extended phenotype for CSCs derived from patients with GC before treatment, as well as to evaluate its clinical value. In addition, we aim to ensure that cells with this phenotype have stemness and self-renewal capabilities. METHODS This is a cohort study including 127 treatment-naïve patients with GC who attended the Instituto Nacional de Cancerología. Multiparametric flow cytometry analysis was performed to determine the extended phenotype of cells derived from gastric biopsies. The tumorigenic capability of cells identified in patients was assessed in a zebrafish model. RESULTS CD24+CD44+CD54+EpCAM+ cells were present in all treatment-naïve patients included, with a median abundance of 1.16% (0.57-1.89%). The percentage of CD24+CD44+CD54+EpCAM+ cells was categorized as high or low using 1.19% as the cutoff for the CD24+CD44+CD54+EpCAM+ cell subset. Additionally, a higher TNM stage correlated with a higher percentage of CD24+CD44+CD54+EpCAM+ cells (Rho coefficient 0.369; p < 0.0001). We also demonstrated that a higher percentage of CD24+CD44+CD54+EpCAM+ cells was positively associated with metastasis. The metastatic potential of these cells was confirmed in a zebrafish model. Ultimately, under our conditions, we conclude that CD24+CD44+CD54+EpCAM+ cells are true gastric cancer stem cells (GCSCs). CONCLUSION The CD24+CD44+CD54+EpCAM+ cells present in tissue samples from patients are true GCSCs. This extended phenotype results in better and more specific characterization of these highly tumorigenic cells. The relative quantification of CD24+CD44+CD54+EpCAM+ cells has potential clinical value, as these cells are associated with metastatic disease, making their presence an additional prognostic marker and possibly a target for the design of new antineoplastic treatments in the era of precision oncology. Overall, the extended CD24+CD44+CD54+EpCAM+ phenotype of GCSCs could support their isolation for the study of their stemness mechanisms, leading to the identification of better molecular targets for the development of both new therapeutic approaches such as oncoimmunotherapy and new diagnostic and clinical prognostic strategies for GC.
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Affiliation(s)
- Angel A Gómez-Gallegos
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Edificio A, 1° Piso, Circuito de Posgrados, Ciudad Universitaria, C.P. 04510, Coyoacán, Distrito Federal, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Lizbeth Ramírez-Vidal
- Posgrado de Ciencias Biomédicas. Facultad de Medicina, Universidad Nacional Autónoma de México, Circuito Exterior s/n Ciudad Universitaria, Coyoacán, 04510, Mexico City, Mexico
| | - Jared Becerril-Rico
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Edificio A, 1° Piso, Circuito de Posgrados, Ciudad Universitaria, C.P. 04510, Coyoacán, Distrito Federal, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Elizabeth Pérez-Islas
- Departamento de Patología, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Zuly J Hernandez-Peralta
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Mariel E Toledo-Guzmán
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Alejandro García-Carrancá
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
- Unidad de Investigación en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Elizabeth Langley
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Angélica Hernández-Guerrero
- Unidad de Endoscopia, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Fernando López-Casillas
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Circuito Exterior s/n Ciudad Universitaria, Coyoacán, 04510, Mexico City, Mexico
| | - Roberto Herrera-Goepfert
- Departamento de Patología, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Luis F Oñate-Ocaña
- Subdirección de Investigación Clínica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Sección XVI, Tlalpan, 14080, Mexico City, Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico City, Mexico.
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Tsochantaridis I, Roupas A, Mohlin S, Pappa A, Voulgaridou GP. The Concept of Cancer Stem Cells: Elaborating on ALDH1B1 as an Emerging Marker of Cancer Progression. LIFE (BASEL, SWITZERLAND) 2023; 13:life13010197. [PMID: 36676146 PMCID: PMC9863106 DOI: 10.3390/life13010197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/29/2022] [Accepted: 01/03/2023] [Indexed: 01/11/2023]
Abstract
Cancer is a multifactorial, complex disease exhibiting extraordinary phenotypic plasticity and diversity. One of the greatest challenges in cancer treatment is intratumoral heterogeneity, which obstructs the efficient eradication of the tumor. Tumor heterogeneity is often associated with the presence of cancer stem cells (CSCs), a cancer cell sub-population possessing a panel of stem-like properties, such as a self-renewal ability and multipotency potential. CSCs are associated with enhanced chemoresistance due to the enhanced efflux of chemotherapeutic agents and the existence of powerful antioxidant and DNA damage repair mechanisms. The distinctive characteristics of CSCs make them ideal targets for clinical therapeutic approaches, and the identification of efficient and specific CSCs biomarkers is of utmost importance. Aldehyde dehydrogenases (ALDHs) comprise a wide superfamily of metabolic enzymes that, over the last years, have gained increasing attention due to their association with stem-related features in a wide panel of hematopoietic malignancies and solid cancers. Aldehyde dehydrogenase 1B1 (ALDH1B1) is an isoform that has been characterized as a marker of colon cancer progression, while various studies suggest its importance in additional malignancies. Here, we review the basic concepts related to CSCs and discuss the potential role of ALDH1B1 in cancer development and its contribution to the CSC phenotype.
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Affiliation(s)
- Ilias Tsochantaridis
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Angelos Roupas
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Sofie Mohlin
- Division of Pediatrics, Clinical Sciences, Lund Stem Cell Center, Lund University Cancer Center, 22384 Lund, Sweden
| | - Aglaia Pappa
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Georgia-Persephoni Voulgaridou
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Correspondence:
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31
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Quiroz Reyes AG, Lozano Sepulveda SA, Martinez-Acuña N, Islas JF, Gonzalez PD, Heredia Torres TG, Perez JR, Garza Treviño EN. Cancer Stem Cell and Hepatic Stellate Cells in Hepatocellular Carcinoma. Technol Cancer Res Treat 2023; 22:15330338231163677. [PMID: 36938618 PMCID: PMC10028642 DOI: 10.1177/15330338231163677] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer. It is highly lethal and has high recurrence. Death among HCC patients occur mainly due to tumor progression, recurrence, metastasis, and chemoresistance. Cancer stem cells (CSCs) are cell subpopulations within the tumor that promote invasion, recurrence, metastasis, and drug resistance. Hepatic stellate cells (HSCs) are important components of the tumor microenvironment (TME) responsible for primary secretory ECM proteins during liver injury and inflammation. These cells promote fibrogenesis, infiltrate the tumor stroma, and contribute to HCC development. Interactions between HSC and CSC and their microenvironment help promote carcinogenesis through different mechanisms. This review summarizes the roles of CSCs and HSCs in establishing the TME in primary liver tumors and describes their involvement in HCC chemoresistance.
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Affiliation(s)
- Adriana G Quiroz Reyes
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Sonia A Lozano Sepulveda
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Natalia Martinez-Acuña
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Jose F Islas
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Paulina Delgado Gonzalez
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Tania Guadalupe Heredia Torres
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Jorge Roacho Perez
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
| | - Elsa N Garza Treviño
- Facultad de Medicina, Department of Biochemistry and Molecular Medicine, 27771Universidad Autonoma de Nuevo Leon, Monterrey, Mexico
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Lee YH, Kim M, Park HJ, Park JY, Song ES, Lee H, Ko G, Ahn S, Kwon HW, Byun Y, Kim C, Choi J, Park JT. Chemical screening identifies the anticancer properties of Polyporous parvovarius. J Cancer 2023; 14:50-60. [PMID: 36605488 PMCID: PMC9809329 DOI: 10.7150/jca.78302] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 11/28/2022] [Indexed: 01/04/2023] Open
Abstract
One of the biggest obstacles in cancer treatment is the development of chemoresistance. To overcome this, attempts have been made to screen novel anticancer substances derived from natural products. The purpose of this study is to find new anticancer candidates in the mycelium culture extract of mushrooms belonging to Polyporus. Here, we used a high-throughput screening to find agents capable of inhibiting cancer cell proliferation. The culture extract of Polyporus Parvovarius mycelium in DY medium (pp-DY) was effective. pp-DY inhibited cancer cell proliferation by inducing apoptosis and S-phase arrest. The anticancer property of pp-DY was not only effective against one type of cancer, but also against another type of cancer. Compound fractionation was performed, and the active ingredient exhibiting anticancer effects in pp-DY was identified as 3,4-dihydroxybenzaldehyde (Protocatechualdehyde, PCA). PCA, like pp-DY, inhibited the proliferation of cancer cells by inducing apoptosis and S-phase arrest. Furthermore, unlike conventional anticancer drugs, PCA did not increase the proportion of the side population that plays the most important role in the development of chemoresistance. Taken together, our data revealed the novel mycelium culture extract that exhibited anticancer property, and identified active ingredients that did not activate a proportion of the side population. These novel findings may have clinical applications in the treatment of cancer, particularly chemo-resistant cancer.
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Affiliation(s)
- Yun Haeng Lee
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Minkyeong Kim
- Microorganism Resources Division, National Institute of Biological Resources, Incheon 22689, Korea
| | - Hyon Jin Park
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Ji Yun Park
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Eun Seon Song
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Haneur Lee
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Gahyun Ko
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Soonkil Ahn
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea
| | - Hyung Wook Kwon
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea.,Convergence Research Center for Insect Vectors, Incheon National University, Incheon 22012, Korea
| | - Youngjoo Byun
- College of Pharmacy, Korea University, Sejong 30019, Republic of Korea
| | - Changmu Kim
- Microorganism Resources Division, National Institute of Biological Resources, Incheon 22689, Korea.,✉ Corresponding authors: Changmu Kim, Ph. D. Microorganism Resources Division, National Institute of Biological Resources, Incheon 22689, Korea. Tel: +82-32-590-7344, E-mail address: ; Jaehyuk Choi, Ph.D Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea. Tel: +82-32-835-8242, E-mail address: ; Joon Tae Park, Ph.D. Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea. Tel: +82-32-835-8841, E-mail address:
| | - Jaehyuk Choi
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea.,✉ Corresponding authors: Changmu Kim, Ph. D. Microorganism Resources Division, National Institute of Biological Resources, Incheon 22689, Korea. Tel: +82-32-590-7344, E-mail address: ; Jaehyuk Choi, Ph.D Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea. Tel: +82-32-835-8242, E-mail address: ; Joon Tae Park, Ph.D. Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea. Tel: +82-32-835-8841, E-mail address:
| | - Joon Tae Park
- Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, Korea.,Convergence Research Center for Insect Vectors, Incheon National University, Incheon 22012, Korea.,✉ Corresponding authors: Changmu Kim, Ph. D. Microorganism Resources Division, National Institute of Biological Resources, Incheon 22689, Korea. Tel: +82-32-590-7344, E-mail address: ; Jaehyuk Choi, Ph.D Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea. Tel: +82-32-835-8242, E-mail address: ; Joon Tae Park, Ph.D. Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea. Tel: +82-32-835-8841, E-mail address:
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Evaluation of X-ray and carbon-ion beam irradiation with chemotherapy for the treatment of cervical adenocarcinoma cells in 2D and 3D cultures. Cancer Cell Int 2022; 22:391. [PMID: 36494817 PMCID: PMC9733259 DOI: 10.1186/s12935-022-02810-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Cervical cancer is the second most common cancer in women and causes more than 250,000 deaths worldwide. Among these, the incidence of cervical adenocarcinomas is increasing. Cervical adenocarcinoma is not only difficult to detect and prevent in the early stages with screening, but it is also resistant to chemotherapy and radiotherapy, and its prognosis worsens significantly as the disease progresses. Furthermore, when recurrence or metastasis is observed, treatment options are limited and there is no curative treatment. Recently, heavy-particle radiotherapy has attracted attention owing to its high tumor control and minimal damage to normal tissues. In addition, heavy particle irradiation is effective for cancer stem cells and hypoxic regions, which are difficult to treat. METHODS In this study, we cultured cervical adenocarcinoma cell lines (HeLa and HCA-1) in two-dimensional (2D) or three-dimensional (3D) spheroid cultures and evaluated the effects of X-ray and carbon-ion (C-ion) beams. RESULTS X-ray irradiation decreased the cell viability in a dose-dependent manner in 2D cultures, whereas this effect was attenuated in 3D spheroid cultures. In contrast, C-ion irradiation demonstrated the same antitumor effect in 3D spheroid cultures as in 2D cultures. In 3D spheroid cultures, X-rays and anticancer drugs are attenuated because of hypoxia inside the spheroids. However, the impact of the C-ion beam was almost the same as that of the 2D culture, because heavy-particle irradiation was not affected by hypoxia. CONCLUSION These results suggest that heavy-particle radiotherapy may be a new therapeutic strategy for overcoming the resistance of cervical adenocarcinoma to treatment.
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Chou YJ, Lin CC, Hsu YC, Syu JL, Tseng LM, Chiu JH, Lo JF, Lin CH, Fu SL. Andrographolide suppresses the malignancy of triple-negative breast cancer by reducing THOC1-promoted cancer stem cell characteristics. Biochem Pharmacol 2022; 206:115327. [PMID: 36330949 DOI: 10.1016/j.bcp.2022.115327] [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: 08/02/2022] [Revised: 10/11/2022] [Accepted: 10/19/2022] [Indexed: 12/14/2022]
Abstract
Triple-negative breast cancers (TNBCs) are difficult to cure and currently lack of effective treatment strategies. Cancer stem cells (CSCs) are highly associated with the poor clinical outcome of TNBCs. Thoc1 is a core component of the THO complex (THOC) that regulates the elongation, processing and nuclear export of mRNA. The function of thoc1 in TNBC and whether Thoc1 serves as a drug target are poorly understood. In this study, we demonstrated that thoc1 expression is elevated in TNBC cell lines and human TNBC patient tissues. Knockdown of thoc1 decreased cancer stem cell populations, reduced mammosphere formation, impaired THOC function, and downregulated the expression of stemness-related proteins. Moreover, the thoc1-knockdown 4T1 cells showed less lung metastasis in an orthotopic breast cancer mouse model. Overexpression of Thoc1 promoted TNBC malignancy and the mRNA export of stemness-related genes. Furthermore, treatment of TNBC cells with the natural compound andrographolide reduced the expression of Thoc1 expression, impaired homeostasis of THOC, suppressed CSC properties, and delayed tumor growth in a 4T1-implanted orthotopic mouse model. Andrographolide also reduced the activity of NF-κB, an upstream transcriptional regulator of Thoc1. Notably, thoc1 overexpression attenuates andrographolide-suppressed cellular proliferation. Altogether, our results demonstrate that THOC1 promotes cancer stem cell characteristics of TNBC, and andrographolide is a potential natural compound for eliminating CSCs of TNBCs by downregulating the NF-κB-thoc1 axis.
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Affiliation(s)
- Yi-Ju Chou
- Program in Molecular Medicine, School of Life Sciences, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 11221, Taiwan
| | - Ching-Cheng Lin
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Ya-Chi Hsu
- Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Jia-Ling Syu
- Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Ling-Ming Tseng
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jen-Hwey Chiu
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jeng-Fan Lo
- Institute of Oral Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Chao-Hsiung Lin
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Shu-Ling Fu
- Program in Molecular Medicine, School of Life Sciences, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 11221, Taiwan; Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
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35
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Manni W, Min W. Signaling pathways in the regulation of cancer stem cells and associated targeted therapy. MedComm (Beijing) 2022; 3:e176. [PMID: 36226253 PMCID: PMC9534377 DOI: 10.1002/mco2.176] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/07/2022] Open
Abstract
Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self-renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well-established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor-associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy-resistant or -refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC-directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC-directed therapeutics, with a special focus on those with application approval or under clinical evaluation.
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Affiliation(s)
- Wang Manni
- Department of Biotherapy, Cancer Center, West China HospitalSichuan UniversityChengduP. R. China
| | - Wu Min
- Department of Biomedical Sciences, School of Medicine and Health SciencesUniversity of North DakotaGrand ForksNorth DakotaUSA
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Chen J, Li H, Zhang B, Xiong Z, Jin Z, Chen J, Zheng Y, Zhu X, Zhang S. ABI2-mediated MEOX2/KLF4-NANOG axis promotes liver cancer stem cell and drives tumour recurrence. Liver Int 2022; 42:2562-2576. [PMID: 36017822 PMCID: PMC9825985 DOI: 10.1111/liv.15412] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 01/11/2023]
Abstract
Tumour recurrence and drug resistance in hepatocellular carcinoma remain challenging. Cancer stem cells (CSCs) are responsible for tumour initiation because of their stemness characteristics. CSCs accounting for drug resistance and tumour relapse are promising therapeutic targets. We report that Abelson interactor 2 (ABI2) is a novel therapeutic target of HCC CSCs. First, ABI2 was upregulated in HCC tissues compared with liver tissues and was associated with tumour size, pathological grade, liver cirrhosis, worse prognosis and a high recurrence rate. Functional studies illustrate that ABI2 knockdown suppresses cell growth, migration, invasion and sorafenib resistance in vitro. Furthermore, ABI2 knockdown inhibited HCC sphere formation and decreased the CD24+ , CD133+ and CD326+ CSCs populations, suggesting the suppression of HCC stemness characteristics. A tumour xenograft model and limiting dilution assay demonstrated the inhibition of tumorigenicity and tumour initiation. Moreover, molecular mechanism studies showed that ABI2 recruits and directly interacts with the transcription factor MEOX2, which binds to the KLF4 and NANOG promoter regions to activate their transcription. Furthermore, overexpression of MEOX2 restored HCC malignant behaviour and the CSC population. The ABI2-mediated transcriptional axis MEOX2/KLF4-NANOG promotes HCC growth, metastasis and sorafenib resistance by maintaining the CSC population, suggesting that ABI2 is a promising CSC target in HCC treatment.
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Affiliation(s)
- Jiandi Chen
- Department of RadiologyThe First Affiliated Hospital of Jinan UniversityGuangzhouChina
| | - Huizi Li
- Department of General SurgeryThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Bin Zhang
- Department of RadiologyThe First Affiliated Hospital of Jinan UniversityGuangzhouChina
| | - Zhiyuan Xiong
- Department of RadiologyThe First Affiliated Hospital of Jinan UniversityGuangzhouChina
| | - Zhe Jin
- Department of RadiologyThe First Affiliated Hospital of Jinan UniversityGuangzhouChina
| | - Jiaxi Chen
- Department of General SurgeryThe Fourth Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Yang Zheng
- Department of General SurgeryThe Fourth Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Xiangnan Zhu
- Department of General SurgeryThe Fourth Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Shuixing Zhang
- Department of RadiologyThe First Affiliated Hospital of Jinan UniversityGuangzhouChina
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Jubelin C, Muñoz-Garcia J, Griscom L, Cochonneau D, Ollivier E, Heymann MF, Vallette FM, Oliver L, Heymann D. Three-dimensional in vitro culture models in oncology research. Cell Biosci 2022; 12:155. [PMID: 36089610 PMCID: PMC9465969 DOI: 10.1186/s13578-022-00887-3] [Citation(s) in RCA: 125] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 08/18/2022] [Indexed: 11/10/2022] Open
Abstract
AbstractCancer is a multifactorial disease that is responsible for 10 million deaths per year. The intra- and inter-heterogeneity of malignant tumors make it difficult to develop single targeted approaches. Similarly, their diversity requires various models to investigate the mechanisms involved in cancer initiation, progression, drug resistance and recurrence. Of the in vitro cell-based models, monolayer adherent (also known as 2D culture) cell cultures have been used for the longest time. However, it appears that they are often less appropriate than the three-dimensional (3D) cell culture approach for mimicking the biological behavior of tumor cells, in particular the mechanisms leading to therapeutic escape and drug resistance. Multicellular tumor spheroids are widely used to study cancers in 3D, and can be generated by a multiplicity of techniques, such as liquid-based and scaffold-based 3D cultures, microfluidics and bioprinting. Organoids are more complex 3D models than multicellular tumor spheroids because they are generated from stem cells isolated from patients and are considered as powerful tools to reproduce the disease development in vitro. The present review provides an overview of the various 3D culture models that have been set up to study cancer development and drug response. The advantages of 3D models compared to 2D cell cultures, the limitations, and the fields of application of these models and their techniques of production are also discussed.
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38
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Rong L, Chen D, Huang X, Sun L. Delivery of Cas9-guided ABE8e into stem cells using poly(l-lysine) polypeptides for correction of the hemophilia-associated FIX missense mutation. Biochem Biophys Res Commun 2022; 628:49-56. [DOI: 10.1016/j.bbrc.2022.08.076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 08/22/2022] [Indexed: 11/15/2022]
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Stearoyl-CoA desaturase 1 as a therapeutic target for cancer: a focus on hepatocellular carcinoma. Mol Biol Rep 2022; 49:8871-8882. [PMID: 35906508 DOI: 10.1007/s11033-021-07094-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 12/16/2021] [Indexed: 01/14/2023]
Abstract
One of the main characteristics of cancer cells is the alteration in lipid composition, which is associated with a significant monounsaturated fatty acids (MUFAs) enrichment. In addition to their structural functions in newly synthesized membranes in proliferating cancer cells, these fatty acids are involved in tumorigenic signaling. Increased expression and activity of stearoyl CoA desaturase (SCD1), i.e., an enzyme converting saturated fatty acids to Δ9-monounsaturated fatty acids, has been observed in various cancer cells. This increase in expression and activity has also been associated with cancer aggressiveness and poor patient outcome. Previous studies have also indicated the SCD1 involvement in increased cancer cells proliferation, growth, migration, epithelial to mesenchymal transition, metastasis, chemoresistance, and maintenance of cancer stem cells properties. Hence, SCD1 seems to be a player in malignancy development and may be considered a novel therapeutic target in cancers, including hepatocellular carcinoma (HCC). This review study aims to discuss the impact of SCD1 as a major component in lipid signaling in HCC.
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40
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Feng T, Wu T, Zhang Y, Zhou L, Liu S, Li L, Li M, Hu E, Wang Q, Fu X, Zhan L, Xie Z, Xie W, Huang X, Shang X, Yu G. Stemness Analysis Uncovers That The Peroxisome Proliferator-Activated Receptor Signaling Pathway Can Mediate Fatty Acid Homeostasis In Sorafenib-Resistant Hepatocellular Carcinoma Cells. Front Oncol 2022; 12:912694. [PMID: 35957896 PMCID: PMC9361019 DOI: 10.3389/fonc.2022.912694] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/22/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) stem cells are regarded as an important part of individualized HCC treatment and sorafenib resistance. However, there is lacking systematic assessment of stem-like indices and associations with a response of sorafenib in HCC. Our study thus aimed to evaluate the status of tumor dedifferentiation for HCC and further identify the regulatory mechanisms under the condition of resistance to sorafenib. Datasets of HCC, including messenger RNAs (mRNAs) expression, somatic mutation, and clinical information were collected. The mRNA expression-based stemness index (mRNAsi), which can represent degrees of dedifferentiation of HCC samples, was calculated to predict drug response of sorafenib therapy and prognosis. Next, unsupervised cluster analysis was conducted to distinguish mRNAsi-based subgroups, and gene/geneset functional enrichment analysis was employed to identify key sorafenib resistance-related pathways. In addition, we analyzed and confirmed the regulation of key genes discovered in this study by combining other omics data. Finally, Luciferase reporter assays were performed to validate their regulation. Our study demonstrated that the stemness index obtained from transcriptomic is a promising biomarker to predict the response of sorafenib therapy and the prognosis in HCC. We revealed the peroxisome proliferator-activated receptor signaling pathway (the PPAR signaling pathway), related to fatty acid biosynthesis, that was a potential sorafenib resistance pathway that had not been reported before. By analyzing the core regulatory genes of the PPAR signaling pathway, we identified four candidate target genes, retinoid X receptor beta (RXRB), nuclear receptor subfamily 1 group H member 3 (NR1H3), cytochrome P450 family 8 subfamily B member 1 (CYP8B1) and stearoyl-CoA desaturase (SCD), as a signature to distinguish the response of sorafenib. We proposed and validated that the RXRB and NR1H3 could directly regulate NR1H3 and SCD, respectively. Our results suggest that the combined use of SCD inhibitors and sorafenib may be a promising therapeutic approach.
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Affiliation(s)
- Tingze Feng
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Tianzhi Wu
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yanxia Zhang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Lang Zhou
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Shanshan Liu
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
- Country Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lin Li
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Ming Li
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Erqiang Hu
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Qianwen Wang
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaocong Fu
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Li Zhan
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zijing Xie
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Wenqin Xie
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xianying Huang
- Division of Vascular and Interventional Radiology, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Xianying Huang, ; Xuan Shang, ; Guangchuang Yu,
| | - Xuan Shang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
- *Correspondence: Xianying Huang, ; Xuan Shang, ; Guangchuang Yu,
| | - Guangchuang Yu
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
- Division of Vascular and Interventional Radiology, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Xianying Huang, ; Xuan Shang, ; Guangchuang Yu,
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41
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Mechanism of cancer stemness maintenance in human liver cancer. Cell Death Dis 2022; 13:394. [PMID: 35449193 PMCID: PMC9023565 DOI: 10.1038/s41419-022-04848-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 04/05/2022] [Accepted: 04/07/2022] [Indexed: 11/08/2022]
Abstract
Primary liver cancer mainly includes the following four types: hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), hepatoblastoma (HB), and combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA). Recent studies have indicated that there are differences in cancer stem cell (CSC) properties among different types of liver cancer. Liver cancer stem cells (LCSCs), also called liver tumor-initiating cells, have been viewed as drivers of tumor initiation and metastasis. Many mechanisms and factors, such as mitophagy, mitochondrial dynamics, epigenetic modifications, the tumor microenvironment, and tumor plasticity, are involved in the regulation of cancer stemness in liver cancer. In this review, we analyze cancer stemness in different liver cancer types. Moreover, we further evaluate the mechanism of cancer stemness maintenance of LCSCs and discuss promising treatments for eradicating LCSCs.
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Paul B, Lewinska M, Andersen JB. Lipid alterations in chronic liver disease and liver cancer. JHEP Rep 2022; 4:100479. [PMID: 35469167 PMCID: PMC9034302 DOI: 10.1016/j.jhepr.2022.100479] [Citation(s) in RCA: 136] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Lipids are a complex and diverse group of molecules with crucial roles in many physiological processes, as well as in the onset, progression, and maintenance of cancers. Fatty acids and cholesterol are the building blocks of lipids, orchestrating these crucial metabolic processes. In the liver, lipid alterations are prevalent as a cause and consequence of chronic hepatitis B and C virus infections, alcoholic hepatitis, and non-alcoholic fatty liver disease and steatohepatitis. Recent developments in lipidomics have also revealed that dynamic changes in triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol are involved in the development and progression of primary liver cancer. Accordingly, the transcriptional landscape of lipid metabolism suggests a carcinogenic role of increasing fatty acids and sterol synthesis. However, limited mechanistic insights into the complex nature of the hepatic lipidome have so far hindered the development of effective therapies.
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43
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Wang SY, Hu QC, Wu T, Xia J, Tao XA, Cheng B. Abnormal lipid synthesis as a therapeutic target for cancer stem cells. World J Stem Cells 2022; 14:146-162. [PMID: 35432735 PMCID: PMC8963380 DOI: 10.4252/wjsc.v14.i2.146] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/19/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.
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Affiliation(s)
- Si-Yu Wang
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Qin-Chao Hu
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Tong Wu
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Juan Xia
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Xiao-An Tao
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Bin Cheng
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
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Varadarajan SN, Mathew KA, Chandrasekharan A, Lupitha SS, Lekshmi A, Mini M, Darvin P, Santhoshkumar TR. Real-time visualization and quantitation of cell death and cell cycle progression in 2D and 3D cultures utilizing genetically encoded probes. J Cell Biochem 2022; 123:782-797. [PMID: 35106828 DOI: 10.1002/jcb.30222] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 12/23/2021] [Accepted: 01/11/2022] [Indexed: 12/17/2022]
Abstract
Cancer cells grown as 3D-structures are better models for mimicking in vivo conditions than the 2D-culture systems employable in drug discovery applications. Cell cycle and cell death are important determinants for preclinical drug screening and tumor growth studies in laboratory conditions. Though several 3D-models and live-cell compatible approaches are available, a method for simultaneous real-time detection of cell cycle and cell death is required. Here we demonstrate a high-throughput adaptable method using genetically encoded fluorescent probes for the real-time quantitative detection of cell death and cell cycle. The cell-cycle indicator cdt1-Kusabira orange (KO) is stably integrated into cancer cells and further transfected with the Fluorescence Resonance Energy Transfer-based ECFP-DEVD-EYFP caspase activation sensor. The nuclear cdt1-KO expression serves as the readout for cell-cycle, and caspase activation is visualized by ECFP/EYFP ratiometric imaging. The image-based platform allowed imaging of growing spheres for prolonged periods in 3D-culture with excellent single-cell resolution through confocal microscopy. High-throughput screening (HTS) adaptation was achieved by targeting the caspase-sensor at the nucleus, which enabled the quantitation of cell death in 3D-models. The HTS using limited compound libraries, identified two lead compounds that induced caspase-activation both in 2D and 3D-cultures. This is the first report of an approach for noninvasive stain-free quantitative imaging of cell death and cell cycle with potential drug discovery applications.
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Affiliation(s)
| | - Krupa Ann Mathew
- Cancer Research Program-1, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Aneesh Chandrasekharan
- Cancer Research Program-1, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | | | - Asha Lekshmi
- Cancer Research Program-1, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Minsa Mini
- Cancer Research Program-1, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - Pramod Darvin
- Cancer Research Program-1, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
| | - T R Santhoshkumar
- Cancer Research Program-1, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
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Jin Y, Park S, Park SY, Lee CY, Eum DY, Shim JW, Choi SH, Choi YJ, Park SJ, Heo K. G9a Knockdown Suppresses Cancer Aggressiveness by Facilitating Smad Protein Phosphorylation through Increasing BMP5 Expression in Luminal A Type Breast Cancer. Int J Mol Sci 2022; 23:ijms23020589. [PMID: 35054776 PMCID: PMC8776044 DOI: 10.3390/ijms23020589] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/30/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Epigenetic abnormalities affect tumor progression, as well as gene expression and function. Among the diverse epigenetic modulators, the histone methyltransferase G9a has been focused on due to its role in accelerating tumorigenesis and metastasis. Although epigenetic dysregulation is closely related to tumor progression, reports regarding the relationship between G9a and its possible downstream factors regulating breast tumor growth are scarce. Therefore, we aimed to verify the role of G9a and its presumable downstream regulators during malignant progression of breast cancer. G9a-depleted MCF7 and T47D breast cancer cells exhibited suppressed motility, including migration and invasion, and an improved response to ionizing radiation. To identify the possible key factors underlying these effects, microarray analysis was performed, and a TGF-β superfamily member, BMP5, was selected as a prominent target gene. It was found that BMP5 expression was markedly increased by G9a knockdown. Moreover, reduction in the migration/invasion ability of MCF7 and T47D breast cancer cells was induced by BMP5. Interestingly, a G9a-depletion-mediated increase in BMP5 expression induced the phosphorylation of Smad proteins, which are the intracellular signaling mediators of BMP5. Accordingly, we concluded that the observed antitumor effects may be based on the G9a-depletion-mediated increase in BMP5 expression and the consequent facilitation of Smad protein phosphorylation.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Kyu Heo
- Correspondence: (S.-J.P.); (K.H.)
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46
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Shin YY, Seo Y, Oh SJ, Ahn JS, Song MH, Kang MJ, Oh JM, Lee D, Kim YH, Sung ES, Kim HS. Melatonin and verteporfin synergistically suppress the growth and stemness of head and neck squamous cell carcinoma through the regulation of mitochondrial dynamics. J Pineal Res 2022; 72:e12779. [PMID: 34826168 DOI: 10.1111/jpi.12779] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/15/2021] [Accepted: 11/15/2021] [Indexed: 12/01/2022]
Abstract
The prevalence of head and neck squamous cell carcinoma (HNSCC) has continued to rise for decades. However, drug resistance to chemotherapeutics and relapse, mediated by cancer stem cells (CSCs), remains a significant impediment in clinical oncology to achieve successful treatment. Therefore, we focused on analyzing CSCs in HNSCC and demonstrated the effect of melatonin (Mel) and verteporfin (VP) on SCC-25 cells. HNSCC CSCs were enriched in the reactive oxygen species-low state and in sphere-forming cultures. Combination treatment with Mel and VP decreased HNSCC viability and increased apoptosis without causing significant damage to normal cells. Sphere-forming ability and stem cell population were reduced by co-treatment with Mel and VP, while mitochondrial ROS level was increased by the treatment. Furthermore, the expression of mitophagy markers, parkin and PINK1, was significantly decreased in the co-treated cells. Mel and VP induced mitochondrial depolarization and inhibited mitochondrial function. Parkin/TOM20 was localized near the nucleus and formed clusters of mitochondria in the cells after treatment. Moreover, Mel and VP downregulated the expression of markers involved in epithelial-mesenchymal transition and metastasis. The migration capacity of cells was significantly decreased by co-treatment with Mel and VP, accompanied by the down-regulation of MMP-2 and MMP-9 expression. Taken together, these results indicate that co-treatment with Mel and VP induces mitochondrial dysfunction, resulting in the apoptosis of CSCs. Mel and VP could thus be further investigated as potential therapies for HNSCC through their action on CSCs.
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Affiliation(s)
- Ye Young Shin
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Korea
| | - Yoojin Seo
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Su-Jeong Oh
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Korea
| | - Ji-Su Ahn
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Korea
| | - Min-Hye Song
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Min-Jung Kang
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Jung-Min Oh
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Dongjun Lee
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, Korea
| | - Yun Hak Kim
- Department of Anatomy, Pusan National University School of Medicine, Yangsan, Korea
- Department of Biomedical Informatics, Pusan National University School of Medicine, Yangsan, Korea
| | - Eui-Suk Sung
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Hyung-Sik Kim
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Korea
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Bao L, Xu T, Lu X, Huang P, Pan Z, Ge M. Metabolic Reprogramming of Thyroid Cancer Cells and Crosstalk in Their Microenvironment. Front Oncol 2021; 11:773028. [PMID: 34926283 PMCID: PMC8674491 DOI: 10.3389/fonc.2021.773028] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/05/2021] [Indexed: 12/18/2022] Open
Abstract
Metabolism differs significantly between tumor and normal cells. Metabolic reprogramming in cancer cells and metabolic interplay in the tumor microenvironment (TME) are important for tumor formation and progression. Tumor cells show changes in both catabolism and anabolism. Altered aerobic glycolysis, known as the Warburg effect, is a well-recognized characteristic of tumor cell energy metabolism. Compared with normal cells, tumor cells consume more glucose and glutamine. The enhanced anabolism in tumor cells includes de novo lipid synthesis as well as protein and nucleic acid synthesis. Although these forms of energy supply are uneconomical, they are required for the functioning of cancer cells, including those in thyroid cancer (TC). Increasing attention has recently focused on alterations of the TME. Understanding the metabolic changes governing the intricate relationship between TC cells and the TME may provide novel ideas for the treatment of TC.
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Affiliation(s)
- Lisha Bao
- Second Clinical College, Zhejiang Chinese Medical School, Hangzhou, China
- ENT-Head & Neck Surgery Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Tong Xu
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Xixuan Lu
- ENT-Head & Neck Surgery Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Ping Huang
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, China
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Zongfu Pan
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, China
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Minghua Ge
- ENT-Head & Neck Surgery Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, China
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Aptamer-mediated doxorubicin delivery reduces HCC burden in 3D organoids model. J Control Release 2021; 341:341-350. [PMID: 34848243 DOI: 10.1016/j.jconrel.2021.11.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 11/15/2021] [Accepted: 11/22/2021] [Indexed: 11/20/2022]
Abstract
Epithelial cell adhesion molecule (EpCAM) is a surface marker which is frequently overexpressed in hepatocellular carcinoma (HCC) but minimally expressed on mature hepatocytes. We developed a specific aptamer against EpCAM (EpCAM-apt) and tested its potential as a drug delivery agent for HCC. The targeting ability of EpCAM-apt was confirmed in vitro and in vivo after which the complex was conjugated with doxorubicin (Dox) to form EpCAM-apt-Dox. The targeting efficacy of the drug-loaded complex against liver cancer stem-like cells (LCSCs) and therapeutic effects in HCC were evaluated. EpCAM-expressing (EpCAM+) HCC cells showed characteristics of stem like cells including greater proliferative capacity and tumour sphere formation. EpCAM-apt-Dox selectively delivered Dox to EpCAM+ HCC cells with high drug retention and accumulation versus control. EpCAM-apt-Dox reduced the self-renewal capacity and stem-like cell frequency in vitro. Elimination of cancer stem-like cells (CSCs) with EpCAM-apt-Dox significantly inhibited the growth of HCC cells and patient-derived HCC organoids but exerted minimal cytotoxicity to normal liver organoids. Moreover, EpCAM-apt-Dox suppressed the growth of xenograft tumours derived from HCC organoids in vivo and prolonged mouse survival without inducing adverse effects to major organs. Thus, aptamer-based drug delivery to the stem-like cell population is a promising strategy for HCC treatment.
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Noh KH, Lee SH, Lee H, Jeong AJ, Kim KO, Shin HM, Kim HR, Park MJ, Park JB, Lee J, Ye SK. Novel cancer stem cell marker MVP enhances temozolomide-resistance in glioblastoma. Transl Oncol 2021; 15:101255. [PMID: 34742152 PMCID: PMC8577150 DOI: 10.1016/j.tranon.2021.101255] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 10/18/2021] [Indexed: 12/20/2022] Open
Abstract
MVP level were up-regulated in temozolomide-resistant glioblastoma cells and glioblastoma stem cells. MVP decreased the sensitization to temozolomide of glioblastoma cells and glioblastoma stem cells. Knockdown of MVP reduced temozolomide-resistance, sphere formation ability and invasive capacity. Negative correlation between MVP expression and prognosis of glioblastoma patients The resistance of highly aggressive glioblastoma multiforme (GBM) to chemotherapy is a major clinical problem resulting in a poor prognosis. GBM contains a rare population of self-renewing cancer stem cells (CSCs) that proliferate, spurring the growth of new tumors, and evade chemotherapy. In cancer, major vault protein (MVP) is thought to contribute to drug resistance. However, the role of MVP as CSCs marker remains unknown and whether MVP could sensitize GBM cells to Temozolomide (TMZ) also is unclear. We found that sensitivity to TMZ was suppressed by significantly increasing the MVP expression in GBM cells with TMZ resistance. Also, MVP was associated with the expression of other multidrug-resistant proteins in tumorsphere of TMZ-resistant GBM cell, and was highly co-expressed with CSC markers in tumorsphere culture. On the other hands, knockdown of MVP resulted in reduced sphere formation and invasive capacity. Moreover, high expression of MVP was associated with tumor malignancy and survival rate in glioblastoma patients. Our study describes that MVP is a potentially novel maker for glioblastoma stem cells and may be useful as a target for preventing TMZ resistance in GBM patients.
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Affiliation(s)
- Kum Hee Noh
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Song-Hee Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Haeri Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ae Jin Jeong
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyu Oh Kim
- Department of Fiber-System Engineering, Dankook University, Gyeonggi-do, Republic of Korea
| | - Hyun Mu Shin
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul, Republic of Korea; Wide River Institute of Immunology, Seoul National University, Hongcheon, 25159, Republic of Korea
| | - Hang-Rae Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul, Republic of Korea; Wide River Institute of Immunology, Seoul National University, Hongcheon, 25159, Republic of Korea; Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Myung-Jin Park
- Divisions of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Jong Bae Park
- Department of Clinical Research, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
| | - Jiyoung Lee
- Advanced Multidisciplinary Research Cluster, Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Sang-Kyu Ye
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Fiber-System Engineering, Dankook University, Gyeonggi-do, Republic of Korea; Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
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Sung K, Hosoya K, Murase Y, Deguchi T, Kim S, Sunaga T, Okumura M. Visualizing the cancer stem-like properties of canine tumour cells with low proteasome activity. Vet Comp Oncol 2021; 20:324-335. [PMID: 34719098 DOI: 10.1111/vco.12779] [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: 06/29/2021] [Accepted: 10/15/2021] [Indexed: 11/26/2022]
Abstract
Cancer stem-like cells (CSCs) cause treatment failure in various tumours; however, establishing CSC-targeted therapies has been hampered by difficulties in the identification and isolation of this small sub-population of cells. Recent studies have revealed that tumour cells with low proteasome activity display a CSC phenotype that can be utilized to image CSCs in canines. This study visualizes and reveals the CSC-like properties of tumour cells with low proteasome activity in HMPOS (osteosarcoma) and MegTCC (transitional cell carcinoma), which are canine cell lines. The parent cells were genetically engineered to express ZsGreen1, a fluorescent protein connected to the carboxyl-terminal degron of canine ornithine decarboxylase that accumulates with low proteasome activity (ZsG+ cells). ZsG+ cells were imaged and the mode of action of this system was confirmed using a proteasome inhibitor (MG-132), which increased the ZsGreen1 fluorescence intensity. The CSC-like properties of ZsG+ cells were evaluated on the basis of cell divisions, cell cycle, the expression of CSC markers and tumourigenicity. ZsG+ cells underwent asymmetric divisions and had a low percentage of G0/G1 phase cells; moreover, ZsG+ cells expressed CSC markers such as CD133 and showed a large tumourigenic capability. In histopathological analysis, ZsG+ cells were widely distributed in the tumour samples derived from ZsG+ cells and in the proliferative regions of the tumours. The results of this study indicate that visualized canine tumour cells with low proteasome activity have a CSC-like phenotype and that this visualization system can be utilized to identify and isolate canine CSCs.
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Affiliation(s)
- Koangyong Sung
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Kenji Hosoya
- Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Yusuke Murase
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Tatsuya Deguchi
- Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Sangho Kim
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Takafumi Sunaga
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Masahiro Okumura
- Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan
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