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Shao F, Wang R, Li X, Hu Y, Zhang Z, Cai J, Yang J, Feng X, Ren S, Huang Z, Xie Y. TTC36 promotes proliferation and drug resistance in hepatocellular carcinoma cells by inhibiting c-Myc degradation. Cell Death Dis 2025; 16:332. [PMID: 40274799 PMCID: PMC12022016 DOI: 10.1038/s41419-025-07663-4] [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: 09/10/2024] [Revised: 04/08/2025] [Accepted: 04/11/2025] [Indexed: 04/26/2025]
Abstract
High c-Myc protein accumulation contributes to the proliferation, invasion, and drug resistance in multiple cancer cells, but the underlying mechanism about c-Myc accumulation remains not to be elucidated. Here, we demonstrate that TTC36 promotes c-Myc protein accumulation in hepatocellular carcinoma cells, thereby driving the proliferation and sorafenib resistance in hepatocellular carcinoma cells. Ttc36 depletion disrupts the interaction between SET and PPP2R1A, consequently activating PP2A. Activated PP2A directly dephosphorylates p-c-MycS62 and activates GSK3β, relying on AKT, leading increased phosphorylation of p-c-MycT58, finally promotes FBXW7-mediated polyubiquitination and degradation of c-Myc. Inhibitors targeting GSK3β and PP2A effectively reverse the sorafenib resistance promoted by TTC36. These findings highlight the crucial role of TTC36 in c-Myc accumulation-caused proliferation and sorafenib resistance in HCC, providing a promising combination strategy for treating patients with c-Myc protein accumulation in advanced HCC.
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Affiliation(s)
- Fengling Shao
- The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Runzhi Wang
- The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Xinyi Li
- The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Yanxia Hu
- School of Life and Health Sciences, Hainan University, Haikou, China
| | - Zaikuan Zhang
- The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Jing Cai
- College of Basic Medical Sciences, Harbin Medical University, Harbin, China
| | - Jieru Yang
- The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Xiaosong Feng
- The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Suxia Ren
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
| | - Zengyi Huang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
- Mitomedical laboratory of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China.
| | - Yajun Xie
- The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
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Ji PX, Zhang P, Zhou HL, Yu H, Fu Y. MEX3A promotes cell proliferation by regulating the RORA/β-catenin pathway in hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:102084. [PMID: 40235874 PMCID: PMC11995337 DOI: 10.4251/wjgo.v17.i4.102084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 01/27/2025] [Accepted: 02/14/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND MEX3A is a member of the human homologous gene MEX-3 family. It has been shown to promote cell proliferation and migration in various cancers, indicating its potential clinical significance. However, the role of MEX3A in hepatocellular carcinoma (HCC) remains largely unexplored, with limited reports available in the literature. AIM To investigate expression and clinical significance of MEX3A in HCC and explore its potential role in tumor progression. METHODS We analyzed MEX3A mRNA expression in HCC and adjacent tissues using data from The Cancer Genome Atlas (TCGA). The correlation between MEX3A expression and overall survival (OS) was evaluated. Immunohistochemistry was performed on HCC surgical specimens to validate MEX3A expression and its association with clinical parameters, including hepatitis B virus (HBV) positivity, tumor differentiation and tumor size. Additionally, MEX3A knockdown HCC cell lines were constructed to explore the biological functions of MEX3A. Cell proliferation was assessed using cell counting kit-8 and clone formation assays, while cell cycle progression was analyzed by flow cytometry. The effects of MEX3A on the Wnt/β-catenin signaling pathway were examined by western blotting and immunofluorescence. Cell migration was evaluated using scratch and Transwell assays. Finally, the role of the transcription factor RORA in mediating MEX3A effects was explored by silencing RORA and analyzing its impact on cell proliferation and protein expression. RESULTS TCGA data analysis revealed that MEX3A mRNA expression was significantly higher in HCC tissues compared to adjacent tissues. Higher MEX3A expression was associated with poorer OS. These findings were validated in HCC surgical specimens. Immunohistochemistry confirmed elevated MEX3A expression in HCC tissues and showed positive correlations with Ki-67 and vimentin levels. MEX3A expression was closely related to HBV positivity, tumor differentiation and tumor size. Mechanistic studies demonstrated that MEX3A knockdown inhibited cell proliferation and cell cycle progression, as shown by reduced expression of β-catenin, c-Myc and cyclin D1. Additionally, MEX3A knockdown inhibited the nuclear entry of β-catenin, thereby suppressing the activation of downstream oncogenic pathways. MEX3A depletion significantly reduced the migratory ability of HCC cells, likely through downregulation of the epithelial-mesenchymal transition pathway. Transcription factor analysis identified RORA as a potential mediator of MEX3A effects. Silencing RORA antagonized the effects of MEX3A on cell proliferation and the expression of β-catenin, c-Myc and cyclin D1. CONCLUSION MEX3A promotes cell proliferation in HCC by regulating the RORA/β-catenin pathway. Our findings suggest that MEX3A could serve as a prognostic marker and therapeutic target for HCC.
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Affiliation(s)
- Peng-Xiang Ji
- Hand Surgery Laboratory, Suzhou Ruihua Orthopedic Hospital, Suzhou Medical College of Soochow University, Suzhou 215104, Jiangsu Province, China
| | - Ping Zhang
- Hand Surgery Laboratory, Suzhou Ruihua Orthopedic Hospital, Suzhou Medical College of Soochow University, Suzhou 215104, Jiangsu Province, China
| | - Hui-Ling Zhou
- Department of Pathology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, Jiangsu Province, China
| | - Hong Yu
- Department of Pathology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, Jiangsu Province, China
| | - Yi Fu
- Department of Human Anatomy, Histology and Embryology, Suzhou Medical College of Soochow University, Suzhou 215123, Jiangsu Province, China
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Lam WLM, Gabernet G, Poth T, Sator-Schmitt M, Oquendo MB, Kast B, Lohr S, de Ponti A, Weiß L, Schneider M, Helm D, Müller-Decker K, Schirmacher P, Heikenwälder M, Klingmüller U, Schneller D, Geisler F, Nahnsen S, Angel P. RAGE is a key regulator of ductular reaction-mediated fibrosis during cholestasis. EMBO Rep 2025; 26:880-907. [PMID: 39747668 PMCID: PMC11811172 DOI: 10.1038/s44319-024-00356-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 12/09/2024] [Accepted: 12/13/2024] [Indexed: 01/04/2025] Open
Abstract
Ductular reaction (DR) is the hallmark of cholestatic diseases manifested in the proliferation of bile ductules lined by biliary epithelial cells (BECs). It is commonly associated with an increased risk of fibrosis and liver failure. The receptor for advanced glycation end products (RAGE) was identified as a critical mediator of DR during chronic injury. Yet, the direct link between RAGE-mediated DR and fibrosis as well as the mode of interaction between BECs and hepatic stellate cells (HSCs) to drive fibrosis remain elusive. Here, we delineate the specific function of RAGE on BECs during DR and its potential association with fibrosis in the context of cholestasis. Employing a biliary lineage tracing cholestatic liver injury mouse model, combined with whole transcriptome sequencing and in vitro analyses, we reveal a role for BEC-specific Rage activity in fostering a pro-fibrotic milieu. RAGE is predominantly expressed in BECs and contributes to DR. Notch ligand Jagged1 is secreted from activated BECs in a Rage-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.
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Affiliation(s)
- Wai-Ling Macrina Lam
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
- Faculty of Biosciences, Ruprecht Karl University of Heidelberg, Heidelberg, Germany
| | - Gisela Gabernet
- Quantitative Biology Center (QBiC), Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Tanja Poth
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Melanie Sator-Schmitt
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Morgana Barroso Oquendo
- Quantitative Biology Center (QBiC), Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Bettina Kast
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Sabrina Lohr
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Aurora de Ponti
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Lena Weiß
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Martin Schneider
- Protein Analysis Unit, Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dominic Helm
- Protein Analysis Unit, Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Karin Müller-Decker
- Tumor Models Unit, Center for Preclinical Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ursula Klingmüller
- Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Doris Schneller
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Fabian Geisler
- TUM School of Medicine and Health, Department of Clinical Medicine - Clinical Department for Internal Medicine II, University Medical Center, Technical University of Munich, München, Germany
| | - Sven Nahnsen
- Quantitative Biology Center (QBiC), Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Peter Angel
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
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Zhang D, Zhang X, Chang S, Zhao Y, Zhang L. E2F1 activates USP19 to affect the stability of c-Myc to facilitate the progression of hepatocellular carcinoma. Mutat Res 2025; 830:111902. [PMID: 40020513 DOI: 10.1016/j.mrfmmm.2025.111902] [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: 12/03/2024] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 03/03/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common malignant tumor worldwide with a high mortality rate. Herein, this study aims to explore the molecular mechanisms of E2F transcription factor 1 (E2F1), ubiquitin specific peptidase 19 (USP19) and c-Myc in regulating HCC progression. METHODS RT-qPCR and western blotting were utilized to assess mRNA and protein expression, respectively. The behavior of cells was examined through Methylthiazolyldiphenyl-tetrazolium bromide (MTT), flow cytometry, transwell, and cell sphere formation assays. Glycolysis-related indicators were detected by kits. The interaction between USP19 and c-Myc was measured by co-immunoprecipitation (Co-IP). Dual-luciferase reporter assay and Chromatin Immunoprecipitation (ChIP) assays were used to assess the binding of E2F1 and USP19 promoter. A mouse xenograft model was established for the purpose of analysis in vivo. RESULTS High level of c-Myc was observed in HCC tissues and cells. Silencing c-Myc results in the suppression of cell migration, invasion, proliferation, and glycolysis or promotion of apoptosis. USP19 directly bound to c-Myc, and maintained its stability by removing ubiquitination on c-Myc. Overexpression of c-Myc in HCC cells rescued the anti-tumor effect of USP19 deletion. E2F1 promoted USP19 transcription, and increased USP19 expression counteracts the effects of E2F1 depletion on cell behaviors. In vivo, USP19 knockdown controlled HCC growth by modulating c-Myc. CONCLUSION E2F1 activated USP19 transcription, thereby stabilizing c-Myc via deubiquitination and accelerating HCC progression.
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Affiliation(s)
- Di Zhang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710000, China
| | - Xinwu Zhang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710000, China
| | - Shuai Chang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710000, China
| | - Yao Zhao
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710000, China
| | - Li Zhang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710000, China.
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Mahboobnia K, Beveridge DJ, Yeoh GC, Kabir TD, Leedman PJ. MicroRNAs in Hepatocellular Carcinoma Pathogenesis: Insights into Mechanisms and Therapeutic Opportunities. Int J Mol Sci 2024; 25:9393. [PMID: 39273339 PMCID: PMC11395074 DOI: 10.3390/ijms25179393] [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: 07/21/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets.
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Affiliation(s)
- Khadijeh Mahboobnia
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Dianne J Beveridge
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - George C Yeoh
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - Tasnuva D Kabir
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Peter J Leedman
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
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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: 84] [Impact Index Per Article: 84.0] [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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7
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Nishikawa Y. Aberrant differentiation and proliferation of hepatocytes in chronic liver injury and liver tumors. Pathol Int 2024; 74:361-378. [PMID: 38837539 PMCID: PMC11551836 DOI: 10.1111/pin.13441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 04/29/2024] [Accepted: 05/12/2024] [Indexed: 06/07/2024]
Abstract
Chronic liver injury induces liver cirrhosis and facilitates hepatocarcinogenesis. However, the effects of this condition on hepatocyte proliferation and differentiation are unclear. We showed that rodent hepatocytes display a ductular phenotype when they are cultured within a collagenous matrix. This process involves transdifferentiation without the emergence of hepatoblastic features and is at least partially reversible. During the ductular reaction in chronic liver diseases with progressive fibrosis, some hepatocytes, especially those adjacent to ectopic ductules, demonstrate ductular transdifferentiation, but the majority of increased ductules originate from the existing bile ductular system that undergoes extensive remodeling. In chronic injury, hepatocyte proliferation is weak but sustained, and most regenerative nodules in liver cirrhosis are composed of clonally proliferating hepatocytes, suggesting that a small fraction of hepatocytes maintain their proliferative capacity in chronic injury. In mouse hepatocarcinogenesis models, hepatocytes activate the expression of various fetal/neonatal genes, indicating that these cells undergo dedifferentiation. Hepatocyte-specific somatic integration of various oncogenes in mice demonstrated that hepatocytes may be the cells of origin for a broad spectrum of liver tumors through transdifferentiation and dedifferentiation. In conclusion, the phenotypic plasticity and heterogeneity of mature hepatocytes are important for understanding the pathogenesis of chronic liver diseases and liver tumors.
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Affiliation(s)
- Yuji Nishikawa
- President's OfficeAsahikawa Medical UniversityAsahikawaHokkaidoJapan
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8
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Ma Y, Lv H, Xing F, Xiang W, Wu Z, Feng Q, Wang H, Yang W. Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression. Front Med 2024; 18:430-445. [PMID: 38600350 DOI: 10.1007/s11684-023-1049-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/15/2023] [Indexed: 04/12/2024]
Abstract
Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.
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Affiliation(s)
- Yue Ma
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongwei Lv
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China
| | - Fuxue Xing
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Wei Xiang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Zixin Wu
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Qiyu Feng
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China
| | - Hongyang Wang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
| | - Wen Yang
- Cancer Research Center, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China.
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China.
- Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai, 200438, China.
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
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Hsu CY, Mustafa MA, Kumar A, Pramanik A, Sharma R, Mohammed F, Jawad IA, Mohammed IJ, Alshahrani MY, Ali Khalil NAM, Shnishil AT, Abosaoda MK. Exploiting the immune system in hepatic tumor targeting: Unleashing the potential of drugs, natural products, and nanoparticles. Pathol Res Pract 2024; 256:155266. [PMID: 38554489 DOI: 10.1016/j.prp.2024.155266] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/05/2024] [Accepted: 03/15/2024] [Indexed: 04/01/2024]
Abstract
Hepatic tumors present a formidable challenge in cancer therapeutics, necessitating the exploration of novel treatment strategies. In recent years, targeting the immune system has attracted interest to augment existing therapeutic efficacy. The immune system in hepatic tumors includes numerous cells with diverse actions. CD8+ T lymphocytes, T helper 1 (Th1) CD4+ T lymphocytes, alternative M1 macrophages, and natural killer (NK) cells provide the antitumor immunity. However, Foxp3+ regulatory CD4+ T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) are the key immune inhibitor cells. Tumor stroma can also affect these interactions. Targeting these cells and their secreted molecules is intriguing for eliminating malignant cells. The current review provides a synopsis of the immune system components involved in hepatic tumor expansion and highlights the molecular and cellular pathways that can be targeted for therapeutic intervention. It also overviews the diverse range of drugs, natural products, immunotherapy drugs, and nanoparticles that have been investigated to manipulate immune responses and bolster antitumor immunity. The review also addresses the potential advantages and challenges associated with these approaches.
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Affiliation(s)
- Chou-Yi Hsu
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City 71710, Taiwan
| | | | - Ashwani Kumar
- Department of Life Sciences, School of Sciences, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Pharmacy, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Atreyi Pramanik
- Institute of Pharma Sciences and Research, Chandigarh University, Mohali, India
| | - Rajiv Sharma
- Institute of Pharma Sciences and Research, Chandigarh University, Mohali, India
| | - Faraj Mohammed
- Department of Pharmacy, Al-Manara College for Medical Sciences, Maysan, Iraq
| | | | - Imad Jasim Mohammed
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia.
| | | | | | - Munther Kadhim Abosaoda
- College of technical engineering, the Islamic University, Najaf, Iraq; College of technical engineering, the Islamic University of Al Diwaniyah, Iraq; College of technical engineering, the Islamic University of Babylon, Iraq
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10
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Beaufrère A, Ouzir N, Zafar PE, Laurent-Bellue A, Albuquerque M, Lubuela G, Grégory J, Guettier C, Mondet K, Pesquet JC, Paradis V. Primary liver cancer classification from routine tumour biopsy using weakly supervised deep learning. JHEP Rep 2024; 6:101008. [PMID: 38379584 PMCID: PMC10877109 DOI: 10.1016/j.jhepr.2024.101008] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 12/09/2023] [Accepted: 12/17/2023] [Indexed: 02/22/2024] Open
Abstract
Background & Aims The diagnosis of primary liver cancers (PLCs) can be challenging, especially on biopsies and for combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We automatically classified PLCs on routine-stained biopsies using a weakly supervised learning method. Method We selected 166 PLC biopsies divided into training, internal and external validation sets: 90, 29 and 47 samples, respectively. Two liver pathologists reviewed each whole-slide hematein eosin saffron (HES)-stained image (WSI). After annotating the tumour/non-tumour areas, tiles of 256x256 pixels were extracted from the WSIs and used to train a ResNet18 neural network. The tumour/non-tumour annotations served as labels during training, and the network's last convolutional layer was used to extract new tumour tile features. Without knowledge of the precise labels of the malignancies, we then applied an unsupervised clustering algorithm. Results Pathological review classified the training and validation sets into hepatocellular carcinoma (HCC, 33/90, 11/29 and 26/47), intrahepatic cholangiocarcinoma (iCCA, 28/90, 9/29 and 15/47), and cHCC-CCA (29/90, 9/29 and 6/47). In the two-cluster model, Clusters 0 and 1 contained mainly HCC and iCCA histological features. The diagnostic agreement between the pathological diagnosis and the two-cluster model predictions (major contingent) in the internal and external validation sets was 100% (11/11) and 96% (25/26) for HCC and 78% (7/9) and 87% (13/15) for iCCA, respectively. For cHCC-CCA, we observed a highly variable proportion of tiles from each cluster (cluster 0: 5-97%; cluster 1: 2-94%). Conclusion Our method applied to PLC HES biopsy could identify specific morphological features of HCC and iCCA. Although no specific features of cHCC-CCA were recognized, assessing the proportion of HCC and iCCA tiles within a slide could facilitate the identification of cHCC-CCA. Impact and implications The diagnosis of primary liver cancers can be challenging, especially on biopsies and for combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We automatically classified primary liver cancers on routine-stained biopsies using a weakly supervised learning method. Our model identified specific features of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Despite no specific features of cHCC-CCA being recognized, the identification of hepatocellular carcinoma and intrahepatic cholangiocarcinoma tiles within a slide could facilitate the diagnosis of primary liver cancers, and particularly cHCC-CCA.
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Affiliation(s)
- Aurélie Beaufrère
- AP-HP. Nord, Department of Pathology, FHU MOSAIC, Beaujon Hospital, Clichy, France
- Université Paris Cité, Paris, France
- Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Paris, France
| | - Nora Ouzir
- University of Paris-Saclay, CentraleSupélec, CVN, OPIS Inria, Gif-sur-Yvette 91190, France
| | - Paul Emile Zafar
- AP-HP. Nord, Department of Pathology, FHU MOSAIC, Beaujon Hospital, Clichy, France
- University of Paris-Saclay, CentraleSupélec, CVN, OPIS Inria, Gif-sur-Yvette 91190, France
| | - Astrid Laurent-Bellue
- AP-HP, Department of Pathology, Hôpital Bicêtre, Le Kremlin- Bicêtre, France; UMR-S 1193, Université Paris-Saclay, Kremlin-Bicêtre, France
| | - Miguel Albuquerque
- AP-HP. Nord, Department of Pathology, FHU MOSAIC, Beaujon Hospital, Clichy, France
| | | | - Jules Grégory
- AP-HP. Nord, Department of Pathology, FHU MOSAIC, Beaujon Hospital, Clichy, France
- Université Paris Cité, Paris, France
- AP-HP.Nord, Department of Imaging, Beaujon Hospital, Clichy, France
| | - Catherine Guettier
- AP-HP, Department of Pathology, Hôpital Bicêtre, Le Kremlin- Bicêtre, France; UMR-S 1193, Université Paris-Saclay, Kremlin-Bicêtre, France
| | - Kévin Mondet
- AP-HP. Nord, Department of Pathology, FHU MOSAIC, Beaujon Hospital, Clichy, France
| | | | - Valérie Paradis
- AP-HP. Nord, Department of Pathology, FHU MOSAIC, Beaujon Hospital, Clichy, France
- Université Paris Cité, Paris, France
- Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Paris, France
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11
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Pérez Millán MI, Cheung LYM, Mercogliano F, Camilletti MA, Chirino Felker GT, Moro LN, Miriuka S, Brinkmeier ML, Camper SA. Pituitary stem cells: past, present and future perspectives. Nat Rev Endocrinol 2024; 20:77-92. [PMID: 38102391 PMCID: PMC10964491 DOI: 10.1038/s41574-023-00922-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/31/2023] [Indexed: 12/17/2023]
Abstract
Pituitary cells that express the transcription factor SOX2 are stem cells because they can self-renew and differentiate into multiple pituitary hormone-producing cell types as organoids. Wounding and physiological challenges can activate pituitary stem cells, but cell numbers are not fully restored, and the ability to mobilize stem cells decreases with increasing age. The basis of these limitations is still unknown. The regulation of stem cell quiescence and activation involves many different signalling pathways, including those mediated by WNT, Hippo and several cytokines; more research is needed to understand the interactions between these pathways. Pituitary organoids can be formed from human or mouse embryonic stem cells, or from human induced pluripotent stem cells. Human pituitary organoid transplantation is sufficient to induce corticosterone release in hypophysectomized mice, raising the possibility of therapeutic applications. Today, pituitary organoids have the potential to assess the role of individual genes and genetic variants on hormone production ex vivo, providing an important tool for the advancement of exciting frontiers in pituitary stem cell biology and pituitary organogenesis. In this article, we provide an overview of notable discoveries in pituitary stem cell function and highlight important areas for future research.
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Affiliation(s)
- María Inés Pérez Millán
- Institute of Bioscience, Biotechnology and Translational Biology (IB3-UBA), University of Buenos Aires, Buenos Aires, Argentina
| | - Leonard Y M Cheung
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, NY, USA
| | - Florencia Mercogliano
- Institute of Bioscience, Biotechnology and Translational Biology (IB3-UBA), University of Buenos Aires, Buenos Aires, Argentina
| | - Maria Andrea Camilletti
- Institute of Bioscience, Biotechnology and Translational Biology (IB3-UBA), University of Buenos Aires, Buenos Aires, Argentina
| | - Gonzalo T Chirino Felker
- Laboratory of Applied Research of Neurosciences (LIAN-CONICET), FLENI Sede Escobar, Buenos Aires, Argentina
| | - Lucia N Moro
- Laboratory of Applied Research of Neurosciences (LIAN-CONICET), FLENI Sede Escobar, Buenos Aires, Argentina
| | - Santiago Miriuka
- Laboratory of Applied Research of Neurosciences (LIAN-CONICET), FLENI Sede Escobar, Buenos Aires, Argentina
| | - Michelle L Brinkmeier
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Sally A Camper
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
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12
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Ye L, Schneider JS, Ben Khaled N, Schirmacher P, Seifert C, Frey L, He Y, Geier A, De Toni EN, Zhang C, Reiter FP. Combined Hepatocellular-Cholangiocarcinoma: Biology, Diagnosis, and Management. Liver Cancer 2024; 13:6-28. [PMID: 38344449 PMCID: PMC10857821 DOI: 10.1159/000530700] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 04/03/2023] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND Combined hepatocellular-cholangiocarcinoma (cHCC-iCCA) is a rare type of primary liver cancer displaying characteristics of both hepatocytic and cholangiocytic differentiation. SUMMARY Because of its aggressive nature, patients with cHCC-iCCA exhibit a poorer prognosis than those with HCC. Surgical resection and liver transplantation may be considered curative treatment approaches; however, only a minority of patients are eligible at the time of diagnosis, and postoperative recurrence rates are high. For cases that are not eligible for surgery, locoregional and systemic therapy are often administered based on treatment protocols applied for HCC or iCCA. Owing to the rarity of this cancer, there are still no established standard treatment protocols; therefore, the choice of therapy is often personalized and guided by the suspected predominant component. Further, the genomic and molecular heterogeneity of cHCC-iCCA can severely compromise the efficacy of the available therapies. KEY MESSAGES In the present review, we summarize the latest advances in cHCC-iCCA and attempt to clarify its terminology and molecular biology. We provide an overview of the etiology of cHCC-iCCA and present new insights into the molecular pathology of this disease that could contribute to further studies aiming to improve the patient outcomes through new systemic therapies.
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Affiliation(s)
- Liangtao Ye
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Julia S. Schneider
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | | | - Carolin Seifert
- Institute for Pathology, University Würzburg, Würzburg, Germany
| | - Lea Frey
- Institute for Pathology, University Würzburg, Würzburg, Germany
| | - Yulong He
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Enrico N. De Toni
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Changhua Zhang
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Florian P. Reiter
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
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13
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Sukowati CH, El-Khobar K, Jasirwan COM, Kurniawan J, Gani RA. Stemness markers in hepatocellular carcinoma of Eastern vs. Western population: Etiology matters? Ann Hepatol 2024; 29:101153. [PMID: 37734662 DOI: 10.1016/j.aohep.2023.101153] [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: 08/08/2023] [Accepted: 08/22/2023] [Indexed: 09/23/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. HCC development is associated with its underlying etiologies, mostly caused by infection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol, non-alcoholic fatty liver disease, and exposure to aflatoxins. These variables, together with human genetic susceptibility, contribute to HCC molecular heterogeneity, including at the cellular level. HCC initiation, tumor recurrence, and drug resistance rates have been attributed to the presence of liver cancer stem cells (CSC). This review summarizes available data regarding whether various HCC etiologies may be associated to the appearance of CSC biomarkers. It also described the genetic variations of tumoral tissues obtained from Western and Eastern populations, in particular to the oncogenic effect of HBV in the human genome.
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Affiliation(s)
- Caecilia Hc Sukowati
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park campus Basovizza, SS14 km 163.5, Trieste 34149, Italy; Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), B.J. Habibie Building, Jl. M.H. Thamrin No. 8, Jakarta Pusat 10340, Indonesia.
| | - Korri El-Khobar
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), B.J. Habibie Building, Jl. M.H. Thamrin No. 8, Jakarta Pusat 10340, Indonesia
| | - Chyntia Olivia Maurine Jasirwan
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
| | - Juferdy Kurniawan
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
| | - Rino Alvani Gani
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
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15
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Kuburich NA, Sabapathy T, Demestichas BR, Maddela JJ, den Hollander P, Mani SA. Proactive and reactive roles of TGF-β in cancer. Semin Cancer Biol 2023; 95:120-139. [PMID: 37572731 PMCID: PMC10530624 DOI: 10.1016/j.semcancer.2023.08.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/04/2023] [Accepted: 08/05/2023] [Indexed: 08/14/2023]
Abstract
Cancer cells adapt to varying stress conditions to survive through plasticity. Stem cells exhibit a high degree of plasticity, allowing them to generate more stem cells or differentiate them into specialized cell types to contribute to tissue development, growth, and repair. Cancer cells can also exhibit plasticity and acquire properties that enhance their survival. TGF-β is an unrivaled growth factor exploited by cancer cells to gain plasticity. TGF-β-mediated signaling enables carcinoma cells to alter their epithelial and mesenchymal properties through epithelial-mesenchymal plasticity (EMP). However, TGF-β is a multifunctional cytokine; thus, the signaling by TGF-β can be detrimental or beneficial to cancer cells depending on the cellular context. Those cells that overcome the anti-tumor effect of TGF-β can induce epithelial-mesenchymal transition (EMT) to gain EMP benefits. EMP allows cancer cells to alter their cell properties and the tumor immune microenvironment (TIME), facilitating their survival. Due to the significant roles of TGF-β and EMP in carcinoma progression, it is essential to understand how TGF-β enables EMP and how cancer cells exploit this plasticity. This understanding will guide the development of effective TGF-β-targeting therapies that eliminate cancer cell plasticity.
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Affiliation(s)
- Nick A Kuburich
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Thiru Sabapathy
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Breanna R Demestichas
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Joanna Joyce Maddela
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Petra den Hollander
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Sendurai A Mani
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
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16
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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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17
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Haerinck J, Goossens S, Berx G. The epithelial-mesenchymal plasticity landscape: principles of design and mechanisms of regulation. Nat Rev Genet 2023; 24:590-609. [PMID: 37169858 DOI: 10.1038/s41576-023-00601-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2023] [Indexed: 05/13/2023]
Abstract
Epithelial-mesenchymal plasticity (EMP) enables cells to interconvert between several states across the epithelial-mesenchymal landscape, thereby acquiring hybrid epithelial/mesenchymal phenotypic features. This plasticity is crucial for embryonic development and wound healing, but also underlies the acquisition of several malignant traits during cancer progression. Recent research using systems biology and single-cell profiling methods has provided novel insights into the main forces that shape EMP, which include the microenvironment, lineage specification and cell identity, and the genome. Additionally, key roles have emerged for hysteresis (cell memory) and cellular noise, which can drive stochastic transitions between cell states. Here, we review these forces and the distinct but interwoven layers of regulatory control that stabilize EMP states or facilitate epithelial-mesenchymal transitions (EMTs) and discuss the therapeutic potential of manipulating the EMP landscape.
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Affiliation(s)
- Jef Haerinck
- Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Steven Goossens
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Unit for Translational Research in Oncology, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Geert Berx
- Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
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18
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Calvisi DF, Boulter L, Vaquero J, Saborowski A, Fabris L, Rodrigues PM, Coulouarn C, Castro RE, Segatto O, Raggi C, van der Laan LJW, Carpino G, Goeppert B, Roessler S, Kendall TJ, Evert M, Gonzalez-Sanchez E, Valle JW, Vogel A, Bridgewater J, Borad MJ, Gores GJ, Roberts LR, Marin JJG, Andersen JB, Alvaro D, Forner A, Banales JM, Cardinale V, Macias RIR, Vicent S, Chen X, Braconi C, Verstegen MMA, Fouassier L. Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance. Nat Rev Gastroenterol Hepatol 2023; 20:462-480. [PMID: 36755084 DOI: 10.1038/s41575-022-00739-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/20/2022] [Indexed: 02/10/2023]
Abstract
Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.
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Affiliation(s)
- Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Scottish Centre, Institute of Genetics and Cancer, Edinburgh, UK
| | - Javier Vaquero
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Pedro M Rodrigues
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Cédric Coulouarn
- Inserm, Univ Rennes 1, OSS (Oncogenesis Stress Signalling), UMR_S 1242, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Oreste Segatto
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC Transplantation Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Benjamin Goeppert
- Institute of Pathology and Neuropathology, Ludwigsburg, Germany
- Institute of Pathology, Kantonsspital Baselland, Liestal, Switzerland
| | - Stephanie Roessler
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Timothy J Kendall
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Ester Gonzalez-Sanchez
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Mitesh J Borad
- Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Jose J G Marin
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Alejandro Forner
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Liver Unit, Barcelona Clinic Liver Cancer (BCLC) Group, Hospital Clinic Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Jesus M Banales
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Rocio I R Macias
- National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Silve Vicent
- University of Navarra, Centre for Applied Medical Research, Program in Solid Tumours, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, Instituto de Salud Carlos III), Madrid, Spain
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Monique M A Verstegen
- Department of Surgery, Erasmus MC Transplantation Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Laura Fouassier
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
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19
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Yao Z, Dai C, Yang J, Xu M, Meng H, Hu X, Lin N. Time-trends in liver cancer incidence and mortality rates in the U.S. from 1975 to 2017: a study based on the Surveillance, Epidemiology, and End Results database. J Gastrointest Oncol 2023; 14:312-324. [PMID: 36915450 PMCID: PMC10007921 DOI: 10.21037/jgo-23-25] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/02/2023] [Indexed: 02/25/2023] Open
Abstract
Background A previous study has examined the overall cancer statistics. However, more detailed statistics regarding liver cancer have not been provided. We evaluated the incidence and mortality trends of liver and intrahepatic bile duct cancer in the United States from 1975 to 2017 based on the data in the Surveillance, Epidemiology, and End Results (SEER) database. Methods Age, gender, race, metastasis, tumor site, and tumor grade of patients were extracted from the SEER database. Codes C22.0 and C22.1 of the International Classification of Disease for Oncology were applied to identify patients with hepatocellular carcinoma (HCC) and/or intrahepatic cholangiocarcinoma (ICC). Age-specified incidence, age-standardized incidence and mortality, 5-year relative survival, race-specific accumulative incidence and mortality, and geographic-specific accumulative mortality were calculated in different groups. Changes in trends of liver cancer incidence and mortality were assessed using Joinpoint regression. Results The overall incidence increased significantly from 2.641/100,000 person-years in 1975 to 8.657/100,000 person-years in 2017 [average annual percent change (AAPC) =3.42, 95% confidence interval (CI): 3.28-3.62, P<0.001]. The steepest incidence rate increase was observed in the 60-69-year-old age group (AAPC =4.40, 95% CI: 4.10-4.70, P<0.001). Males exhibited a more rapid increase in cancer incidence, from 3.928/100,000 to 13.128/100,000 person-years (AAPC =3.41, 95% CI: 3.21-3.61, P<0.001), than females [from 1.642/100,000 to 4.783/100,000 person-years (AAPC =3.03, 95% CI: 2.91-3.21, P=0.001)]. The overall mortality rate increased from 2.808/100,000 person-years in 1975 to 6.648/100,000 person-years in 2017 (AAPC =2.41, 95% CI: 2.29-2.51, P<0.001). The highest mortality rate was observed in Hawaii (6.996/100,000 person-years). Conclusions The incidence and mortality rates of HCC and ICC increased from 1975 to 2017, especially in males, non-Hispanic Blacks and older individuals. Comprehensive policy and control measures should be implemented to reduce the burden of disease, particularly through health monitoring and intervention for high-risk groups.
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Affiliation(s)
- Zhicheng Yao
- Department of General Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cao Dai
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiawei Yang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mingxing Xu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hongyu Meng
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xueqiao Hu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Nan Lin
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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20
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Zhao J, Stephan-Falkenau S, Schuler M, Arndt B. Management of Locally Advanced or Metastatic Combined Hepatocellular Cholangiocarcinoma. Cancers (Basel) 2023; 15:988. [PMID: 36765942 PMCID: PMC9913543 DOI: 10.3390/cancers15030988] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/25/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy that comprises features of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Due to the rarity of this tumor, the treatment of choice has not yet been defined. For resectable disease, liver resection is the mainstay treatment. However, most patients relapse or display advanced disease and were not surgical candidates. Although the majority of patients are either primarily or secondarily treated in palliative intent, no guideline recommendations or prospective trial reports exist to allow reliable evaluation of debated treatment options. We review different locoregional or medical treatment options for advanced combined hepatocellular cholangiocarcinoma (cHCC-CC) in the neoadjuvant, adjuvant, or palliative setting and discuss the possibility of predictive biomarker-guided therapeutic options.
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Affiliation(s)
- Jemmy Zhao
- National Center of Tumor Diseases, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Susann Stephan-Falkenau
- Institute of Pathology, Medizinisches Versorgungszentrum am Helios Klinikum Emil von Behring, Walterhöferstr. 11, 14165 Berlin, Germany
| | - Markus Schuler
- Onkologischer Schwerpunkt am Oskar-Helene Heim, Clayallee 225a, 14195 Berlin, Germany
| | - Börge Arndt
- Department of Hematology and Oncology, Helios Klinikum Emil von Behring, Walterhöferstr. 11, 14165 Berlin, Germany
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21
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Gromowski T, Lukacs-Kornek V, Cisowski J. Current view of liver cancer cell-of-origin and proposed mechanisms precluding its proper determination. Cancer Cell Int 2023; 23:3. [PMID: 36609378 PMCID: PMC9824961 DOI: 10.1186/s12935-022-02843-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/30/2022] [Indexed: 01/09/2023] Open
Abstract
Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are devastating primary liver cancers with increasing prevalence in many parts of the world. Despite intense investigation, many aspects of their biology are still largely obscure. For example, numerous studies have tackled the question of the cell-of-origin of primary liver cancers using different experimental approaches; they have not, however, provided a clear and undisputed answer. Here, we will review the evidence from animal models supporting the role of all major types of liver epithelial cells: hepatocytes, cholangiocytes, and their common progenitor as liver cancer cell-of-origin. Moreover, we will also propose mechanisms that promote liver cancer cell plasticity (dedifferentiation, transdifferentiation, and epithelial-to-mesenchymal transition) which may contribute to misinterpretation of the results and which make the issue of liver cancer cell-of-origin particularly complex.
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Affiliation(s)
- Tomasz Gromowski
- grid.5522.00000 0001 2162 9631Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Veronika Lukacs-Kornek
- grid.10388.320000 0001 2240 3300Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Jaroslaw Cisowski
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
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22
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Gattupalli M, Dey P, Poovizhi S, Patel RB, Mishra D, Banerjee S. The Prospects of RNAs and Common Significant Pathways in Cancer Therapy and Regenerative Medicine. Regen Med 2023. [DOI: 10.1007/978-981-19-6008-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
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23
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Wang T, Xu C, Zhang Z, Wu H, Li X, Zhang Y, Deng N, Dang N, Tang G, Yang X, Shi B, Li Z, Li L, Ye K. Cellular heterogeneity and transcriptomic profiles during intrahepatic cholangiocarcinoma initiation and progression. Hepatology 2022; 76:1302-1317. [PMID: 35340039 PMCID: PMC9790314 DOI: 10.1002/hep.32483] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS Intrahepatic cholangiocarcinoma (ICC) is not fully investigated, and how stromal cells contribute to ICC formation is poorly understood. We aimed to uncover ICC origin, cellular heterogeneity, and critical modulators during ICC initiation/progression, and to decipher how fibroblast and endothelial cells in the stromal compartment favor ICC progression. APPROACH AND RESULTS We performed single-cell RNA sequencing (scRNA-seq) using AKT/Notch intracellular domain-induced mouse ICC tissues at early, middle, and late stages. We analyzed the transcriptomic landscape, cellular classification and evolution, and intercellular communication during ICC initiation/progression. We confirmed the findings using quantitative real-time PCR, western blotting, immunohistochemistry or immunofluorescence, and gene knockout/knockdown analysis. We identified stress-responding and proliferating subpopulations in late-stage mouse ICC tissues and validated them using human scRNA-seq data sets. By integrating weighted correlation network analysis and protein-protein interaction through least absolute shrinkage and selection operator regression, we identified zinc finger, MIZ-type containing 1 (Zmiz1) and Y box protein 1 (Ybx1) as core transcription factors required by stress-responding and proliferating ICC cells, respectively. Knockout of either one led to the blockade of ICC initiation/progression. Using two other ICC mouse models (YAP/AKT, KRAS/p19) and human ICC scRNA-seq data sets, we confirmed the orchestrating roles of Zmiz1 and Ybx1 in ICC occurrence and development. In addition, hes family bHLH transcription factor 1, cofilin 1, and inhibitor of DNA binding 1 were identified as driver genes for ICC. Moreover, periportal liver sinusoidal endothelial cells could differentiate into tip endothelial cells to promote ICC development, and this was Dll4-Notch4-Efnb2 signaling-dependent. CONCLUSIONS Stress-responding and ICC proliferating subtypes were identified, and Zmiz1 and Ybx1 were revealed as core transcription factors in these subtypes. Fibroblast-endothelial cell interaction promotes ICC development.
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Affiliation(s)
- Tingjie Wang
- School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
| | - Chuanrui Xu
- School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Zhijing Zhang
- School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Hua Wu
- School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiujuan Li
- School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
| | - Yu Zhang
- School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Nan Deng
- School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Ningxin Dang
- Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
| | - Guangbo Tang
- School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
| | - Xiaofei Yang
- School of Computer Science and TechnologyFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina,Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina,MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
| | - Bingyin Shi
- Department of Endocrinologythe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina
| | - Zihang Li
- School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina
| | - Lei Li
- School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Kai Ye
- School of Automation Science and EngineeringFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina,Genome Institutethe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxiChina,School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anShaanxiChina,Faculty of ScienceLeiden UniversityLeidenthe Netherlands,MOE Key Lab for Intelligent Networks & Networks SecurityFaculty of Electronic and Information EngineeringXi’an Jiaotong UniversityXi’anShaanxiChina
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24
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Hua Y, Dong J, Hong J, Wang B, Yan Y, Li Z. Clinical applications of circulating tumor cells in hepatocellular carcinoma. Front Oncol 2022; 12:968591. [PMID: 36091119 PMCID: PMC9448983 DOI: 10.3389/fonc.2022.968591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/01/2022] [Indexed: 12/09/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor and ranked as the fourth cause of cancer-related mortality. The poor clinical prognosis is due to an advanced stage and resistance to systemic treatment. There are no obvious clinical symptoms in the early stage and the early diagnosis rate remains low. Novel effective biomarkers are important for early diagnosis and tumor surveillance to improve the survival of HCC patients. Circulating tumor cells (CTCs) are cancer cells shed from primary or metastatic tumor and extravasate into the blood system. The number of CTCs is closely related to the metastasis of various solid tumors. CTCs escape from blood vessels and settle in target organs, then form micro-metastasis. Epithelial-mesenchymal transformation (EMT) plays a crucial role in distant metastasis, which confers strong invasiveness to CTCs. The fact that CTCs can provide complete cellular biological information, which allows CTCs to be one of the most promising liquid biopsy targets. Recent studies have shown that CTCs are good candidates for early diagnosis, prognosis evaluation of metastasis or recurrence, and even a potential therapeutic target in patients with HCC. It is a new indicator for clinical application in the future. In this review, we introduce the enrichment methods and mechanisms of CTCs, and focus on clinical application in patients with HCC.
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Affiliation(s)
- Yinggang Hua
- Department of General Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
| | - Jingqing Dong
- Department of General Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
| | - Jinsong Hong
- Department of General Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
| | - Bailin Wang
- Department of General Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
| | - Yong Yan
- Department of General Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
| | - Zhiming Li
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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25
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Abdelbaset R, El-Sehrawy Y, Morsy OE, Ghallab YH, Ismail Y. CMOS based capacitive sensor matrix for characterizing and tracking of biological cells. Sci Rep 2022; 12:13839. [PMID: 35974084 PMCID: PMC9381585 DOI: 10.1038/s41598-022-18005-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 08/03/2022] [Indexed: 11/09/2022] Open
Abstract
The characterization and tracking of biological cells using biosensors are necessary for many scientific fields, specifically cell culture monitoring. Capacitive sensors offer a great solution due to their ability to extract many features such as the biological cells' position, shape, and capacitance. Through this study, a CMOS-based biochip that consists of a matrix of capacitive sensors (CSM), utilizing a ring oscillator-based pixel readout circuit (PRC), is designed and simulated to track and characterize a single biological cell based on its aforementioned different features. The proposed biochip is simulated to characterize a single Hepatocellular carcinoma cell (HCC) and a single normal liver cell (NLC). COMSOL Multiphysics was used to extract the capacitance values of the HCC and NLC and test the CSM's performance at different distances from the analyte. The PRC's ability to detect the extracted capacitance values of the HCC and NLC is evaluated using Virtuoso Analog Design Environment. A novel algorithm is developed to animate and predict the location and shape of the tested biological cell depending on CSM's capacitance readings simultaneously using MATLAB R2022a script. The results of both models, the measured capacitance from CSM and the correlated frequency from the readout circuit, show the biochip's ability to characterize and distinguish between HCC and NLC.
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Affiliation(s)
- Reda Abdelbaset
- Biomedical Engineering Department, Faculty of Engineering, Helwan University, Cairo, Egypt. .,Center of Nanoelectronics and Devices (CND), The American University in Cairo (AUC) and Zewail City of Science and Technology, Cairo, Egypt.
| | - Yehia El-Sehrawy
- Center of Nanoelectronics and Devices (CND), The American University in Cairo (AUC) and Zewail City of Science and Technology, Cairo, Egypt
| | - Omar E Morsy
- Center of Nanoelectronics and Devices (CND), The American University in Cairo (AUC) and Zewail City of Science and Technology, Cairo, Egypt
| | - Yehya H Ghallab
- Biomedical Engineering Department, Faculty of Engineering, Helwan University, Cairo, Egypt.,Center of Nanoelectronics and Devices (CND), The American University in Cairo (AUC) and Zewail City of Science and Technology, Cairo, Egypt
| | - Yehea Ismail
- Center of Nanoelectronics and Devices (CND), The American University in Cairo (AUC) and Zewail City of Science and Technology, Cairo, Egypt
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26
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Zhou J, Zhang B, Wang H, Wang D, Zhang M, Zhang M, Wang X, Fan S, Xu Y, Zeng Q, Jia Y, Xi J, Nan X, He L, Zhou X, Li S, Zhong W, Yue W, Pei X. A Functional Screening Identifies a New Organic Selenium Compound Targeting Cancer Stem Cells: Role of c-Myc Transcription Activity Inhibition in Liver Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201166. [PMID: 35652264 PMCID: PMC9353477 DOI: 10.1002/advs.202201166] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/05/2022] [Indexed: 05/04/2023]
Abstract
Cancer stem cells (CSCs) are reported to play essential roles in chemoresistance and metastasis. Pathways regulating CSC self-renewal and proliferation, such as Hedgehog, Notch, Wnt/β-catenin, TGF-β, and Myc, may be potential therapeutic targets. Here, a functional screening from the focused library with 365 compounds is performed by a step-by-step strategy. Among these candidate molecules, phenyl-2-pyrimidinyl ketone 4-allyl-3-amino selenourea (CU27) is chosen for further identification because it proves to be the most effective compound over others on CSC inhibition. Through ingenuity pathway analysis, it is shown CU27 may inhibit CSC through a well-known stemness-related transcription factor c-Myc. Gene set enrichment analysis, dual-luciferase reporter assays, expression levels of typical c-Myc targets, molecular docking, surface plasmon resonance, immunoprecipitation, and chromatin immunoprecipitation are conducted. These results together suggest CU27 binds c-Myc bHLH/LZ domains, inhibits c-Myc-Max complex formation, and prevents its occupancy on target gene promoters. In mouse models, CU27 significantly sensitizes sorafenib-resistant tumor to sorafenib, reduces the primary tumor size, and inhibits CSC generation, showing a dramatic anti-metastasis potential. Taken together, CU27 exerts inhibitory effects on CSC and CSC-associated traits in hepatocellular carcinoma (HCC) via c-Myc transcription activity inhibition. CU27 may be a promising therapeutic to treat sorafenib-resistant HCC.
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Affiliation(s)
- Jun‐Nian Zhou
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Biao Zhang
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Hai‐Yang Wang
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Dong‐Xing Wang
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
| | - Ming‐Ming Zhang
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
| | - Min Zhang
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Xiao‐Kui Wang
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Shi‐Yong Fan
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Ying‐Chen Xu
- Department of Hepatobiliary SurgeryBeijing Tongren HospitalBeijing100730P. R. China
| | - Quan Zeng
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Ya‐Li Jia
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Jia‐Fei Xi
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Xue Nan
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Li‐Juan He
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Xin‐Bo Zhou
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Song Li
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Wu Zhong
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijing100850P. R. China
| | - Wen Yue
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
| | - Xue‐Tao Pei
- Stem Cell and Regenerative Medicine LabBeijing Institute of Radiation MedicineBeijing100850P. R. China
- South China Research Center for Stem Cell and Regenerative MedicineSCIBGuangzhou510005P. R. China
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27
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Holczbauer Á, Wangensteen KJ, Shin S. Cellular origins of regenerating liver and hepatocellular carcinoma. JHEP Rep 2022; 4:100416. [PMID: 35243280 PMCID: PMC8873941 DOI: 10.1016/j.jhepr.2021.100416] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 11/30/2021] [Accepted: 12/02/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant primary cancer arising from the liver and is one of the major causes of cancer-related mortality worldwide. The cellular origin of HCC has been a topic of great interest due to conflicting findings regarding whether it originates in hepatocytes, biliary cells, or facultative stem cells. These cell types all undergo changes during liver injury, and there is controversy about their contribution to regenerative responses in the liver. Most HCCs emerge in the setting of chronic liver injury from viral hepatitis, fatty liver disease, alcohol, and environmental exposures. The injuries are marked by liver parenchymal changes such as hepatocyte regenerative nodules, biliary duct cellular changes, expansion of myofibroblasts that cause fibrosis and cirrhosis, and inflammatory cell infiltration, all of which may contribute to carcinogenesis. Addressing the cellular origin of HCC is the key to identifying the earliest events that trigger it. Herein, we review data on the cells of origin in regenerating liver and HCC and the implications of these findings for prevention and treatment. We also review the origins of childhood liver cancer and other rare cancers of the liver.
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28
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Zhou L, Ma S. Deciphering cancer stem cells in liver cancers: new tools with improved resolution. Carcinogenesis 2022; 43:297-300. [PMID: 35262641 DOI: 10.1093/carcin/bgac028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/13/2022] [Accepted: 03/07/2022] [Indexed: 11/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the major form of liver cancer in the world with the highest prevalence in Asia. Intra-tumoral heterogeneity is a fundamental characteristic of liver cancer that impacts on its disease progression and treatment response. The cancer stem cell (CSC) subpopulation is one of the driving forces of tumor cell heterogeneity because it can regenerate cells of different properties as to maintain the tumor bulk of origin. Tremendous effort has been made in the past two decades to identify liver CSCs and promote corresponding treatment strategies for HCC. From xenotransplantation and lineage tracing techniques to the current state-of-the-art single-cell sequencing technologies, advances in research tools fuel the exciting new discoveries in the field of CSCs. In particular, single-cell analysis has spearheaded a new era, with the ability to detect heterogeneity, cellular dynamics, and transition of CSCs and their progenies at a high resolution. This commentary attempts to briefly review the evolution of tools to evaluate CSCs in liver cancers, discuss their contributions and limitations, as well as their combined and complementary utilization with techniques like human tumor organoid culture. By recognizing the shortcomings of each technique, we can reassess the blind spots of CSC studies and with this knowledge, hopefully contribute to a better understanding of hepatocarcinogenesis.
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Affiliation(s)
- Lei Zhou
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong.,The University of Hong Kong-Shenzhen Hospital
| | - Stephanie Ma
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong.,The University of Hong Kong-Shenzhen Hospital.,State Key Laboratory of Liver Research, The University of Hong Kong
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29
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Moquin-Beaudry G, Benabdallah B, Maggiorani D, Le O, Li Y, Colas C, Raggi C, Ellezam B, M'Callum MA, Dal Soglio D, Guimond JV, Paganelli M, Haddad E, Beauséjour C. Autologous humanized mouse models of iPSC-derived tumors enable characterization and modulation of cancer-immune cell interactions. CELL REPORTS METHODS 2022; 2:100153. [PMID: 35474871 PMCID: PMC9017190 DOI: 10.1016/j.crmeth.2021.100153] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 11/03/2021] [Accepted: 12/21/2021] [Indexed: 01/21/2023]
Abstract
Modeling the tumor-immune cell interactions in humanized mice is complex and limits drug development. Here, we generated easily accessible tumor models by transforming either primary skin fibroblasts or induced pluripotent stem cell-derived cell lines injected in immune-deficient mice reconstituted with human autologous immune cells. Our results showed that fibroblastic, hepatic, or neural tumors were all efficiently infiltrated and partially or totally rejected by autologous immune cells in humanized mice. Characterization of tumor-immune infiltrates revealed high expression levels of the dysfunction markers Tim3 and PD-1 in T cells and an enrichment in regulatory T cells, suggesting rapid establishment of immunomodulatory phenotypes. Inhibition of PD-1 by Nivolumab in humanized mice resulted in increased immune cell infiltration and a slight decrease in tumor growth. We expect that these versatile and accessible cancer models will facilitate preclinical studies and the evaluation of autologous cancer immunotherapies across a range of different tumor cell types.
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Affiliation(s)
- Gaël Moquin-Beaudry
- Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
- Département de Pharmacologie et Physiologie, Montréal, QC, Canada
| | - Basma Benabdallah
- Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
| | - Damien Maggiorani
- Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
| | - Oanh Le
- Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
| | - Yuanyi Li
- Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
| | - Chloé Colas
- Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
- Département de Microbiologie, Immunologie et Infectiologie, Montréal, QC, Canada
| | - Claudia Raggi
- Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
| | - Benjamin Ellezam
- Département de Neurosciences, Montréal, QC, Canada
- Département de Pathologie, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada
| | - Marie-Agnès M'Callum
- Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
- Département de Biologie Moléculaire, Montréal, QC, Canada
| | - Dorothée Dal Soglio
- Département de Pathologie et Biologie Moléculaire, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
- Département de Pathologie, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada
| | - Jean V. Guimond
- CIUSSS du Centre-Sud-de-l’Ile-de-Montréal, Montréal, QC, Canada
| | - Massimiliano Paganelli
- Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
- Département de Biologie Moléculaire, Montréal, QC, Canada
- Division of Gastroenterology, Hepatology and Nutrition and Pediatric Liver Transplantation Program at CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada
- Département de Pédiatrie, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada
| | - Elie Haddad
- Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
- Département de Microbiologie, Immunologie et Infectiologie, Montréal, QC, Canada
- Département de Pédiatrie, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada
| | - Christian Beauséjour
- Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada
- Département de Pharmacologie et Physiologie, Montréal, QC, Canada
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30
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Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications. Nat Rev Gastroenterol Hepatol 2022; 19:26-44. [PMID: 34504325 DOI: 10.1038/s41575-021-00508-3] [Citation(s) in RCA: 281] [Impact Index Per Article: 93.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. The cancer stem cell (CSC) model states that tumour growth is powered by a subset of tumour stem cells within cancers. This model explains several clinical observations in HCC (as well as in other cancers), including the almost inevitable recurrence of tumours after initial successful chemotherapy and/or radiotherapy, as well as the phenomena of tumour dormancy and treatment resistance. The past two decades have seen a marked increase in research on the identification and characterization of liver CSCs, which has encouraged the design of novel diagnostic and treatment strategies for HCC. These studies revealed novel aspects of liver CSCs, including their heterogeneity and unique immunobiology, which are suggestive of opportunities for new research directions and potential therapies. In this Review, we summarize the present knowledge of liver CSC markers and the regulators of stemness in HCC. We also comprehensively describe developments in the liver CSC field with emphasis on experiments utilizing single-cell transcriptomics to understand liver CSC heterogeneity, lineage-tracing and cell-ablation studies of liver CSCs, and the influence of the CSC niche and tumour microenvironment on liver cancer stemness, including interactions between CSCs and the immune system. We also discuss the potential application of liver CSC-based therapies for treatment of HCC.
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31
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Abstract
The ability of modifying the genome of multiple species, precisely and without or minimal off-targeted effects, have opened numerous opportunities for the biotechnology industry. In this chapter, we describe an easy to establish, robust, and practical pipeline that can be used to generate immortalized cell lines, from different tissues, to capture cell linage context and validate the tools required for genome editing and genetic modification. This pipeline serves as a reference for similar approaches for gene interrogation in other species.
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Affiliation(s)
- Luis F Malaver-Ortega
- Monash Functional Genomics Platform, Monash University, Clayton, VIC, Australia.
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
| | - Joseph Rosenbluh
- Monash Functional Genomics Platform, Monash University, Clayton, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
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32
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Desert R, Ge X, Song Z, Han H, Lantvit D, Chen W, Das S, Athavale D, Abraham-Enachescu I, Blajszczak C, Chen Y, Musso O, Guzman G, Hoshida Y, Nieto N. Role of Hepatocyte-Derived Osteopontin in Liver Carcinogenesis. Hepatol Commun 2021; 6:692-709. [PMID: 34730871 PMCID: PMC8948552 DOI: 10.1002/hep4.1845] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 09/13/2021] [Accepted: 10/02/2021] [Indexed: 12/24/2022] Open
Abstract
Osteopontin (OPN) expression correlates with tumor progression in many cancers, including hepatocellular carcinoma (HCC); however, its role in the onset of HCC remains unclear. We hypothesized that increased hepatocyte‐derived OPN is a driver of hepatocarcinogenesis. Analysis of a tissue microarray of 366 human samples revealed a continuous increase in OPN expression during hepatocarcinogenesis. In patients with cirrhosis, a transcriptome‐based OPN correlation network was associated with HCC incidence along 10 years of follow‐up, together with messenger RNA (mRNA) signatures of carcinogenesis. After diethylnitrosamine (DEN) injection, mice with conditional overexpression of Opn in hepatocytes (OpnHep transgenic [Tg]) showed increased tumor burden. Surprisingly, mice with conditional ablation of Opn in hepatocytes (OpnΔHep) expressed a similar phenotype. The acute response to DEN was reduced in OpnΔHep, which also showed more cancer stem/progenitor cells (CSCs, CD44+AFP+) at 5 months. CSCs from OpnHep Tg mice expressed several mRNA signatures known to promote carcinogenesis, and mRNA signatures from OpnHep Tg mice were associated with poor outcome in human HCC patients. Treatment with rOPN had little effect on CSCs, and their progression to HCC was similar in Opn−/− compared with wild‐type mice. Finally, ablation of Cd44, an OPN receptor, did not reduce tumor burden in Cd44−/−OpnHep Tg mice. Conclusions: Hepatocyte‐derived OPN acts as a tumor suppressor at physiological levels by controlling the acute response to DEN and the presence of CSCs, while induction of OPN is pro‐tumorigenic. This is primarily due to intracellular events rather that by the secretion of the protein and receptor activation.
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Affiliation(s)
- Romain Desert
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.,Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Hui Han
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Daniel Lantvit
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Wei Chen
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Ioana Abraham-Enachescu
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Chuck Blajszczak
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Yu Chen
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Orlando Musso
- INSERM, University of Rennes, INRA, Institut NuMeCAN (Nutrition Metabolisms and Cancer), Rennes, France
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.,Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
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33
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Chen S, Wu H, Wang Z, Jia M, Guo J, Jin J, Li X, Meng D, Lin L, He AR, Zhou P, Zhi X. Loss of SPTBN1 Suppresses Autophagy Via SETD7-mediated YAP Methylation in Hepatocellular Carcinoma Initiation and Development. Cell Mol Gastroenterol Hepatol 2021; 13:949-973.e7. [PMID: 34737104 PMCID: PMC8864474 DOI: 10.1016/j.jcmgh.2021.10.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Loss of Spectrin beta, non-erythrocytic 1 (SPTBN1) plays an important role in the carcinogenesis of hepatocellular carcinoma (HCC); however, the mechanisms underlying its involvement remain poorly understood. Defects in autophagy contribute to hepatic tumor formation. Hence, in this study, we explored the role and mechanism of SPTBN1 in the autophagy of hepatic stem cells (HSCs) and HCC cells. METHODS Expansion, autophagy, and malignant transformation of HSCs were detected in the injured liver of Sptbn1+/- mice induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine treatment. Hippo pathway and Yes-associated protein (YAP) stabilization were examined in isolated HSCs, Huh-7, and PLC/PRF/5 HCC cells and hepatocytes with or without loss of SPTBN1. RESULTS We found that heterozygous SPTBN1 knockout accelerated liver tumor development with 3,5-diethoxycarbonyl-1,4-dihydrocollidine induction. Rapamycin promoted autophagy in murine HSCs and reversed the increased malignant transformation induced by heterozygous SPTBN1 deletion. Loss of SPTBN1 also decreased autophagy and increased YAP stability and nuclear localization in human HCC cells and tissues, whereas YAP inhibition attenuated the effects of SPTBN1 deficiency on autophagy. Finally, we found that SPTBN1 positively regulated the expression of suppressor of variegation 3-9-enhancer of zeste-trithorax domain containing lysine methyltransferase 7 to promote YAP methylation, which may lead to YAP degradation and inactivation. CONCLUSIONS Our findings provide the first demonstration that loss of SPTBN1 impairs autophagy of HSCs to promote expansion and malignant transformation during hepatocarcinogenesis. SPTBN1 also cooperates with suppressor of variegation 3-9-enhancer of zeste-trithorax domain containing lysine methyltransferase 7 to inactive YAP, resulting in enhanced autophagy of HCC cells. These results may open new avenues targeting SPTBN1 for the prevention and treatment of HCC.
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Affiliation(s)
- Shuyi Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Huijie Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zhengyang Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Mengping Jia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jieyu Guo
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jiayu Jin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiaobo Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Dan Meng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ling Lin
- Department of Medicine and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Aiwu Ruth He
- Department of Medicine and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
| | - Ping Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
| | - Xiuling Zhi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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34
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Sukowati CHC, El-Khobar KE, Tiribelli C. Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells. World J Stem Cells 2021; 13:795-824. [PMID: 34367478 PMCID: PMC8316870 DOI: 10.4252/wjsc.v13.i7.795] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/25/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy related to diverse etiological factors. Different oncogenic mechanisms and genetic variations lead to multiple HCC molecular classifications. Recently, an immune-based strategy using immune checkpoint inhibitors (ICIs) was presented in HCC therapy, especially with ICIs against the programmed death-1 (PD-1) and its ligand PD-L1. However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. In this review, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells (CSCs). Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to cancer. PD-L1 expression in tumoral tissues is differentially expressed in CSCs, particularly in those with a close association with the tumor microenvironment. This information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.
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Affiliation(s)
| | | | - Claudio Tiribelli
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
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35
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Liu Y, Xin B, Yamamoto M, Goto M, Ooshio T, Kamikokura Y, Tanaka H, Meng L, Okada Y, Mizukami Y, Nishikawa Y. Generation of combined hepatocellular-cholangiocarcinoma through transdifferentiation and dedifferentiation in p53-knockout mice. Cancer Sci 2021; 112:3111-3124. [PMID: 34051011 PMCID: PMC8353893 DOI: 10.1111/cas.14996] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 05/11/2021] [Accepted: 05/19/2021] [Indexed: 12/29/2022] Open
Abstract
The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular‐cholangiocarcinoma (cHCC‐CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for the pathogenesis of cHCC‐CCA, the cells might originate from transformed hepatocytes that undergo ductular transdifferentiation or dedifferentiation. We previously demonstrated that concomitant introduction of mutant HRASV12 (HRAS) and Myc into mouse hepatocytes induced dedifferentiated tumors that expressed fetal/neonatal liver genes and proteins. Here, we examine whether the phenotype of HRAS‐ or HRAS/Myc‐induced tumors might be affected by the disruption of the Trp53 gene, which has been shown to induce biliary differentiation in mouse liver tumors. Hepatocyte‐derived liver tumors were induced in heterozygous and homozygous p53‐knockout (KO) mice by hydrodynamic tail vein injection of HRAS‐ or Myc‐containing transposon cassette plasmids, which were modified by deleting loxP sites, with a transposase‐expressing plasmid. The HRAS‐induced and HRAS/Myc‐induced tumors in the wild‐type mice demonstrated histological features of HCC, whereas the phenotype of the tumors generated in the p53‐KO mice was consistent with cHCC‐CCA. The expression of fetal/neonatal liver proteins, including delta‐like 1, was detected in the HRAS/Myc‐induced but not in the HRAS‐induced cHCC‐CCA tissues. The dedifferentiation in the HRAS/Myc‐induced tumors was more marked in the homozygous p53‐KO mice than in the heterozygous p53‐KO mice and was associated with activation of Myc and YAP and suppression of ERK phosphorylation. Our results suggest that the loss of p53 promotes ductular differentiation of hepatocyte‐derived tumor cells through either transdifferentiation or Myc‐mediated dedifferentiation.
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Affiliation(s)
- Yang Liu
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan.,Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China
| | - Bing Xin
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Masahiro Yamamoto
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Masanori Goto
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Takako Ooshio
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yuki Kamikokura
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroki Tanaka
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Lingtong Meng
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yoko Okada
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yusuke Mizukami
- Department of Medicine, Cancer Genomics and Precision Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yuji Nishikawa
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
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36
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Tu SM. Stem Cell Theory of Cancer: Implications of a Viral Etiology in Certain Malignancies. Cancers (Basel) 2021; 13:cancers13112738. [PMID: 34205851 PMCID: PMC8199000 DOI: 10.3390/cancers13112738] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/20/2021] [Accepted: 05/26/2021] [Indexed: 02/04/2023] Open
Abstract
Simple Summary We postulate that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We propose that the virus may turn out to be a surreptitious agent and a serendipitous model in our quest to investigate the origin of cancer. When it pertains, oncology recapitulates ontogeny, although genetic makeup is king. Cellular context may be the key to elucidating a stem cell origin of cancer. Abstract In 1911, Peyton Rous (Nobel Prize winner in 1966) demonstrated that a virus (i.e., RSV) caused cancer in chickens. In 1976, Bishop and Varmus (Nobel Prize winners in 1989) showed that the cellular origin of retroviral oncogenes was actually normal cellular genes (i.e., proto-oncogenes). In this article, we revisit the role viruses play in the genetic origin of cancer. We review a link between viruses or cancer and autoimmunity in an alternative stem cell origin of cancer. We propose that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We postulate that both known (e.g., HBV and HPV) and novel viruses (e.g., SARS-CoV-2) pose an imminent threat in the emergence of chronic viral diseases as well as virally induced malignancies. Knowing the origin of cancer has profound implications on our current conception and perception of cancer. It affects our conduct in cancer research and our delivery of cancer care. It would be ironic if viruses turn out to be a useful tool and an ideal means in our quest to verify a genetic versus stem cell origin of cancer. When it pertains, oncology recapitulates ontogeny; although genetic makeup is pivotal, cellular context may be paramount to elucidating a stem cell origin of cancer.
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Affiliation(s)
- Shi-Ming Tu
- Department of Genitourinary Medical Oncology, Unit 1374, The University of Texas, MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX 77030-3721, USA
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Fatma H, Siddique HR. Pluripotency inducing Yamanaka factors: role in stemness and chemoresistance of liver cancer. Expert Rev Anticancer Ther 2021; 21:853-864. [PMID: 33832395 DOI: 10.1080/14737140.2021.1915137] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Liver cancer is a major cause of mortality and is characterized by the transformation of cells into an uncontrolled mass of tumor cells with many genetic and epigenetic changes, which lead to the development of tumors. A small subpopulation of cell population known as Cancer Stem Cells (CSCs) is responsible for cancer stemness and chemoresistance. Yamanaka factors [octamer-binding transcription factor 4 (OCT4), SRY (sex-determining region Y)-box 2 (SOX2), kruppel-like factor 4 (KLF4), and Myelocytomatosis (MYC); OSKM] are responsible for cancer cell stemness, chemoresistance, and recurrence.Area covered: We cover recent discoveries and investigate the role of OSKM in inducing pluripotency and stem cell-like properties in various cancers with special emphasis on liver cancer. We review Yamanaka factors' role in stemness and chemoresistance of liver cancer.Expert opinion: In CSCs, including liver CSCs, the deregulation of various signaling pathways is one of the major reasons for stemness and drug resistance and is primarily due to OSKM. OSKM are responsible for tumor heterogeneity which renders targeting drug useless after a certain period. These factors can be exploited to understand the underlying mechanism of cancer stemness and resistance to chemotherapeutic drugs.
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Affiliation(s)
- Homa Fatma
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-Uttar Pradesh, India
| | - Hifzur Rahman Siddique
- Molecular Cancer Genetics & Translational Research Laboratory, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh-Uttar Pradesh, India
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38
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Beaufrère A, Calderaro J, Paradis V. Combined hepatocellular-cholangiocarcinoma: An update. J Hepatol 2021; 74:1212-1224. [PMID: 33545267 DOI: 10.1016/j.jhep.2021.01.035] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 01/08/2021] [Accepted: 01/18/2021] [Indexed: 12/13/2022]
Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a tumour that exhibits both hepatocytic and biliary differentiation. Classical risk factors for hepatocellular carcinoma (HCC) seem to also predispose patients to the development of cHCC-CCA. The pathological definition of cHCC-CCA has significantly evolved over time. The last 2019 WHO classification highlighted that the diagnosis of cHCC-CCA should be primarily based on morphology using routine stainings, with additional immunostaining used to refine the identification of subtypes. Among them, "intermediate cell carcinoma" is recognised as a specific subtype, while "cholangiolocellular carcinoma" is now considered a subtype of iCCA. Increasing molecular evidence supports the clonal nature of cHCC-CCA and parallels its biphenotypic histological appearance, with genetic alterations that are classically observed in HCC and/or iCCA. That said, the morphological diagnosis of cHCC-CCA is still challenging for radiologists and pathologists, especially on biopsy specimens. Identification of cHCC-CCA's cell of origin remains an area of active research. Its prognosis is generally worse than that of HCC, and similar to that of iCCA. Resection with lymph node dissection is unfortunately the only curative option for patients with cHCC-CCA. Thus, there remains an urgent need to develop specific therapeutic strategies for this unique clinical entity.
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Affiliation(s)
- Aurélie Beaufrère
- Université de Paris, INSERM U1149, Hôpital Beaujon, Clichy, France; Pathology Department, Hôpital Beaujon, AP-HP, Clichy, France
| | | | - Valérie Paradis
- Université de Paris, INSERM U1149, Hôpital Beaujon, Clichy, France; Pathology Department, Hôpital Beaujon, AP-HP, Clichy, France.
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39
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Qin XY, Gailhouste L. Non-Genomic Control of Dynamic MYCN Gene Expression in Liver Cancer. Front Oncol 2021; 10:618515. [PMID: 33937011 PMCID: PMC8085327 DOI: 10.3389/fonc.2020.618515] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 12/23/2020] [Indexed: 11/13/2022] Open
Abstract
Upregulated MYCN gene expression is restricted to specialized cell populations such as EpCAM+ cancer stem cells in liver cancer, regardless of DNA amplification and mutation. Here, we reviewed the role of MYCN gene expression in liver homeostasis, regeneration, and tumorigenesis, and discussed the potential non-genomic mechanisms involved in controlling MYCN gene expression in liver cancer, with a focus on inflammation-mediated signal transduction and microRNA-associated post-transcriptional regulation. We concluded that dynamic MYCN gene expression is an integrated consequence of multiple signals in the tumor microenvironment, including tumor growth-promoting signals, lipid desaturation-mediated endoplasmic reticulum stress adaptation signals, and tumor suppressive miRNAs, making it a potential predictive biomarker of tumor stemness and plasticity. Therefore, understanding and tracing the dynamic changes and functions of MYCN gene expression will shed light on the origin of liver tumorigenesis at the cellular level and the development of novel therapeutic and diagnostic strategies for liver cancer treatment.
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Affiliation(s)
- Xian-Yang Qin
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Japan
| | - Luc Gailhouste
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Japan
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Rhee H, Park JH, Park YN. Update on Pathologic and Radiologic Diagnosis of Combined Hepatocellular-Cholangiocarcinoma. JOURNAL OF LIVER CANCER 2021; 21:12-24. [PMID: 37384273 PMCID: PMC10035725 DOI: 10.17998/jlc.21.1.12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/03/2020] [Accepted: 09/13/2020] [Indexed: 06/30/2023]
Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a malignant primary liver carcinoma characterized by the unequivocal presence of both hepatocytic and cholangiocytic differentiation within the same tumor. Recent research has highlighted that cHCC-CCAs are more heterogeneous than previously expected. In the updated consensus terminology and WHO 2019 classification, "classical type" and "subtypes with stem-cell features" of the WHO 2010 classification are no longer recommended. Instead, it is recommended that the presence and percentages of various histopathologic components and stem-cell features be mentioned in the pathologic report. The new terminology and classification enable the exchange of clearer and more objective information about cHCC-CCAs, facilitating multi-center and multi-national research. However, there are limitations to the diagnosis of cHCC-CCA by imaging and biopsy. cHCC-CCAs showing typical imaging findings of HCC could be misdiagnosed as HCC and subjected to inappropriate treatment, if other clinical findings are not sufficiently considered. cHCC-CCAs showing at least one of the CCA-like imaging features or unusual clinical features should be subjected to biopsy. There may be a sampling error for the biopsy diagnosis of cHCC-CCA. An optimized diagnostic algorithm integrating clinical, radiological, and histopathologic information of biopsy is required to resolve these diagnostic pitfalls.
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Affiliation(s)
- Hyungjin Rhee
- Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science, Severance Hospital, Seoul,
Korea
| | - Jae Hyon Park
- Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science, Severance Hospital, Seoul,
Korea
| | - Young Nyun Park
- Department of Pathology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
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Rodrigues PM, Olaizola P, Paiva NA, Olaizola I, Agirre-Lizaso A, Landa A, Bujanda L, Perugorria MJ, Banales JM. Pathogenesis of Cholangiocarcinoma. ANNUAL REVIEW OF PATHOLOGY 2021; 16:433-463. [PMID: 33264573 DOI: 10.1146/annurev-pathol-030220-020455] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.
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Affiliation(s)
- Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Nuno A Paiva
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Alona Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Ana Landa
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; ,
- National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
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Moeini A, Haber PK, Sia D. Cell of origin in biliary tract cancers and clinical implications. JHEP Rep 2021; 3:100226. [PMID: 33665585 PMCID: PMC7902553 DOI: 10.1016/j.jhepr.2021.100226] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022] Open
Abstract
Biliary tract cancers (BTCs) are aggressive epithelial malignancies that can arise at any point of the biliary tree. Albeit rare, their incidence and mortality rates have been rising steadily over the past 40 years, highlighting the need to improve current diagnostic and therapeutic strategies. BTCs show high inter- and intra-tumour heterogeneity both at the morphological and molecular level. Such complex heterogeneity poses a substantial obstacle to effective interventions. It is widely accepted that the observed heterogeneity may be the result of a complex interplay of different elements, including risk factors, distinct molecular alterations and multiple potential cells of origin. The use of genetic lineage tracing systems in experimental models has identified cholangiocytes, hepatocytes and/or progenitor-like cells as the cells of origin of BTCs. Genomic evidence in support of the distinct cell of origin hypotheses is growing. In this review, we focus on recent advances in the histopathological subtyping of BTCs, discuss current genomic evidence and outline lineage tracing studies that have contributed to the current knowledge surrounding the cell of origin of these tumours.
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Key Words
- ARID1A, AT-rich interactive domain-containing protein 1A
- BAP1, BRCA1-associated protein 1
- BRAF, v-Raf murine sarcoma viral oncogene homolog B
- BTC, biliary tract cancer
- Biliary tract cancers
- CCA, cholangiocarcinoma
- CDKN2A/B, cyclin-dependent kinase inhibitor 2A/B
- CK, cytokeratin
- CLC, cholangiolocarcinoma
- Cell of origin
- Cholangiocarcinoma
- CoH, Canal of Hering
- DCR, disease control rate
- ER, estrogen receptor
- ERBB2/3, Erb-B2 Receptor Tyrosine Kinase 2/3
- FGFR, fibroblast growth factor receptor
- FGFR2, Fibroblast Growth Factor Receptor 2
- GBC, gallbladder cancer
- GEMM, genetically engineered mouse models
- Genomics
- HCC, hepatocellular carcinoma
- HPCs, hepatic progenitor cells
- IDH, isocitrate dehydrogenase
- KRAS, Kirsten Rat Sarcoma Viral Oncogene Homolog
- Lineage tracing
- MET, Hepatocyte Growth Factor Receptor
- MST1, Macrophage Stimulating 1
- NA, not applicable
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- NGS, next-generation sequencing
- NR, not reported
- NTRK, Neurotrophic Receptor Tyrosine Kinase 1
- ORR, objective response rate
- OS, overall survival
- PBG, peribiliary gland
- PFS, progression- free survival
- PIK3CA, Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha
- PLC, primary liver cancer
- PRKACA/B, Protein Kinase CAMP-Activated Catalytic Subunit Alpha/Beta
- PROM1, Prominin 1
- PSC, primary sclerosing cholangitis
- Personalized therapy
- RNF43, Ring Finger Protein 43
- SMAD4, SMAD Family Member 4
- TBG, thyroid binding globulin
- TP53, Tumor Protein P53
- WHO, World Health Organization
- dCCA, distal cholangiocarcinoma
- eCCA, extrahepatic cholangiocarcinoma
- iCCA, intrahepatic cholangiocarcinoma
- mo, months
- pCCA, perihilar cholangiocarcinoma
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Affiliation(s)
- Agrin Moeini
- Cancer Inflammation and Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Manchester, UK
| | - Philipp K Haber
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Daniela Sia
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
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Matsumori T, Kodama Y, Takai A, Shiokawa M, Nishikawa Y, Matsumoto T, Takeda H, Marui S, Okada H, Hirano T, Kuwada T, Sogabe Y, Kakiuchi N, Tomono T, Mima A, Morita T, Ueda T, Tsuda M, Yamauchi Y, Kuriyama K, Sakuma Y, Ota Y, Maruno T, Uza N, Marusawa H, Kageyama R, Chiba T, Seno H. Hes1 Is Essential in Proliferating Ductal Cell-Mediated Development of Intrahepatic Cholangiocarcinoma. Cancer Res 2020; 80:5305-5316. [PMID: 33067264 DOI: 10.1158/0008-5472.can-20-1161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 08/11/2020] [Accepted: 10/13/2020] [Indexed: 11/16/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is frequently driven by aberrant KRAS activation and develops in the liver with chronic inflammation. Although the Notch signaling pathway is critically involved in ICC development, detailed mechanisms of Notch-driven ICC development are still unknown. Here, we use mice whose Notch signaling is genetically engineered to show that the Notch signaling pathway, specifically the Notch/Hes1 axis, plays an essential role in expanding ductular cells in the liver with chronic inflammation or oncogenic Kras activation. Activation of Notch1 enhanced the development of proliferating ductal cells (PDC) in injured livers, while depletion of Hes1 led to suppression. In correlation with PDC expansion, ICC development was also regulated by the Notch/Hes1 axis and suppressed by Hes1 depletion. Lineage-tracing experiments using EpcamcreERT2 mice further confirmed that Hes1 plays a critical role in the induction of PDC and that ICC could originate from PDC. Analysis of human ICC specimens showed PDC in nonneoplastic background tissues, confirming HES1 expression in both PDC and ICC tumor cells. Our findings provide novel direct experimental evidence that Hes1 plays an essential role in the development of ICC via PDC. SIGNIFICANCE: This study contributes to the identification of the cells of origin that initiate ICC and suggests that HES1 may represent a therapeutic target in ICC.
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Affiliation(s)
- Tomoaki Matsumori
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuzo Kodama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. .,Department of Gastroenterology, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masahiro Shiokawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshihiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomonori Matsumoto
- Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Saiko Marui
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirokazu Okada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomonori Hirano
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeshi Kuwada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuko Sogabe
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Nobuyuki Kakiuchi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Teruko Tomono
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Atsushi Mima
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Toshihiro Morita
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tatsuki Ueda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Motoyuki Tsuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuki Yamauchi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Katsutoshi Kuriyama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yojiro Sakuma
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuji Ota
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takahisa Maruno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Norimitsu Uza
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology, Japanese Red Cross Hospital Osaka, Osaka, Japan
| | - Ryoichiro Kageyama
- Institute for Frontier Life and Medical Sciences, Kyoto University, Shogoin-Kawahara, Sakyo-Ku, Kyoto, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Kansai Electric Power Hospital, Osaka, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Walcher L, Kistenmacher AK, Suo H, Kitte R, Dluczek S, Strauß A, Blaudszun AR, Yevsa T, Fricke S, Kossatz-Boehlert U. Cancer Stem Cells-Origins and Biomarkers: Perspectives for Targeted Personalized Therapies. Front Immunol 2020; 11:1280. [PMID: 32849491 PMCID: PMC7426526 DOI: 10.3389/fimmu.2020.01280] [Citation(s) in RCA: 571] [Impact Index Per Article: 114.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023] Open
Abstract
The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.
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Affiliation(s)
- Lia Walcher
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Ann-Kathrin Kistenmacher
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Huizhen Suo
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Reni Kitte
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Sarah Dluczek
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Alexander Strauß
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - André-René Blaudszun
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Tetyana Yevsa
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Stephan Fricke
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Uta Kossatz-Boehlert
- Department of Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
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Gu Y, Zheng X, Ji J. Liver cancer stem cells as a hierarchical society: yes or no? Acta Biochim Biophys Sin (Shanghai) 2020; 52:723-735. [PMID: 32490517 DOI: 10.1093/abbs/gmaa050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer stem cells (CSCs) are cells possessing abilities of self-renewal, differentiation, and tumorigenicity in NOD/SCID mice. Based on this definition, multiple cell surface markers (such as CD24, CD133, CD90, and EpCAM) as well as chemical methods are discovered to enrich liver CSCs in the recent decade. Accumulated studies have revealed molecular signatures and signaling pathways involved in regulating different liver CSCs. Among liver CSCs positive for different markers, some molecular features and regulatory pathways are commonly shared, while some are only unique in certain CSC populations. These studies imply that liver CSCs exhibit diverse heterogeneity, while a functional relationship also exists. The aim of this review is to revisit the society of liver CSCs and summarize the common or unique molecular features of known liver CSCs. We hope to call for attention of researchers on the relationship of the liver CSC subgroups and to provide clues on the hierarchical structure of the liver CSC society.
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Affiliation(s)
- Yuanzhuo Gu
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xin Zheng
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Junfang Ji
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
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46
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Zhu Y, Kwong LN. Insights Into the Origin of Intrahepatic Cholangiocarcinoma From Mouse Models. Hepatology 2020; 72:305-314. [PMID: 32096245 DOI: 10.1002/hep.31200] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/17/2020] [Accepted: 02/11/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Yan Zhu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Lawrence N Kwong
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
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Strauss RP, Audsley KM, Passman AM, van Vuuren JH, Finch-Edmondson ML, Callus BA, Yeoh GC. Loss of ARF/INK4A Promotes Liver Progenitor Cell Transformation Toward Tumorigenicity Supporting Their Role in Hepatocarcinogenesis. Gene Expr 2020; 20:39-52. [PMID: 32317048 PMCID: PMC7284103 DOI: 10.3727/105221620x15874935364268] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Liver progenitor cells (LPCs) contribute to liver regeneration during chronic damage and are implicated as cells of origin for liver cancers including hepatocellular carcinoma (HCC). The CDKN2A locus, which encodes the tumor suppressors alternate reading frame protein (ARF) and INK4A, was identified as one of the most frequently altered genes in HCC. This study demonstrates that inactivation of CDKN2A enhances tumorigenic transformation of LPCs. The level of ARF and INK4A expression was determined in a panel of transformed and nontransformed wild-type LPC lines. Moreover, the transforming potential of LPCs with inactivated CDKN2A was shown to be enhanced in LPCs derived from Arf-/- and CDKN2Afl/fl mice and in wild-type LPCs following CRISPR-Cas9 suppression of CDKN2A. ARF and INK4A abundance is consistently reduced or ablated following LPC transformation. Arf-/- and CDKN2A-/- LPCs displayed hallmarks of transformation such as anchorage-independent and more rapid growth than control LPC lines with unaltered CDKN2A. Transformation was not immediate, suggesting that the loss of CDKN2A alone is insufficient. Further analysis revealed decreased p21 expression as well as reduced epithelial markers and increased mesenchymal markers, indicative of epithelial-to-mesenchymal transition, following inactivation of the CDKN2A gene were required for tumorigenic transformation. Loss of ARF and INK4A enhances the propensity of LPCs to undergo a tumorigenic transformation. As LPCs represent a cancer stem cell candidate, identifying CDKN2A as a driver of LPC transformation highlights ARF and INK4A as viable prognostic markers and therapeutic targets for HCC.
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Affiliation(s)
- Robyn P. Strauss
- *School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia
- †Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia
| | - Katherine M. Audsley
- *School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Adam M. Passman
- *School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia
- †Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia
| | - Joanne H. van Vuuren
- †Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia
| | | | - Bernard A. Callus
- *School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia
| | - George C. Yeoh
- *School of Molecular Sciences, The University of Western Australia, Crawley, WA, Australia
- †Centre for Medical Research, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia
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48
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The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors. Cell Death Dis 2020; 11:333. [PMID: 32382012 PMCID: PMC7206028 DOI: 10.1038/s41419-020-2536-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 04/08/2020] [Accepted: 04/09/2020] [Indexed: 02/07/2023]
Abstract
Autophagy is an intracellular lysosomal degradative pathway important for tumor surveillance. Autophagy deficiency can lead to tumorigenesis. Autophagy is also known to be important for the aggressive growth of tumors, yet the mechanism that sustains the growth of autophagy-deficient tumors is not unclear. We previously reported that progression of hepatic tumors developed in autophagy-deficient livers required high mobility group box 1 (HMGB1), which was released from autophagy-deficient hepatocytes. In this study we examined the pathological features of the hepatic tumors and the mechanism of HMGB1-mediated tumorigenesis. We found that in liver-specific autophagy-deficient (Atg7ΔHep) mice the tumors cells were still deficient in autophagy and could also release HMGB1. Histological analysis using cell-specific markers suggested that fibroblast and ductular cells were present only outside the tumor whereas macrophages were present both inside and outside the tumor. Genetic deletion of Hmgb1 or one of its receptors, receptor for advanced glycated end product (Rage), retarded liver tumor development. HMGB1 and RAGE enhanced the proliferation capability of the autophagy-deficient hepatocytes and tumors. However, RAGE expression was only found on ductual cells and Kupffer’s cells but not on hepatoctyes, suggesting that HMGB1 might promote hepatic tumor growth through a paracrine mode, which altered the tumor microenvironment. Finally, RNAseq analysis of the tumors indicated that HMGB1 induced a much broad changes in tumors. In particular, genes related to mitochondrial structures or functions were enriched among those differentially expressed in tumors in the presence or absence of HMGB1, revealing a potentially important role of mitochondria in sustaining the growth of autophagy-deficient liver tumors via HMGB1 stimulation.
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Cai X, Li H, Kaplan DE. Murine hepatoblast-derived liver tumors resembling human combined hepatocellular-cholangiocarcinoma with stem cell features. Cell Biosci 2020; 10:38. [PMID: 32190288 PMCID: PMC7071781 DOI: 10.1186/s13578-020-00395-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 02/26/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Combined hepatocellular-cholangiocarcinoma (CHC) is a primary hepatic malignancy with heterogeneously combined histological features of putative hepatic progenitor cells (HPC) origin. We describe a mouse model that exhibits the heterogenous histological and phenotypic finding similar to human CHC. METHODS We injected hepatoblasts isolated from p53-/- C57BL/6 mice into syngeneic wild-type pre-conditioned C57BL/6 mice. We confirmed that p53-/- murine hepatoblasts act as tumor-initiating cells (TICs) that generate CHC both in situ and within metastases. For comparative pathological study, 8 human cases of CHC with stem cell features were recruited by immunohistochemistry and multicolor fluorescence immunostaining. RESULTS We identified corresponding areas in murine tumors matching each WHO criteria-described subtype of human CHC. In both murine and human tumors, HPC-like cells in tumor nests and associated stem cell features/traits are suggested histologically to be the progenitor origin of the cancer. CONCLUSIONS The pathological characteristics of murine tumors recapitulate human CHC with stem cell features. These data provide additional comparative pathological evidence that CHC with stem cell features originate from HPCs and validate a model to study this cancer type in vivo.
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Affiliation(s)
- Xiong Cai
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 3400 Civic Center Drive, PCAM GI 7S, Philadelphia, PA 19104-6145 USA
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, 430022 China
| | - Heli Li
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - David E. Kaplan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 3400 Civic Center Drive, PCAM GI 7S, Philadelphia, PA 19104-6145 USA
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Stem Cell Therapy for Hepatocellular Carcinoma: Future Perspectives. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1237:97-119. [PMID: 31728916 DOI: 10.1007/5584_2019_441] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer and results in a high mortality rate worldwide. Unfortunately, most cases of HCC are diagnosed in an advanced stage, resulting in a poor prognosis and ineffective treatment. HCC is often resistant to both radiotherapy and chemotherapy, resulting in a high recurrence rate. Although the use of stem cells is evolving into a potentially effective approach for the treatment of cancer, few studies on stem cell therapy in HCC have been published. The administration of stem cells from bone marrow, adipose tissue, the amnion, and the umbilical cord to experimental animal models of HCC has not yielded consistent responses. However, it is possible to induce the apoptosis of cancer cells, repress angiogenesis, and cause tumor regression by administration of genetically modified stem cells. New alternative approaches to cancer therapy, such as the use of stem cell derivatives, exosomes or stem cell extracts, have been proposed. In this review, we highlight these experimental approaches for the use of stem cells as a vehicle for local drug delivery.
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