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Luo J, Peng S, Bai W, Wu Z, Shan Z, Wu Z, Yuan X, Che X, Duan Z, Peng J, Wang Y, Zhang S. Matrilin-2 prevents the TNFα-induced apoptosis of WB-F344 cells via suppressing JNK pathway. Biotechnol Appl Biochem 2019; 66:309-315. [PMID: 30624798 DOI: 10.1002/bab.1726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Accepted: 01/04/2019] [Indexed: 12/23/2022]
Abstract
Oval cells, a kind of hepatic progenitor cell quiescent at normal condition, activates to proliferate and differentiate into hepatocytes under severe and long-term liver injury, which usually raises severe inflammation. However, how oval cell survives in the inflammatory milieu interne is still unclear. Tumor necrosis factor α (TNFα), mimicking inflammatory hepatic milieu interne, was used to treat oval cell line, WB-F344, to test the protective function of matrilin-2. In this study, our data suggested that matrilin-2 prevented TNFα-induced apoptosis in WB-F344 cells via inhibiting ASK1/MKK7/JNK pathway. In conclusion, we determined that matrilin-2 plays the key role in maintaining the survival of oval cell and guarantees its proliferation under various injury factors.
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Affiliation(s)
- Junming Luo
- Department of Pathology, Qinghai Provincial People's Hospital, Xining, Qinghai Province, People's Republic of China
- Department of Intensive Care Unit, Hunan Provincial Tumor Hospital, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, People's Republic of China
| | - Shaohua Peng
- Department of Pathology, Medical School of Hunan Normal University, Changsha, Hunan Province, People's Republic of China
| | - Wenbin Bai
- Department of Orthopedics, Qinghai Provincial People's Hospital, Xining, Qinghai Province, People's Republic of China
| | - Zhaoyu Wu
- Department of Oncology, the Affiliated Hospital of Qinghai University, Xining, Qinghai Province, People's Republic of China
| | - Zhongshu Shan
- Department of Internal Medicine, Qinghai Provincial People's Hospital, Xining, Qinghai Province, People's Republic of China
| | - Zetao Wu
- Department of Internal Medicine, Qinghai Provincial People's Hospital, Xining, Qinghai Province, People's Republic of China
| | - Xin Yuan
- Department of Internal Medicine, Qinghai Provincial People's Hospital, Xining, Qinghai Province, People's Republic of China
| | - Xiaoming Che
- Department of Orthopedics, Qinghai Provincial People's Hospital, Xining, Qinghai Province, People's Republic of China
| | - Zhili Duan
- Department of Pathology, Qinghai Provincial People's Hospital, Xining, Qinghai Province, People's Republic of China
| | - Jinwu Peng
- Department of Pathology, the Affiliated Changde Hospital of Xiangya Medical School of Central South University, Changsha, People's Republic of China
| | - Yichun Wang
- Department of Intensive Care Unit, Hunan Provincial Tumor Hospital, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, People's Republic of China
| | - Shukun Zhang
- Department of Pathology, Weihai Municipal Hospital, Weihai, 264200, Shandong Province, China
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2
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Zhang P, Zhu X, Wu Y, Hu R, Li D, Du J, Jiao X, He X. Histone deacetylase inhibitors reduce WB-F344 oval cell viability and migration capability by suppressing AKT/mTOR signaling in vitro. Arch Biochem Biophys 2015; 590:1-9. [PMID: 26558695 DOI: 10.1016/j.abb.2015.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 11/03/2015] [Accepted: 11/04/2015] [Indexed: 12/12/2022]
Abstract
Histone deacetylase (HDAC) can blockDNA replication and transcription and altered HDAC expression was associated with tumorigenesis. This study investigated the effects of HDAC inhibitors on hepatic oval cells and aimed to delineate the underlying molecular events. Hepatic oval cells were treated with two different HDAC inhibitors, suberoylanilidehydroxamic acid (SAHA) and trichostatin-A (TSA). Cells were subjected to cell morphology, cell viability, cell cycle, and wound healing assays. The expression of proteins related to both apoptosis and the cell cycle, and proteins of the AKT/mammalian target of rapamycin (mTOR) signaling pathway were analyzed by Western blot. The data showed that HDAC inhibitors reduced oval cell viability and migration capability, and arrested oval cells at the G0/G1 and S phases of the cell cycle, in a dose- and time-dependent manner. HDAC inhibitors altered cell morphology and reduced oval cell viability, and downregulated the expression of PCNA, cyclinD1, c-Myc and Bmi1 proteins, while also suppressing AKT/mTOR and its downstream target activity. In conclusion, this study demonstrates that HDAC inhibitors affect oval cells by suppressing AKT/mTOR signaling.
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Affiliation(s)
- Peng Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaofeng Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ying Wu
- Department of Biostatistics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ronglin Hu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Dongming Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jun Du
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xingyuan Jiao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
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Tu T, Budzinska MA, Shackel NA, Jilbert AR. Conceptual models for the initiation of hepatitis B virus-associated hepatocellular carcinoma. Liver Int 2015; 35:1786-800. [PMID: 25640596 DOI: 10.1111/liv.12773] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 12/18/2014] [Indexed: 12/18/2022]
Abstract
Although chronic hepatitis B virus (HBV) infection is a known risk factor for the development of hepatocellular carcinoma (HCC), the steps involved in the progression from normal liver to HCC are poorly understood. In this review, we apply five conceptual models, previously proposed by Vineis et al. to explain carcinogenesis in general, to explore the possible steps involved in the initiation and evolution of HBV-associated HCC. Available data suggest that the most suitable and inclusive model is based on evolution of hepatocyte subpopulations. In this evolutionary model, HCC-associated changes are driven by selection and subsequent clonal expansion of phenotypically altered hepatocyte subpopulations in the microenvironment of the HBV-infected liver. This model can incorporate the wide range of mechanisms proposed to play a role in the initiation of HCC including oncogenic HBV proteins, integration of HBV DNA and chronic inflammation of the liver. The model may assist in the early prevention, detection and treatment of HCC and may guide future studies of the initiation of HBV-associated HCC.
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Affiliation(s)
- Thomas Tu
- Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.,Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Magdalena A Budzinska
- Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Nicholas A Shackel
- Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia.,A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Allison R Jilbert
- Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
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4
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Chang TS, Wu YC, Chi CC, Su WC, Chang PJ, Lee KF, Tung TH, Wang J, Liu JJ, Tung SY, Kuo LM, Ho HN, Ling TY, Huang YH. Activation of IL6/IGFIR confers poor prognosis of HBV-related hepatocellular carcinoma through induction of OCT4/NANOG expression. Clin Cancer Res 2015; 21:201-210. [PMID: 25564572 DOI: 10.1158/1078-0432.ccr-13-3274] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE To unravel the role of interleukin (IL)-6 and insulin-like growth factor (IGF)-I receptor (IGFIR) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGFIR in hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN Serum levels of IL6 were detected using ELISA assays (n = 120). The effects of IL6/IGFI on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGFI receptor (p-IGFIR) in tissues were detected by Western blotting (n = 8) and immunohistochemical staining (n = 85). OCT4, NANOG, and IGFIR expression levels in tissues (n = 191) were analyzed by real-time qRT-PCR and was correlated with early tumor recurrence using the Kaplan-Meier survival analysis. RESULTS A high positive correlation between the expression levels of OCT4/NANOG and IGFIR/p-IGFIR in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGFIR was mostly confined to hepatitis B virus (HBV)-related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL6 were significantly correlated with high OCT4/NANOG expression. IL6 stimulated an autocrine IGFI/IGFIR expression STAT3 dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGFIR activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL6-induced stemness-related properties both in vitro and in vivo. CONCLUSIONS The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL6-induced IGF/IGFIR activation, particularly in HBV-HCC.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Hepatitis B virus/pathogenicity
- Homeodomain Proteins/biosynthesis
- Humans
- Interleukin-6/blood
- Kaplan-Meier Estimate
- Liver Neoplasms/blood
- Liver Neoplasms/genetics
- Liver Neoplasms/virology
- Mice
- Nanog Homeobox Protein
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Octamer Transcription Factor-3/biosynthesis
- Prognosis
- Receptors, Somatomedin/biosynthesis
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Te-Sheng Chang
- Department of Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei, Taiwan. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yu-Chih Wu
- Department of Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ching-Chi Chi
- College of Medicine, Chang Gung University, Taoyuan, Taiwan. Department of Dermatology and Centre for Evidence-Based Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Wei-Chi Su
- Department of Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei, Taiwan. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Pey-Jium Chang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kam-Fai Lee
- Department of Pathology, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Tao-Hsin Tung
- Department of Medical Research and Education, Cheng-Hsin General Hospital, and Faculty of Public Health, School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan
| | - Jui Wang
- School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
| | - Jun-Jen Liu
- School of Medical Laboratory Sciences and Biotechnology, Taipei Medical University, Taipei, Taiwan
| | - Shui-Yi Tung
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi, Taiwan. College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Liang-Mou Kuo
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Hong-Nerng Ho
- Graduate Institute of Clinical Genomics, College of Medicine, National Taiwan University, Taipei, Taiwan. Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, National Taiwan University and Hospital, Taipei, Taiwan
| | - Thai-Yen Ling
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
| | - Yen-Hua Huang
- Department of Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei, Taiwan. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei, Taiwan. Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan. The Ph.D. Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan.
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Wang HY, Yang SL, Liang HF, Li CH. HBx protein promotes oval cell proliferation by up-regulation of cyclin D1 via activation of the MEK/ERK and PI3K/Akt pathways. Int J Mol Sci 2014; 15:3507-18. [PMID: 24577313 PMCID: PMC3975350 DOI: 10.3390/ijms15033507] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 02/18/2014] [Accepted: 02/18/2014] [Indexed: 12/13/2022] Open
Abstract
Growing evidence has shown that hepatic oval cells, also named liver progenitor cells, play an important role in the process of liver regeneration in various liver diseases. Oval cell proliferation has been reported in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and chronic liver disease. Studies have found expression of HBV surface and core antigens in oval cells in the livers of patients with HCC, suggesting that HBV infection of oval cells could be a mechanism of human hepatocarcinogenesis. In addition, there is evidence of multiplication of HBV in oval cell culture. However, little research has been performed to explore the role of HBV-encoded proteins in the proliferation of hepatic oval cells. Previously, we successfully transfected the HBV x (HBx) gene, one of the four genes in the HBV genome, into a rat LE/6 oval cell line. In this study, we tested whether or not the transfected HBx gene could affect oval cell proliferation in vitro. Our results show that overexpression of HBx promotes the proliferation of oval cells and increases cyclin D1 expression, assessed at both the mRNA and protein levels. We also found that HBx activated the PI-3K/Akt and MEK/ERK1/2 pathways in HBx-transfected oval cells. Furthermore, the HBx-induced increases in cyclin D1 expression and oval cell proliferation were completely abolished by treatment with either MEK inhibitor PD184352 or PI-3K inhibitor LY294002. These results demonstrated that HBx has the ability to promote oval cell proliferation in vitro, and its stimulatory effects on cell proliferation and expression of cyclin D1 depend on the activation of the MEK/ERK and PI3K/Akt signaling pathways in cultured oval cells.
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Affiliation(s)
- Heng-Yi Wang
- Department of Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| | - Sheng-Li Yang
- Department of General Surgery, Liyuan Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430077, China.
| | - Hui-Fang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430030, China.
| | - Chang-Hai Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430030, China.
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6
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Spaniel C, Honda M, Selitsky SR, Yamane D, Shimakami T, Kaneko S, Lanford RE, Lemon SM. microRNA-122 abundance in hepatocellular carcinoma and non-tumor liver tissue from Japanese patients with persistent HCV versus HBV infection. PLoS One 2013; 8:e76867. [PMID: 24130799 PMCID: PMC3793926 DOI: 10.1371/journal.pone.0076867] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2013] [Accepted: 08/29/2013] [Indexed: 02/06/2023] Open
Abstract
Mechanisms of hepatic carcinogenesis in chronic hepatitis B and hepatitis C are incompletely defined but often assumed to be similar and related to immune-mediated inflammation. Despite this, several studies hint at differences in expression of miR-122, a liver-specific microRNA with tumor suppressor properties, in hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV) versus hepatitis C virus (HCV) infection. Differences in the expression of miR-122 in these cancers would be of interest, as miR-122 is an essential host factor for HCV but not HBV replication. To determine whether the abundance of miR-122 in cancer tissue is influenced by the nature of the underlying virus infection, we measured miR-122 by qRT-PCR in paired tumor and non-tumor tissues from cohorts of HBV- and HCV-infected Japanese patients. miR-122 abundance was significantly reduced from normal in HBV-associated HCC, but not in liver cancer associated with HCV infection. This difference was independent of the degree of differentiation of the liver cancer. Surprisingly, we also found significant differences in miR-122 expression in non-tumor tissue, with miR-122 abundance reduced from normal in HCV- but not HBV-infected liver. Similar differences were observed in HCV- vs. HBV-infected chimpanzees. Among HCV-infected Japanese subjects, reductions in miR-122 abundance in non-tumor tissue were associated with a single nucleotide polymorphism near the IL28B gene that predicts poor response to interferon-based therapy (TG vs. TT genotype at rs8099917), and correlated negatively with the abundance of multiple interferon-stimulated gene transcripts. Reduced levels of miR-122 in chronic hepatitis C thus appear to be associated with endogenous interferon responses to the virus, while differences in miR-122 expression in HCV- versus HBV-associated HCC likely reflect virus-specific mechanisms contributing to carcinogenesis. The continued expression of miR-122 in HCV-associated HCC may signify an important role for HCV replication late in the progression to malignancy.
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Affiliation(s)
- Carolyn Spaniel
- Departments of Medicine and Microbiology & Immunology and the Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Takara-Machi, Kanazawa, Japan
| | - Sara R. Selitsky
- Departments of Medicine and Microbiology & Immunology and the Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Genetics, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Daisuke Yamane
- Departments of Medicine and Microbiology & Immunology and the Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Takara-Machi, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Takara-Machi, Kanazawa, Japan
| | - Robert E. Lanford
- Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas, United States of America
| | - Stanley M. Lemon
- Departments of Medicine and Microbiology & Immunology and the Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- * E-mail:
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7
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Mason WS. Hepadnaviruses and Hepatocellular Carcinoma. CANCER ASSOCIATED VIRUSES 2012:531-569. [DOI: 10.1007/978-1-4614-0016-5_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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8
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Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, Li J. Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma. Int J Cancer 2010; 126:2067-78. [PMID: 19711346 DOI: 10.1002/ijc.24868] [Citation(s) in RCA: 221] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Both our previous study and other reports have suggested that CD133, originally classified as a hematopoietic stem cell marker, could be used for enrichment of cancer stem cells (CSCs) in human hepatocellular carcinoma (HCC). It was also noted that not all of CD133(+) cells were representative of CSCs. Further identification and characterization of CSCs or tumor-initiating cells in HCC are necessary to better understand hepatocarcinogenesis. In present study, we demonstrated that CSC phenotype could be precisely defined by co-expression of CD133 and CD44 cell surface markers. CD133(+)CD44(+) HCC cells showed stem cell properties, including extensive proliferation, self-renewal, and differentiation into the bulk of cancer cells. In vivo xenograft experiments revealed that, actually, the highly tumorigenic capacity of CD133(+) cells as previously described was primarily attributed to CD133(+)CD44(+) cell subpopulation, instead of their CD133(+)CD44(-) counterparts. Moreover, cells double-positive for CD133 and CD44 exhibited preferential expression of some stem cell-associated genes and were more resistant to chemotherapeutic agents due to the upregulation of ATP-binding cassette (ABC) superfamily transporters, including ABCB1, ABCC1, and ABCG2, further supporting these cells as HCC cell origin. Our findings suggest that CD133(+)CD44(+) cells might represent true cancer stem/progenitor cells in HCC, which could allow a better understanding of HCC initiation and progression, as well as establish a precise target for the development of more effective therapies.
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Affiliation(s)
- Zheng Zhu
- Shanghai Medical College, Fudan University, Shanghai, China
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9
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Abstract
Increasing evidence suggests that many, perhaps all solid tumors contain a subset of cells that possess functional properties similar to the normal tissue stem cells, including self-renewal, unlimited proliferative capacity, and pluripotency. The hierarchical cancer model that places a cancer stem cell (CSC) population at the apex of tumor formation is based on this notion. The cancer stem cell hypothesis posits that CSCs are responsible not only for tumor initiation, but also generation of metastasis and local recurrence after therapy. Current definitions of the CSC are based only on functional properties regardless of potential cellular origin. Histopathology investigations of chronic liver diseases and experimental studies support the existence of CSCs in liver cancer. In particular, recent advances in microarray technologies utilizing integrative comparative genomic analysis of human hepatocellular carcinoma specimens, cancer cell lines, and transgenic models establish the molecular similarities between CSC and normal tissue stem cells and highlight the importance of CSC for the prognosis of liver cancer patients. The results have also uncovered the key "stemness" and oncogenic pathways frequently disrupted during hepatocarcinogenesis providing the basis for identifying novel therapeutic targets against CSC.
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Affiliation(s)
- Jens U. Marquardt
- Laboratory of Experimental Carcinogenesis (LEC), Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
| | - Snorri S. Thorgeirsson
- Laboratory of Experimental Carcinogenesis (LEC), Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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10
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Wang H, Gao Y, Jin X, Xiao J. Expression of contactin associated protein-like 2 in a subset of hepatic progenitor cell compartment identified by gene expression profiling in hepatitis B virus-positive cirrhosis. Liver Int 2010; 30:126-38. [PMID: 19889080 DOI: 10.1111/j.1478-3231.2009.02151.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND Hepatic progenitor cells (HPC), a cell compartment capable of differentiating into hepatocytic and biliary lineages, may give rise to the formation of intermediate hepatobiliary cells (IHBC) or ductular reactions (DR). AIMS The aim of this study was to analyse the gene expression profiles of DR in cirrhosis and further investigate novel proteins expressed by HPC and their intermediate progeny. METHODS DR in hepatitis B virus (HBV)-positive cirrhotic liver tissues adjacent to hepatocellular carcinoma and interlobular bile ducts (ILBDs) in normal liver tissues were isolated by laser capture microdissection and then subjected to microarray analysis. Differential gene expression patterns were verified by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry on serial sections. HPC and their intermediate progeny were recognized by immunostaining with hepatocytic and biliary markers [HepPar1, cytokeratin (CK)7, CK19, neural cell adhesion molecule (NCAM), epithelial cell adhesion molecule (EpCAM)]. RESULTS A total of 88 genes showed upregulation in DR compared with ILBDs. Gene ontology analyses revealed that these upregulated genes were mostly associated with cell adhesion, immune response and the metabolic process. Contactin associated protein-like 2 (CNTNAP2) was first confirmed to be a novel protein expressed in a subpopulation of DR that was positive for CK7, NCAM or EpCAM. In addition, immunoreactivity for CNTNAP2 was also noted in a subset of isolated CK7-positive HPC as well as some ductular IHBC positive for CK19 and HepPar1 in DR. CONCLUSION CNTNAP2 is specifically associated with the emergence of ductular populations and may be identified as a novel protein for defining a subset of HPC and their intermediate progeny in cirrhosis.
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Affiliation(s)
- Huafeng Wang
- Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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11
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Alison MR, Islam S, Lim S. Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly. J Pathol 2009; 217:282-98. [PMID: 18991329 DOI: 10.1002/path.2453] [Citation(s) in RCA: 168] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The worldwide shortage of donor livers to transplant end stage liver disease patients has prompted the search for alternative cell therapies for intractable liver diseases, such as acute liver failure, cirrhosis and hepatocellular carcinoma (HCC). Under normal circumstances the liver undergoes a low rate of hepatocyte 'wear and tear' renewal, but can mount a brisk regenerative response to the acute loss of two-thirds or more of the parenchymal mass. A body of evidence favours placement of a stem cell niche in the periportal regions, although the identity of such stem cells in rodents and man is far from clear. In animal models of liver disease, adopting strategies to provide a selective advantage for transplanted hepatocytes has proved highly effective in repopulating recipient livers, but the poor success of today's hepatocyte transplants can be attributed to the lack of a clinically applicable procedure to force a similar repopulation of the human liver. The activation of bipotential hepatic progenitor cells (HPCs) is clearly vital for survival in many cases of acute liver failure, and the signals that promote such reactions are being elucidated. Bone marrow cells (BMCs) make, at best, a trivial contribution to hepatocyte replacement after damage, but other BMCs contribute to the hepatic collagen-producing cell population, resulting in fibrotic disease; paradoxically, BMC transplantation may help alleviate established fibrotic disease. HCC may have its origins in either hepatocytes or HPCs, and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.
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Affiliation(s)
- M R Alison
- Centre for Diabetes and Metabolic Medicine, St Bartholomew's Hospital and the London School of Medicine and Dentistry, London, UK.
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12
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Bird TG, Lorenzini S, Forbes SJ. Activation of stem cells in hepatic diseases. Cell Tissue Res 2008; 331:283-300. [PMID: 18046579 PMCID: PMC3034134 DOI: 10.1007/s00441-007-0542-z] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2007] [Accepted: 10/23/2007] [Indexed: 02/06/2023]
Abstract
The liver has enormous regenerative capacity. Following acute liver injury, hepatocyte division regenerates the parenchyma but, if this capacity is overwhelmed during massive or chronic liver injury, the intrinsic hepatic progenitor cells (HPCs) termed oval cells are activated. These HPCs are bipotential and can regenerate both biliary epithelia and hepatocytes. Multiple signalling pathways contribute to the complex mechanism controlling the behaviour of the HPCs. These signals are delivered primarily by the surrounding microenvironment. During liver disease, stem cells extrinsic to the liver are activated and bone-marrow-derived cells play a role in the generation of fibrosis during liver injury and its resolution. Here, we review our current understanding of the role of stem cells during liver disease and their mechanisms of activation.
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Affiliation(s)
- T G Bird
- MRC/University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
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Burra P, Tomat S, Villa E, Gasbarrini A, Costa AN, Conconi MT, Forbes SJ, Farinati F, Cozzi E, Alison MR, Russo FP. Experimental hepatology applied to stem cells. Dig Liver Dis 2008; 40:54-61. [PMID: 17997371 DOI: 10.1016/j.dld.2007.08.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2007] [Accepted: 08/27/2007] [Indexed: 12/11/2022]
Abstract
Transplantation is an accepted treatment today for many people suffering from organ failure. More and more patients are referred for transplant surgery, and the waiting lists are growing longer because not enough organs and tissues are donated for transplantation. This has led to several potentially viable alternatives being considered, including bio-artificial support devices, the transplantation of mature cells or stem/progenitor cells and the potential transplantation of xenogenic organs and cells [Burra P, Samuel D, Wendon J, Pietrangelo A, Gupta S. Strategies for liver support: from stem cells to xenotransplantation. J Hepatol 2004;41:1050-9]. Numerous investigators around the world are engaged in these investigations and the pace of discovery has begun to accelerate in recent years. To take stock of the achievements of recent years, the AISF sponsored a Single-Topic Conference, held in Padua on 26-27 May, 2006, with the participation of many leading investigators from various parts of Italy and Europe. This present paper summarizes the content of the Conference. Different issues were analysed, from the biology of stem cells to the possible use of gene therapy. The speakers were clinicians and scientists interested in diseases not only of the liver but also of other organs such as the kidney or heart. The fact that numerous specialties were represented helped the audience to understand the stem cell research area from different standpoints, and what research has achieved so far.
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Affiliation(s)
- P Burra
- Department of Surgical and Gastroenterological Sciences, University of Padua, Italy.
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14
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Yeh MM, Larson AM, Campbell JS, Fausto N, Rulyak SJ, Swanson PE. The expression of transforming growth factor-alpha in cirrhosis, dysplastic nodules, and hepatocellular carcinoma: an immunohistochemical study of 70 cases. Am J Surg Pathol 2007; 31:681-9. [PMID: 17460450 DOI: 10.1097/pas.0b013e31802ff7aa] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The emergence of hepatocellular carcinoma (HCC) is thought to be a stepwise process, with high-grade dysplastic nodules (HGDN) representing premalignant lesions arising in a background of cirrhosis. Earlier studies have revealed altered expression of transforming growth factor-alpha (TGF-alpha) (a mitogen capable of inducing hepatocarcinogenesis in mice) in HCC and its surrounding parenchyma. DNA topoisomerase II-alpha (Topo II-alpha) is a nuclear protein targeted by several chemotherapeutic agents and is overexpressed in HCC. The expression of both TGF-alpha and Topo II-alpha in putative preneoplastic hepatocytic lesions, however, has not been extensively studied. We examined the patterns of TGF-alpha and Topo II-alpha expression in noncirrhotic liver, liver cirrhosis, low-grade dysplastic nodules (LGDN), HGDN, and HCC to define the possible relationships of these markers to tumor progression. Paraffin sections from formalin-fixed material were immunostained with antibodies against TGF-alpha, Topo II-alpha, and Ki-67. Forty-six HCC, 17 HGDN, and 12 low-grade dysplastic nodules were identified in 52 cirrhotic livers from explanted or resected specimens. Nuclear staining for Ki-67 and Topo II-alpha was significantly increased in the progression from cirrhosis, through HGDN, to HCC, whereas the scores for TGF-alpha in these lesions showed an inverse relationship. In comparison with 18 HCC arising in noncirrhotic livers, the expression of TGF-alpha is significantly stronger in cirrhotic liver than in noncirrhotic parenchyma and its expression is also stronger in HCC arising in cirrhosis than in HCC arising in noncirrhotic parenchyma. The increased expression of Topo II-alpha and Ki-67 from HGDN to HCC, when compared with cirrhosis, suggests that HGDN is a precursor lesion in hepatocarcinogenesis. The inverse relationship between these proliferative markers and TGF-alpha expression in these lesions and stronger expression of TGF-alpha in HCC arising in cirrhosis suggest that TGF-alpha may play an important role in the early events of liver carcinogenesis.
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Affiliation(s)
- Matthew M Yeh
- Department of Pathology, School of Medicine, University of Washington, Seattle, WA 98195-6100, USA.
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15
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Abstract
Numerous studies point to the fact that liver tumors are derived from single cells (monoclonal), but the important question is, which cell? Stem cell biology and cancer are inextricably linked. In continually renewing tissues such as the intestinal mucosa and epidermis, in which a steady flux of cells occurs from the stem cell zone to the terminally differentiated cells that are imminently to be lost, it is widely accepted that cancer is a disease of stem cells, as these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic development. In the liver the identity of the founder cells for the two major primary tumors, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), is more problematic. The reason for this is that no such obvious unidirectional flux occurs in the liver, though it is held that the centrilobular hepatocytes may be more differentiated (polyploid) and closer to cell senescence than those cells closest to the portal areas. Moreover the existence of bipotential hepatic progenitor cells (HPCs), along with hepatocytes endowed with longevity and long-term repopulating potential suggests there may be more than one type of carcinogen target cell. Irrespective of which target cell is involved, cell proliferation at the time of carcinogen exposure is pivotal for "fixation" of the genotoxic injury into a heritable form. Taking this view, any proliferative cell in the liver can be susceptible to neoplastic transformation. Thus, hepatocytes are implicated in many instances of HCC, direct injury to the biliary epithelium implicates cholangiocytes in some cases of CC, whereas HPC/oval cell activation accompanies very many instances of liver damage irrespective of etiology, making such cells very likely carcinogen targets. Of course, we must qualify this assertion by stating that many carcinogens are both cytotoxic and cytostatic, and that HPC proliferation may be merely a bystander effect of this toxicity. An indepth discussion of causes of cancer in the liver are beyond the scope of this review, but infectious agents (e.g., hepatitis B and C viruses) play a major role, not just in transactivating or otherwise disrupting cellular proto-oncogenes (hepatitis B virus [HBV]), but in also causing chronic inflammation (hepatitis C virus [HCV] and HBV). Sustained epithelial proliferation in a milieu rich in inflammatory cells, growth factors, and DNA-damaging agents (reactive oxygen and nitrogen species produced to fight infection), will lead to permanent genetic changes in proliferating cells. The upregulation of the transcription factor nuclear factor kappaB (NF-kappaB) in transformed hepatocytes, through the paracrine action of tumor necrosis factor-alpha from neighboring endothelia and inflammatory cells, may be critical for tumor progression given the mitogenic and anti-apoptotic properties of proteins encoded by many of NF-kappaB's target genes.
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16
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Alison MR. Liver stem cells: implications for hepatocarcinogenesis. STEM CELL REVIEWS 2007. [PMID: 17142862 DOI: 10.1385/scr: 1: 3: 253] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Numerous studies point to the fact that liver tumors are derived from single cells (monoclonal), but the important question is, which cell? Stem cell biology and cancer are inextricably linked. In continually renewing tissues such as the intestinal mucosa and epidermis, in which a steady flux of cells occurs from the stem cell zone to the terminally differentiated cells that are imminently to be lost, it is widely accepted that cancer is a disease of stem cells, as these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic development. In the liver the identity of the founder cells for the two major primary tumors, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), is more problematic. The reason for this is that no such obvious unidirectional flux occurs in the liver, though it is held that the centrilobular hepatocytes may be more differentiated (polyploid) and closer to cell senescence than those cells closest to the portal areas. Moreover the existence of bipotential hepatic progenitor cells (HPCs), along with hepatocytes endowed with longevity and long-term repopulating potential suggests there may be more than one type of carcinogen target cell. Irrespective of which target cell is involved, cell proliferation at the time of carcinogen exposure is pivotal for "fixation" of the genotoxic injury into a heritable form. Taking this view, any proliferative cell in the liver can be susceptible to neoplastic transformation. Thus, hepatocytes are implicated in many instances of HCC, direct injury to the biliary epithelium implicates cholangiocytes in some cases of CC, whereas HPC/oval cell activation accompanies very many instances of liver damage irrespective of etiology, making such cells very likely carcinogen targets. Of course, we must qualify this assertion by stating that many carcinogens are both cytotoxic and cytostatic, and that HPC proliferation may be merely a bystander effect of this toxicity. An indepth discussion of causes of cancer in the liver are beyond the scope of this review, but infectious agents (e.g., hepatitis B and C viruses) play a major role, not just in transactivating or otherwise disrupting cellular proto-oncogenes (hepatitis B virus [HBV]), but in also causing chronic inflammation (hepatitis C virus [HCV] and HBV). Sustained epithelial proliferation in a milieu rich in inflammatory cells, growth factors, and DNA-damaging agents (reactive oxygen and nitrogen species produced to fight infection), will lead to permanent genetic changes in proliferating cells. The upregulation of the transcription factor nuclear factor kappaB (NF-kappaB) in transformed hepatocytes, through the paracrine action of tumor necrosis factor-alpha from neighboring endothelia and inflammatory cells, may be critical for tumor progression given the mitogenic and anti-apoptotic properties of proteins encoded by many of NF-kappaB's target genes.
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17
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Abstract
In recent years, the results of several studies suggest that human liver tumors can be derived from hepatic progenitor cells rather than from mature cell types. The available data indeed strongly suggest that most combined hepatocellular-cholangiocarcinomas arise from hepatic progenitor cells that retained their potential to differentiate into the hepatocytic and biliary lineages. Hepatic progenitor cells could also be the basis for some hepatocellular carcinomas and hepatocellular adenomas, although it is very difficult to determine the origin of an individual hepatocellular carcinoma. There is currently not enough data to make statements regarding a hepatic progenitor cell origin of cholangiocarcinoma. The presence of hepatic progenitor cell markers and the presence and extent of the cholangiocellular component are factors that are related to the prognosis of hepatocellular carcinomas and combined hepatocellular-cholangiocarcinomas, respectively.
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Affiliation(s)
- Louis Libbrecht
- Laboratory of Morphology and Molecular Pathology, Minderbroedersstraat 12, Leuven 3000, Belgium.
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18
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Alison MR, Lovell MJ. Liver cancer: the role of stem cells. Cell Prolif 2005; 38:407-21. [PMID: 16300653 PMCID: PMC6496116 DOI: 10.1111/j.1365-2184.2005.00354.x] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2005] [Accepted: 07/28/2005] [Indexed: 01/12/2023] Open
Abstract
Studies of aggregation chimaeras and X-linked polymorphisms strongly suggest that liver tumours are derived from single cells (monoclonal), but the important question is, which cell? Stem cell biology and cancer are inextricably linked. In continually renewing tissues such as the gut mucosa and epidermis, where a steady flux of cells occurs from the stem cell zone to the terminally differentiated cells that are imminently to be lost, it is widely accepted that cancer is a disease of stem cells, since these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic development. In the liver the identity of the founder cells for the two major primary tumours, hepatocellular carcinoma and cholangiocarcinoma, is more problematic. The reason for this is that no such obvious unidirectional flux occurs in the liver, although it is held that the centrilobular hepatocytes may be more differentiated (polyploid) and closer to cell senescence than those cells closest to the portal areas. Moreover, the existence of bipotential hepatic progenitor cells, along with hepatocytes endowed with longevity and long-term repopulating potential suggests there may be more than one type of carcinogen target cell. Cell proliferation at the time of carcinogen exposure is pivotal for 'fixing' any genotoxic injury into a heritable form, thus any proliferative cell in the liver can be susceptible to neoplastic transformation. Hepatocytes are implicated in many instances of hepatocellular carcinoma, direct injury to the biliary epithelium implicates cholangiocytes in some cases of cholangiocarcinoma, while hepatic progenitor cell/oval cell activation accompanies many instances of liver damage irrespective of aetiology, making such cells very likely carcinogen targets. Of course, we must qualify this assertion by stating that many carcinogens are both cytotoxic and cytostatic, and that hepatic progenitor cell proliferation may be merely a bystander effect of this toxicity. An in-depth discussion of causes of cancer in the liver is beyond the scope of this review, but infectious agents (e.g. hepatitis B and C viruses) play a major role, not just in transactivating or otherwise disrupting cellular proto-oncogenes (hepatitis B virus), but also in causing chronic inflammation (hepatitis C and B viruses). Sustained epithelial proliferation in a milieu rich in inflammatory cells, growth factors and DNA-damaging agents (reactive oxygen and nitrogen species--produced to fight infection), will lead to permanent genetic changes in proliferating cells. Up-regulation of the transcription factor NF-kappaB in transformed hepatocytes, through the paracrine action of TNF-alpha from neighbouring endothelia and inflammatory cells, may be critical for tumour progression given the mitogenic and antiapoptotic properties of proteins encoded by many of NF-kappaB's target genes.
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Affiliation(s)
- M R Alison
- Cancer Research UK and Queen Mary University of London, London, UK.
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19
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Sano T, Kagawa M, Okuno M, Ishibashi N, Hashimoto M, Yamamoto M, Suzuki R, Kohno H, Matsushima-Nishiwaki R, Takano Y, Tsurumi H, Kojima S, Friedman SL, Moriwaki H, Tanaka T. Prevention of rat hepatocarcinogenesis by acyclic retinoid is accompanied by reduction in emergence of both TGF-alpha-expressing oval-like cells and activated hepatic stellate cells. Nutr Cancer 2005; 51:197-206. [PMID: 15860442 DOI: 10.1207/s15327914nc5102_10] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
We investigated the preventive effects of a synthetic acyclic retinoid, NIK-333, on the early and late events of hepatocarcinogenesis in male F344 rats treated with 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB). NIK-333 was administered once a day on consecutive days at a dose of 10, 40, or 80 mg/kg body weight along with the supplementation with 3'-MeDAB-containing diet for 16 wk. Animals from each group were sacrificed at 4 and 16 wk after the commencement of the experiment to determine the effect of NIK-333 on the early and late stages of carcinogenesis, respectively. NIK-333 suppressed the emergence of both oval-like cells expressing transforming growth factor (TGF)-alpha, putative progenitors of hepatocellular carcinoma (HCC), and activated hepatic stellate cells, major matrix-producing cells of the liver, in the early stage and inhibited the incidence of HCC in the late phase. These results suggest that NIK-333 is a promising drug for the chemoprevention of HCC by uniquely suppressing the early events of hepatocarcinogenesis, that is, development of both oval-like cells and fibrogenesis.
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Affiliation(s)
- Tetsuro Sano
- Pharmaceutical Research Laboratories, Nikken Chemicals Co., Saitama, Japan
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20
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Maronpot RR, Flake G, Huff J. Relevance of animal carcinogenesis findings to human cancer predictions and prevention. Toxicol Pathol 2004; 32 Suppl 1:40-8. [PMID: 15209402 DOI: 10.1080/01926230490425003] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Use of laboratory animals to identify carcinogenic potential of chemicals, mixtures, and other agents has a modern history of greater than 40 years from which much useful scientific and public health information can be derived. While laboratory animals differ from humans in some respects that may affect responses to hazardous exposures, use of such models is based on experimental evidence indicating that there are more genetic, genomic, physiological, biochemical, and metabolic similarities than differences among mammalian species. Issues of concordance of responses between rodent species and between rodents and humans as well as repeatability and site-specificity are important considerations in evaluating laboratory animal carcinogenicity results. Variables in experimental design such as animal strain, diet, route of exposure, and study, duration as well as single-site versus multisite carcinogenic responses all influence interpretation and intelligent use of study data. Similarities and differences in site-specific laboratory animal and corresponding human cancers should also be considered in study evaluation. Recent attempts to explore genetically engineered mice and to humanize the mouse for more relevant identification of carcinogen hazard identification have yielded mixed results. In the end we are confronted by the realization that virtually all animal cancer models are useful but imperfect surrogates for humans. Assuming the percentage of chemicals currently in commerce that are estimated to be potent animal or human carcinogens is quite low, the task of identifying agents with significant carcinogenic potential is daunting and important. The biological conundrum of scientific debate regarding the relevance of carcinogenicity studies in laboratory animals is likely to continue. Nonetheless public health considerations must take precedence when deciding human safety issues.
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Affiliation(s)
- R R Maronpot
- National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
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21
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Cheng J, Nakamura H, Imanishi H, Liu W, Morisaki T, Sugiyama T, Hada T. Peroxisome proliferator-activated receptor γ ligands, 15-deoxy-Δ12,14-prostaglandin J2, and ciglitazone, induce growth inhibition and cell cycle arrest in hepatic oval cells. Biochem Biophys Res Commun 2004; 322:458-64. [PMID: 15325252 DOI: 10.1016/j.bbrc.2004.07.133] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2004] [Indexed: 01/31/2023]
Abstract
There is growing evidence to show that hepatic oval cells contribute to liver regeneration, dysplastic nodule formation, and hepato-carcinogenesis. Peroxisome proliferator-activated receptors (PPARs) and their ligands play an important role in cell growth, inflammatory responses, and liver pathogenesis including fibrosis and cancer. However, little is known about the role of PPARgamma/its ligands in the growth and differentiation of hepatic oval cells. In this study, we found that OC15-5, a rat hepatic oval cell line, expressed PPARgamma at mRNA and protein levels, and a natural ligand for PPARgamma, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), and a synthetic ligand, ciglitazone, inhibited growth of OC15-5 cells by arresting at G1-S in a dose-dependent manner. Apoptosis was also induced in OC15-5 cells by 15d-PGJ2 treatment. In OC15-5 cells treated with 15d-PGJ2, the expression of CDK inhibitor, p27(Kip1), was up-regulated, while that of p21(WAF1/Cip1), p18(INK4C) CDK2, CDK4, and cyclin E was unchanged. In addition, delayed up-regulation of AFP expression was observed in OC15-5 cells after 15d-PGJ2 or ciglitazone treatment. This is the first report to show that the PPARgamma ligand was involved in the growth, cell cycle, and differentiation of hepatic oval cells, raising the possibility that the PPARgamma ligands may regulate liver regeneration and hepato-carcinogenesis.
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Affiliation(s)
- Jidong Cheng
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo 663-8501, Japan.
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22
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Fotiadu A, Tzioufa V, Vrettou E, Koufogiannis D, Papadimitriou CS, Hytiroglou P. Progenitor cell activation in chronic viralhepatitis. Liver Int 2004; 24:268-74. [PMID: 15189279 DOI: 10.1111/j.1478-3231.2004.00908.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIM Oval cell proliferation is known to occur in experimental models of hepatic regeneration and carcinogenesis. Recent studies have suggested that activation of progenitor cells, representing the human counterpart of oval cells, may play a role in hepatic diseases. Therefore, we evaluated putative progenitor cells in chronic viral hepatitis. METHODS Forty-one needle liver biopsy specimens from patients with chronic hepatitis B and 43 specimens from patients with chronic hepatitis C were examined histologically. The grade (histological activity index (HAI)) and stage (degree of fibrosis) were determined on routinely stained sections. The number of progenitor cells was assessed semiquantitatively on cytokeratin 7- (CK 7-) stained sections. RESULTS In both aetiological categories of chronic viral hepatitis, progenitor cell numbers were found to increase in parallel to the HAI, as well as to the stage of disease. Features suggestive of hepatocytic differentiation of progenitor cells were also noted on immunohistochemical stains for CK 7 and 'hepatocyte-specific' antigen. CONCLUSIONS In chronic hepatitis B and chronic hepatitis C, progenitor cell activation is correlated with the grade and stage of disease. Proliferating progenitor cells may play a role in hepatic regeneration occurring in this setting.
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Affiliation(s)
- Anastasia Fotiadu
- Department of Pathology, Aristotle University Medical School, Thessaloniki, Greece
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23
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Fang CT, Chen PJ, Chen MY, Hung CC, Chang SC, Chang AL, Chen DS. Dynamics of plasma hepatitis B virus levels after highly active antiretroviral therapy in patients with HIV infection. J Hepatol 2003; 39:1028-35. [PMID: 14642622 DOI: 10.1016/s0168-8278(03)00416-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS The optimal strategy to prescribe highly active antiretroviral therapy (HAART) in patients infected with both hepatitis B virus (HBV) and human immunodeficiency virus (HIV) remains unsettled. This study aimed to compare the HBV dynamics between HBeAg-positive and HBeAg-negative coinfected patients treated with lamivudine-containing HAART. METHODS We retrospectively analyzed the serial changes of plasma HBV DNA levels in 24 HBsAg-positive HIV-infected patients who entered the HAART program. A polymerase chain reaction-based assay, capable of quantifying as few as 400 HBV copies/ml, was used. The median follow-up time was 18 months. RESULTS HAART containing lamivudine 300 mg/day effectively suppressed plasma HBV-DNA to 10(-3)-10(-5)-fold of the baseline levels, but a multi-phasic decay of HBV DNA was observed. The later phases became flat, as a persistent residual HBV viremia, in eight of the studied 10 HBeAg-positive patients; in contrast, residual HBV viremia was not observed in the 10 HBeAg-negative patients studied (8/10 vs. 0/10, P=0.0007, Fisher's exact test). HAART without lamivudine did not suppress plasma HBV DNA levels in the remaining four patients. CONCLUSIONS HAART containing lamivudine 300 mg/day effectively suppress HBV replication in HBeAg-negative HIV/HBV-coinfected patients. Nevertheless, residual HBV replication persisted in most HBeAg-positive coinfected patients.
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Affiliation(s)
- Chi-Tai Fang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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24
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Falkowski O, An HJ, Ianus IA, Chiriboga L, Yee H, West AB, Theise ND. Regeneration of hepatocyte 'buds' in cirrhosis from intrabiliary stem cells. J Hepatol 2003; 39:357-64. [PMID: 12927921 DOI: 10.1016/s0168-8278(03)00309-x] [Citation(s) in RCA: 139] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS In massive hepatic necrosis, hepatic stem cells constitute a canal of Hering derived, cytokeratin 19 (CK19) positive 'ductular reaction' (DR). Whether DRs in cirrhosis are activated stem cells (so called 'buds') or biliary metaplasia of cholestatic, injured hepatocytes is still debated. We investigate derivation of intraseptal hepatocytes (ISHs) from DRs and from the biliary tree in cirrhosis. METHODS Explants of hepatitis B and C, alcohol, primary biliary cirrhosis and primary sclerosing cholangitis-related cirrhosis were examined. ISHs were quantified and their associations with DRs and cholestasis recorded. 3D-reconstruction of ISHs and nearby bile ducts was performed in blocks from hepatitis C and primary sclerosing cholangitis cirrhosis. RESULTS Seven hundred seventy five/830 (94%) ISHs were associated with CK19 positive DRs. ISHs without ductular reactions were more likely to show cholestatic features (P<0.0001). In 3D, ISHs were seen to bud directly from the biliary tree. In summary: ISHs: (1) are usually associated with stem cell-like DRs; (2) are rarely cholestatic, leaving the associated DRs unexplained; and (3) are linked to the biliary tree in 3D. Dynamic proliferation rates in hepatitis C over time suggest that hepatocyte replication diminishes in late stages, with an associated activation of the biliary stem cell compartment. CONCLUSIONS We therefore suggest that the biliary tree, from at least its smaller branches up to the canals of Hering, are composed of or at least harbor facultative hepatic stem cells, and that ISH largely represent 'buds' of newly formed hepatocytes.
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Affiliation(s)
- Olga Falkowski
- Department of Pathology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA
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25
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Su Q, Fu Y, Liu YF, Zhang W, Liu J, Wang CM. Laminin induces the expression of cytokeratin 19 in hepatocellular carcinoma cells growing in culture. World J Gastroenterol 2003; 9:921-9. [PMID: 12717831 PMCID: PMC4611398 DOI: 10.3748/wjg.v9.i5.921] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the abnormal cytokeratin (CK) expression, emergence of CK19 with or without CK7, in liver parenchymal cells and the role of laminin (LN), a basement membrane protein, in this process.
METHODS: Six hepatocellular carcinoma (HCC) cell lines were examined for different CKs, LN and its receptor by immunocytochemistry and Western blotting. Double immunofluorescent reaction, laser-scanning confocal microscopy and an in vitro induction procedure were used to demonstrate the role of LN in regulating CK19 expression in these cells.
RESULTS: Immunoreactivities for CK8, CK18, CK7 and the receptor for LN were observed in all the six HCC cell lines examined. However, CK19 was merely found in four of the six cell lines, and was in any case associated with LN expression. Laser-scanning confocal microscopy demonstrated the concomitant presence of these two molecules in most of the positive cells. In the two HCC cell lines, originally negative for CK19, addition of LN to the culture medium resulted in an induction of CK19 in a dose-dependent manner. Both the artificially induced and the intrinsic production of CK19 were completely blocked by an antibody to LN.
CONCLUSION: LN can induce expression of CK19 in HCC cells in vitro, providing direct evidence for our hypothesis that the abnormal hepatocytic CK19 expression in situ is due to pathologic LN deposition.
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Affiliation(s)
- Qin Su
- Department of Pathology, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, Shaanxi Province, China.
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MESH Headings
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/prevention & control
- Carcinoma, Hepatocellular/virology
- Cell Adhesion/genetics
- Cell Transformation, Neoplastic
- Cell Transformation, Viral
- Chronic Disease
- Genes, cdc
- Genes, p53
- Growth Substances/physiology
- Hepacivirus/pathogenicity
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/virology
- Humans
- Liver Diseases/complications
- Liver Diseases/pathology
- Liver Neoplasms/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/prevention & control
- Liver Neoplasms/virology
- Neoplasm Invasiveness/genetics
- Neoplasm Metastasis
- Neovascularization, Pathologic/genetics
- Precancerous Conditions/complications
- Precancerous Conditions/pathology
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27
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Lowes KN, Croager EJ, Olynyk JK, Abraham LJ, Yeoh GCT. Oval cell-mediated liver regeneration: Role of cytokines and growth factors. J Gastroenterol Hepatol 2003; 18:4-12. [PMID: 12519217 DOI: 10.1046/j.1440-1746.2003.02906.x] [Citation(s) in RCA: 134] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In experimental models, which induce liver damage and simultaneously block hepatocyte proliferation, the recruitment of a hepatic progenitor cell population comprised of oval cells is invariably observed. There is a substantial body of evidence to suggest that oval cells are involved in liver regeneration, as they differentiate into hepatocytes and biliary cells. Recently, bone marrow cells were shown to be a source of a stem cells with the capacity to repopulate the liver. Presently, the relationship between bone marrow cells and oval cells is unclear. Investigations will be greatly assisted by the availability of in vitro models based on a knowledge of cytokines that affect oval cells. While the cytokines, which regulate the different hematopoietic lineages, are well characterized, there is relatively little information regarding those that influence oval cells. This review outlines recent developments in the field of oval cell research and focuses on cytokines and growth factors that have been implicated in regulating oval cell proliferation and differentiation.
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Affiliation(s)
- Kym N Lowes
- Western Australian Institute for Medical Research, School of Biomedical and Chemical Sciences, The University of Western Australia, Crawley, Australia
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28
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Uenishi T, Kubo S, Hirohashi K, Yamamoto T, Ogawa M, Tanaka H, Shuto T, Kinoshita H. Expression of bile duct-type cytokeratin in hepatocellular carcinoma in patients with hepatitis C virus and prior hepatitis B virus infection. Cancer Lett 2002; 178:107-12. [PMID: 11849748 DOI: 10.1016/s0304-3835(01)00813-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The clinicopathologic findings in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) positive for biliary markers, those related to the hepatic progenitor cells, were investigated. Cytokeratin (CK) 19 was reactive for HCCs only in patients with prior hepatitis B virus (HBV) infection. The proportions of patients with prior HBV infection and poorly differentiated HCC were significantly higher among those with CK 19-positive HCC than among those with CK 19-negative HCC. Some HCCs develop from the hepatic progenitor cells in patients with HCV infection and prior HBV infection, which may affect the clinicopathologic findings of HCV-related HCCs.
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Affiliation(s)
- Takahiro Uenishi
- Department of Gastroenterological and Hepato-biliary-pancreatic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
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29
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Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death, with over a million new cases annually. It is generally advanced upon detection due to underlying liver disease, which further complicates treatment. Most of the therapeutic strategies in current use (surgery, transplantation, irradiation or chemotherapy) are either palliative or only of benefit to a small percentage of patients. This article reviews the biology of HCC, including many of the molecular changes and mechanisms leading to HCC development. This article discusses the recent innovative strategies to interfere with the progression of HCC, including novel gene therapy strategies. The most recent data supporting the use of immunotherapy for hepatocellular cancer is reviewed in detail.
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Affiliation(s)
- Lisa H Butterfield
- Department of Surgery, Division of Surgical Oncology, University of California, Los Angeles, CA 90095, USA.
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Kim JH, Rho HM. Activation of the human transforming growth factor alpha (TGF-alpha) gene by the hepatitis B viral X protein (HBx) through AP-2 sites. Mol Cell Biochem 2002; 231:155-61. [PMID: 11952158 DOI: 10.1023/a:1014477218369] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The HBx protein is known as a transactivator and potential oncogene, and TGF-alpha as a potent mitogen in hepatocellular carcinoma. By assays of serial deletion of the promoter of TGF-alpha gene and the cotransfection of HBx and AP-2 expression vectors, we observed that the HBx significantly activated the promoter activity through AP-2 sites located in the proximal region of the TGF-alpha promoter (-136 to -30). This effect was also observed in the heterologous promoter assay system containing AP-2 sites. The mutation analyses of three AP-2 sites in the promoter revealed that all three AP-2 sites contributed to the activation of the TGF-a gene in the presence of HBx. Accordingly, the mRNA level of TGF-alpha was significantly elevated in the HBx-expressing cell, HepG2-HBx and the HBV-producing cell, HepG2-K8. These results suggest that the HBx protein could increase the mitogenic effect of TGF-alpha by the transactivation of the gene through AP-2 binding sites and consequently, these interactions may accelerate the process of hepatocarcinogenesis.
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Affiliation(s)
- Jun Hwan Kim
- School of Biological Sciences, Seoul National University, Korea
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31
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Abstract
The existence of a liver stem cell population has only gained credence recently, following the results of animal experiments. These cells are thought to reside in the terminal bile ductules (canals of Hering). Hepatocyte division is responsible for liver regeneration after most causes of injury. However, stem cells may contribute to hepatocyte regeneration, or even take over this role if the liver injury is severe and associated with an impairment of hepatocyte proliferation as in cirrhosis or submassive/massive necrosis, due to drugs, toxins or viruses. "Oval" cells are the descendants of the stem cells and are found in the portal and periportal regions in experimental animals within days of the liver injury. These cells proliferate to form narrow ductules, which may stain positively for biliary cytokeratins CK 19, and radiate out into the damaged parenchyma. Both in vitro and in vivo animal studies now suggest that oval cells can differentiate into bile ductular cells or hepatocytes to allow repopulation of the injured liver. As the oval cells differentiate into hepatocytes they may show positive staining for pyruvate kinase isoenzyme L-PK, albumin and alpha-fetoprotein. There is also growing evidence that bone marrow stem cells may contribute to liver regeneration. The possible involvement of hepatic stem cells in the development of dysplastic nodules, hepatocellular carcinoma and cholangiocarcinoma has been suggested but remains highly controversial. Oval cell isolation and culture techniques, together with stem cell transplantation strategies, may in the future provide novel treatments for individuals with inherited and acquired hepatic disorders.
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Affiliation(s)
- C J Vessey
- Department of Anatomical Pathology, University of Cape Town, South Africa
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32
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Kiss A, Schnur J, Szabó Z, Nagy P. Immunohistochemical analysis of atypical ductular reaction in the human liver, with special emphasis on the presence of growth factors and their receptors. LIVER 2001; 21:237-46. [PMID: 11454186 DOI: 10.1034/j.1600-0676.2001.021004237.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIMS/BACKGROUND The objective of this study was to characterize the expression of transforming growth factor-alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met, transforming growth factor-beta/Type I-II transforming growth factor-beta receptors, stem cell factor, urokinase plasminogen activator, smooth muscle actin, CD34 and alpha-fetoprotein in human liver samples with (sub)massive necrosis of different etiology containing atypical ductular reaction. METHODS Their presence was studied by immunohistochemistry on paraffin-embedded tissue sections. RESULTS Transforming growth factor-alpha and -beta, hepatocyte growth factor and their receptors were demonstrated in the ductules; additionally stem cell factor and urokinase plasminogen activator were also expressed. The atypical ductules were surrounded by smooth muscle actin-positive activated stellate cells. CONCLUSION These phenotypic similarities confirm that the atypical ductules in the human liver may be equivalent of oval cells in the rat liver, which are regarded as the progeny of stem cells. That is, the atypical ductular proliferation may correspond to a stem cell-fed regenerative process.
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Affiliation(s)
- A Kiss
- Ist Institute of Pathology and Experimental Cancer Research, Semmelweis Medical School, Budapest, Hungary
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33
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Chung YH, Kim JA, Song BC, Lee GC, Koh MS, Lee YS, Lee SG, Suh DJ. Expression of transforming growth factor-alpha mRNA in livers of patients with chronic viral hepatitis and hepatocellular carcinoma. Cancer 2000; 89:977-82. [PMID: 10964327 DOI: 10.1002/1097-0142(20000901)89:5<977::aid-cncr6>3.0.co;2-i] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Transforming growth factor-alpha (TGFalpha) is an important autocrine growth factor of hepatocytes. The authors evaluated the roles of TGFalpha in chronic viral hepatitis (CVH) and hepatocellular carcinoma (HCC). METHODS The authors measured the amounts of TGFalpha mRNA in liver tissues from 18 patients with HCC, 31 patients with CVH, and 7 normal controls. " Hot-start" reverse transcription-polymerase chain reaction (RT-PCR) using oligo-dT and specific primers detected TGFalpha mRNA in total cellular RNA extracted from liver tissues. The levels of TGFalpha mRNA were determined by the end point titers of serial, two-fold dilutions of cDNA. The amounts of hepatitis B virus RNA (HBV-RNA) in livers of patients with chronic hepatitis B also were measured by Northern blot hybridization. RESULTS TGFalpha mRNA levels were extremely higher in patients with HCC compared with patients with CVH and normal controls, and the levels in patients with CVH also were elevated compared with normal controls. The levels of TGFalpha mRNA were overexpressed in the underlying livers of patients with HCC compared with patients with CVH, although they were lower than those found in HCC tissues. The levels of TGFalpha mRNA were higher in samples from patients with chronic hepatitis B than in samples from patients with chronic hepatitis C. The levels of TGFalpha mRNA were not correlated with serum alanine aminotransferase or HBV-RNA levels in liver tissues in patients with chronic hepatitis B. However, the expression of TGFalpha mRNA tended to be higher in the livers of patients with raised serum alpha-fetoprotein levels. CONCLUSIONS The overexpression of TGFalpha mRNA in the liver seems to be associated with the regeneration of hepatocytes rather than hepatic necrosis or viral replication. Also, it may be related closely to the development or progression of HCC, especially in the livers of patients with chronic hepatitis B.
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Affiliation(s)
- Y H Chung
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
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34
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Libbrecht L, Desmet V, Van Damme B, Roskams T. The immunohistochemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells. J Hepatol 2000; 33:76-84. [PMID: 10905589 DOI: 10.1016/s0168-8278(00)80162-2] [Citation(s) in RCA: 124] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS In previous studies we found strong evidence for the existence and activation in human liver of putative progenitor cells resembling oval cells in rat liver. In view of the known role of rat oval cells in regeneration and hepatocarcinogenesis, we investigated a possible correlation between human putative progenitor cells and different types of dysplastic foci. METHODS We determined the immunohistochemical phenotype of dysplastic foci found in 20 cirrhotic liver explants of various etiology, using specific antibodies against hepatocyte-type cytokeratin (CK) 8 and CK18, bile duct-type CK7 and CK19, chromogranin-A (chrom-A) and rat oval cell marker OV-6. RESULTS All 12 foci of large cell dysplasia had a phenotype similar to that of surrounding parenchyma. Oncocytic foci showed a strong cytoplasmic staining for CK7. Three out of six of these foci contained "progenitor cells", which are small cells immunoreactive for CK18, CK7, CK19, OV-6, chrom-A and stained more intensely for CK8 than surrounding hepatocytes. Four out of eight glycogen-storing foci contained CK7-positive intermediate hepatocyte-like cells and "progenitor cells". Sixteen out of 29 small cell dysplastic foci consisted of "progenitor cells" and intermediate hepatocyte-like cells which were immunoreactive for CK7, CK18, OV-6, chrom-A and showed a stronger cytoplasmic positivity for CK8 than surrounding hepatocytes. CONCLUSIONS Foci of large cell dysplasia show no correlation with putative progenitor cells. Half of the oncocytic and glycogen-storing foci contain "progenitor cells", while more than half of the foci of small cell dysplasia consist of small cells with the same immunohistochemical phenotype as putative progenitor cells and intermediate hepatocyte-like cells, suggesting that differentiating putative progenitor cells can give rise to foci of small cell dysplasia.
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Affiliation(s)
- L Libbrecht
- Laboratory for Histo- and Cytochemistry, University of Leuven, Belgium.
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35
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Yin L, Lynch D, Sell S. Participation of different cell types in the restitutive response of the rat liver to periportal injury induced by allyl alcohol. J Hepatol 1999; 31:497-507. [PMID: 10488710 DOI: 10.1016/s0168-8278(99)80043-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIM Restitution of periportal liver necrosis induced by allyl alcohol involves proliferation and differentiation of putative liver stem cells. The participation of different non-epithelial cell types required to restore the liver cord structure in this process has not been well documented. The aim of the study was to determine the anatomic relationships among cells of liver lineage, extracellular matrix, and non-parenchymal cells during repair of periportal liver injury. METHODS Periportal liver injury in rats was induced by intraperitoneal injection of allyl alcohol. Cells of the liver lineage, as well as Kupffer cells, hepatic stellate cells, macrophages, and the extracellular matrix components fibronectin and laminin were localized using immunohistologic methods for 7 days after injury. RESULTS During the first day there was loss of periportal hepatocytes, as well as sinusoidal nonparenchymal cells, including macrophages, Kupffer cells and hepatic stellate cells. After day 1 macrophages appeared within the necrotic zone, increased until days 3-4, and then decreased to a few cells within reappearing sinusoids. At days 2-5 there was first proliferation of small "null" intraportal cells, which later acquired markers of ductular (OV-6, CKPan ) and liver cell differentiation (alphafetoprotein, carbamoylphosphate synthetase-I), eventually assuming mature hepatocyte morphology. There was also moderate bile duct hyperplasia with extension of small newly-formed ducts from the intraportal zone into the immediate periportal zone. Kupffer cells and hepatic stellate cells became enlarged at the borders of the necrotic and non-necrotic central zone and then appeared to migrate into the oval cell population expanding across the periportal zone. During the restitution phase, hepatic stellate cells were closely associated with the proliferating oval cells, surrounding small aggregates of oval cells which appeared to be forming liver cords. Kupffer cells also stained for fibronectin, and fibronectin was seen at the intersection of the injured portal and uninjured central zones and around the expanding oval cells. In some intraportal zones, the laminin surrounding the bile ducts was lost. It was speculated that this may permit proliferating ductular cells to migrate out of the bile ducts into the periportal zone. By days 6 and 7 most of the injured liver was restored to normal, with a few foci of chronic inflammation remaining. CONCLUSIONS There is a close anatomic relationship between immature liver lineage cells (oval/duct cells) and non-parenchymal cells during the restitutive repair of periportal injury. The nature of this relationship to the possible production of growth factors and expression of growth factor receptors by the cells involved during the restitution process is discussed.
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Affiliation(s)
- L Yin
- Department of Pathology and Laboratory Medicine, Albany Medical College, NY 12208-3479, USA
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36
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Sell S. Comparison of liver progenitor cells in human atypical ductular reactions with those seen in experimental models of liver injury. Hepatology 1998; 27:317-31. [PMID: 9462626 DOI: 10.1002/hep.510270202] [Citation(s) in RCA: 117] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The ultrastructural characteristics of liver progenitor cell types of human atypical ductular reactions seen in chronic cholestasis, in regenerating human liver after submassive necrosis, in alcoholic liver disease, and in focal nodular hyperplasia are compared with liver progenitor cell types seen during experimental cholangiocarcinogenesis in hamsters; during hepatocarcinogenesis in rats; and in response to periportal liver injury induced by allyl alcohol in rats. Three types of progenitor cells have been identified in human atypical ductular reactions: type I: primitive, has an oval shape, marginal chromatin, few cellular organelles, rare tonofilaments, and forms desmosomal junctions with adjacent liver cells; type II: bile duct-like, is located within ducts, has few organelles, and forms lateral membrane interdigitations with other duct-like cells; and type III: hepatocyte-like, is located in hepatic cords, forms a bile canaliculus, has tight junctions with other hepatocyte-like cells, prominent mitochondria and rough endoplasmic reticulum, and some have lysosomes and a poorly developed Golgi apparatus. Each type is seen during cholangiocarcinogenesis in hamsters, but the most prominent cell type is type II, duct-like. A more primitive cell type ("type 0 cell"), as well as type I cells, are seen in the intraportal zone of the liver within 1 to 2 days after carcinogen exposure or periportal injury in the rat, but both type II and type III are seen later as the progenitor cells expand into the liver lobule. After allyl alcohol injury, type 0 cells precede the appearance of type I and type III cells, but most of the cells that span the periportal necrotic zone are type III hepatocyte-like cells showing different degrees of hepatocytic differentiation. Some type II cells are also seen, but these are essentially limited to ducts. It is concluded that there is a primitive stem cell type in the liver (type 0) that may differentiate directly into type I and then into type II, duct-like or or type III hepatocyte-like cells. The terms oval cell, transitional hepatocyte, biliary hepatocyte, hepatocyte-like cell, atypical ductular cell, neocholangiole, etc., are used to describe these cells. Although these terms are useful as general descriptive terms for liver precursor cells at the light microscopic level, the cells included in these descriptive categories may be very different from one another biologically and ultrastructurally.
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Affiliation(s)
- S Sell
- Department of Pathology and Laboratory Medicine, Albany Medical College, NY 12209-3479, USA
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37
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Isfort RJ, Cody DB, Richards WG, Yoder BK, Wilkinson JE, Woychik RP. Characterization of growth factor responsiveness and alterations in growth factor homeostasis involved in the tumorigenic conversion of mouse oval cells. Growth Factors 1998; 15:81-94. [PMID: 9505165 DOI: 10.3109/08977199809117185] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Five mouse oval cell lines were investigated in regards to their growth and differentiation factor (GDF) responsiveness and to changes in their GDF responsiveness following tumorigenic conversion. In all 59 GDFs and 11 comitogens were evaluated with variable responsiveness, depending on the mouse oval cell line under study, observed. Analysis of oval cell GDF responsiveness during tumorigenic conversion revealed that tumorigenic variants displayed alterations in GDF responsiveness which correlated with tumorigenicity. In addition, analysis of autocrine/paracrine growth factor production demonstrates that most tumorigenic variants produce growth factors. These studies demonstrate for the first time that (1) mouse oval cells respond to a wide variety of GDFs including various members of the interleukin, chemokine, stem cell factor, EGF, FGF, PDGF, TGF-beta, VEGF, insulin, CSF, TNF, HGF, and IFN growth and differentiation factor families in addition to multiple comitogens and (2) during tumorigenic conversion mouse oval cells undergo alterations which result in both alterations in GDF responsiveness and the autocrine/paracrine production of multiple GDFs.
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Affiliation(s)
- R J Isfort
- Procter and Gamble Company, Miami Valley Laboratories, Cincinnati, Ohio 45239-8707, USA
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Tsai JF, Chuang LY, Jeng JE, Yang ML, Chang WY, Hsieh MY, Lin ZY, Tsai JH. Clinical relevance of transforming growth factor-beta 1 in the urine of patients with hepatocellular carcinoma. Medicine (Baltimore) 1997; 76:213-26. [PMID: 9193456 DOI: 10.1097/00005792-199705000-00007] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
To assess the clinical relevance of transforming growth factor-beta 1 (TGF-beta 1) in the urine of patients with hepatocellular carcinoma (HCC), TGF-beta 1 was measured, by radioimmunoassay, in 140 patients with HCC, 50 cirrhotic patients, 30 patients with chronic active hepatitis, and 50 healthy controls. The results indicate that there were significantly increased urinary TGF-beta 1 levels in patients with HCC. Raised TGF-beta 1 levels were associated, in a dose-related fashion, with increased risk for development of HCC (odds ratio, 1.05, 95% confidence interval, 1.03-1.07). HCC patients with raised TGF-beta 1 levels had shorter survival than those with normal TGF-beta 1 levels (p = 0.038). TGF-beta 1 levels decreased after successful anticancer therapy (p < 0.0001). There was an inverse correlation between TGF-beta 1 and serum alpha-fetoprotein (AFP) (r = -0.199, p < 0.04). Receiver operating characteristics (ROC) curve analysis indicated that parallel determination of TGF-beta 1 and AFP significantly increased the sensitivity and diagnostic accuracy, with a high specificity. In conclusion, raised urinary TGF-beta 1 was associated with HCC development. It is a predictor of poor prognosis, and a tumor marker for diagnosis and therapeutic follow-up of HCC.
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Affiliation(s)
- J F Tsai
- Department of Internal Medicine, Kaohsiung Medical College, Taiwan
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Abstract
We consider a cellular model of infection by the hepatitis B virus and describe how it may be used to account for two important features of the disease, namely (i) the wide variety of manifestations of infection and the age dependence thereof, and (ii) the typically long delay before the development of virus-induced liver cancer (primary hepatocellular carcinoma). The model is based on the assumption that the liver is comprised of both immature and mature hepatocytes, with these two subpopulations of cells responding contrastingly upon infection by the virus.
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Affiliation(s)
- R J Payne
- Department of Zoology, University of Oxford, United Kingdom
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40
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Bisgaard HC, Thorgeirsson SS. Hepatic Regeneration: The Role of Regeneration in Pathogenesis of Chronic Liver Diseases. Clin Lab Med 1996. [DOI: 10.1016/s0272-2712(18)30272-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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41
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Affiliation(s)
- V Desmet
- Laboratory of Histo- and Cytochemistry, University Hospital St. Rafael, University of Leuven, Belgium
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