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Kim EM, Hong ST. Clonorchis sinensis and Cholangiocarcinoma. J Korean Med Sci 2025; 40:e145. [PMID: 40296827 PMCID: PMC12040606 DOI: 10.3346/jkms.2025.40.e145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
Clonorchiasis is a parasitic disease caused by Clonorchis sinensis, a trematode that inhabits the intrahepatic bile ducts of humans and mammals. C. sinensis is one of common food-borne trematodes, prevalent in East Asia including Korea. The International Agency for Research on Cancer reclassified C. sinensis as the Group 1 biological carcinogen of human cholangiocarcinoma (CCA). Evidence supporting the carcinogenicity of C. sinensis includes epidemiological studies showing increased prevalence and odds ratio (OR) of CCA in clonorchiasis patients, the development of CCA in experimental animals, and molecular studies. Approximately 10% of CCA in Korea are believed to be solely caused by clonorchiasis, with an OR of 4.7 for CCA risk among clonorchiasis patients. All hamsters exposed to both of C. sinensis and N-nitrosodimethylamine (NDMA) developed CCA while those exposed to either C. sinensis or NDMA alone did not. In vitro studies using cell models investigated carcinogenetic changes of the intracellular molecules and genes following stimulation with a soluble extract of C. sinensis. The in vitro stimulated cells showed a significant shift to G2/M phage, produced oncogenic molecules, changed expression of oncogenes, increased cell proliferation and suppressed apoptosis. Additionally, the gap-junction proteins between cells, such as connexin (Cx) 43, Cx 26, and Cx 32, were changed significantly, disrupting intercellular homeostasis. These findings suggest that C. sinensis and nitrogen compounds synergistically stimulate the cholangiocytes to become neoplastic. C. sinensis is a biological carcinogen of human CCA, and the World Health Organization guidelines enlist food-borne trematodes as one of target neglected tropical diseases to be eliminated by 2030. The present article reviews and updates perspectives on clonorchiasis, focusing on carcinogenesis.
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Affiliation(s)
- Eun-Min Kim
- Department of Microbiology, College of Medicine and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea
| | - Sung-Tae Hong
- Department of Tropical Medicine and Parasitology and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul, Korea.
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Alexander WB, Wang W, Hill MA, O'Dell MR, Ruffolo LI, Guo B, Jackson KM, Ullman N, Friedland SC, McCall MN, Patel A, Figueroa-Guilliani N, Georger M, Belt BA, Whitney-Miller CL, Linehan DC, Murphy PJ, Hezel AF. Smad4 restricts injury-provoked biliary proliferation and carcinogenesis. Dis Model Mech 2024; 17:dmm050358. [PMID: 38415925 PMCID: PMC10924230 DOI: 10.1242/dmm.050358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/10/2023] [Indexed: 02/29/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFβ/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.
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Affiliation(s)
- William B. Alexander
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Medicine, Hematology/Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Wenjia Wang
- Department of Medicine, Hematology/Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Margaret A. Hill
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Medicine, Hematology/Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Michael R. O'Dell
- Department of Medicine, Hematology/Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Luis I. Ruffolo
- Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Bing Guo
- Department of Medicine, Hematology/Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Katherine M. Jackson
- Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Nicholas Ullman
- Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Scott C. Friedland
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Medicine, Hematology/Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Matthew N. McCall
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Ankit Patel
- Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA
| | | | - Mary Georger
- Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Brian A. Belt
- Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Christa L. Whitney-Miller
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - David C. Linehan
- Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Patrick J. Murphy
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Aram F. Hezel
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Medicine, Hematology/Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
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Faccioli LA, Dias ML, Martins-Santos R, Paredes BD, Takiya CM, dos Santos Goldenberg RC. Resident Liver Stem Cells. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:23-51. [DOI: 10.1016/b978-0-443-15289-4.00015-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Jantawong C, Chamgramol Y, Intuyod K, Priprem A, Pairojkul C, Klungsaeng S, Dangtakot R, Pongking T, Sitthirach C, Pinlaor P, Waraasawapati S, Pinlaor S. Curcumin-loaded nanocomplexes alleviate the progression of fluke-related cholangiocarcinoma in hamsters. Cancer Nanotechnol 2023. [DOI: 10.1186/s12645-023-00155-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Abstract
Background
Curcumin-loaded nanocomplexes (CNCs) previously demonstrated lower toxicity and extended release better than is the case for free curcumin. Here, we evaluated the efficacy of CNCs against opisthorchiasis-associated cholangiocarcinoma (CCA) in hamsters.
Method
Dose optimization (dose and frequency) was performed over a 1-month period using hamsters, a model that is widely used for study of opisthorchiasis-associated cholangiocarcinoma. In the main experimental study, CCA was induced by a combination of fluke, Opisthorchis viverrini (OV), infection and N-nitrosodimethylamine (NDMA) treatment. Either blank (empty) nanocomplexes (BNCs) or different concentrations of CNCs (equivalent to 10 and 20 mg cur/kg bw) were given to hamsters thrice a week for 5 months. The histopathological changes, biochemical parameters, and the expression of inflammatory/oncogenic transcription factors were investigated. In addition, the role of CNCs in attenuating CCA genesis, as seen in an animal model, was also confirmed in vitro using CCA cell lines.
Results
The optimization study revealed that treatment with CNCs at a dose equivalent to 10 mg cur/kg bw, thrice a week for 1 month, led to a greater reduction of inflammation and liver injury induced in hamsters by OV + NDMA than did treatments at other dose rates. Oral administration with CNCs (10 mg cur/kg bw), thrice a week for 5 months, significantly increased survival rate, reduced CCA incidence, extent of tumor development, cholangitis, bile duct injury and cholangiofibroma. In addition, this treatment decreased serum ALP and ALT activities and suppressed expression of NF-κB, FOXM1, HMGB1, PCNA and formation of 8-nitroguanine. Treatment of CCA cell lines with CNCs also reduced cell proliferation and colony formation, similar to those treated with NF-κB and/or FOXM1 inhibitors.
Conclusion
CNCs (10 mg cur/kg bw) attenuate the progression of fluke-related CCA in hamsters partly via a NF-κB and FOXM1-mediated pathway.
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Jia Y, Wang Y, Dunmall LSC, Lemoine NR, Wang P, Wang Y. Syrian hamster as an ideal animal model for evaluation of cancer immunotherapy. Front Immunol 2023; 14:1126969. [PMID: 36923404 PMCID: PMC10008950 DOI: 10.3389/fimmu.2023.1126969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 02/09/2023] [Indexed: 03/02/2023] Open
Abstract
Cancer immunotherapy (CIT) has emerged as an exciting new pillar of cancer treatment. Although benefits have been achieved in individual patients, the overall response rate is still not satisfactory. To address this, an ideal preclinical animal model for evaluating CIT is urgently needed. Syrian hamsters present similar features to humans with regard to their anatomy, physiology, and pathology. Notably, the histological features and pathological progression of tumors and the complexity of the tumor microenvironment are equivalent to the human scenario. This article reviews the current tumor models in Syrian hamster and the latest progress in their application to development of tumor treatments including immune checkpoint inhibitors, cytokines, adoptive cell therapy, cancer vaccines, and oncolytic viruses. This progress strongly advocates Syrian hamster as an ideal animal model for development and assessment of CIT for human cancer treatments. Additionally, the challenges of the Syrian hamster as an animal model for CIT are also discussed.
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Affiliation(s)
- Yangyang Jia
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yanru Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Louisa S Chard Dunmall
- Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Nicholas R. Lemoine
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
- Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Pengju Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yaohe Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
- Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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Troglitazone inhibits hepatic oval cell proliferation by inducing cell cycle arrest through Hippo/YAP pathway regulation. Dig Liver Dis 2022; 54:791-799. [PMID: 34531129 DOI: 10.1016/j.dld.2021.08.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 08/21/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022]
Abstract
Hepatic oval cells have strong proliferation and differentiation capabilities and are activated when chronic liver injury occurs or when liver function is severely impaired. Peroxisome proliferation-activated receptors (PPARs) are ligand-dependent, sequence-specific nuclear transcription factors. PPARγ is closely related to liver diseases (such as liver cancer, liver fibrosis and non-alcoholic fatty liver disease). As the main effector downstream of the Hippo signaling pathway, YAP can activate the hepatic progenitor cell program, and different expression or activity levels of YAP can determine different liver cell fates. We found that troglitazone (TRO), a classic PPARγ activator, can inhibit the growth of hepatic oval cells, and flow cytometry results showed that TRO inhibited the growth of WB-F344 cells by arresting the cells in the G0/1 phase. Western blot results also confirmed changes in G0/1 phase-related protein expression. Further experiments showed that PPARγ agonists induced hepatic oval cell proliferation inhibition and cell cycle G0/1 phase arrest through the Hippo/YAP pathway. Our experiment demonstrated, for the first time, the relationship between PPARγ and the Hippo/YAP pathway in liver oval cells and revealed that PPARγ acts as a negative regulator of liver regeneration by inhibiting the proliferation of oval cells.
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In Vivo Models for Cholangiocarcinoma-What Can We Learn for Human Disease? Int J Mol Sci 2020; 21:ijms21144993. [PMID: 32679791 PMCID: PMC7404171 DOI: 10.3390/ijms21144993] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/10/2020] [Accepted: 07/13/2020] [Indexed: 12/11/2022] Open
Abstract
Cholangiocarcinoma (CCA) comprises a heterogeneous group of primary liver tumors. They emerge from different hepatic (progenitor) cell populations, typically via sporadic mutations. Chronic biliary inflammation, as seen in primary sclerosing cholangitis (PSC), may trigger CCA development. Although several efforts were made in the last decade to better understand the complex processes of biliary carcinogenesis, it was only recently that new therapeutic advances have been achieved. Animal models are a crucial bridge between in vitro findings on molecular or genetic alterations, pathophysiological understanding, and new therapeutic strategies for the clinic. Nevertheless, it is inherently difficult to recapitulate simultaneously the stromal microenvironment (e.g., immune-competent cells, cholestasis, inflammation, PSC-like changes, fibrosis) and the tumor biology (e.g., mutational burden, local growth, and metastatic spread) in an animal model, so that it would reflect the full clinical reality of CCA. In this review, we highlight available data on animal models for CCA. We discuss if and how these models reflect human disease and whether they can serve as a tool for understanding the pathogenesis, or for predicting a treatment response in patients. In addition, open issues for future developments will be discussed.
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Loeuillard E, Fischbach SR, Gores GJ, Ilyas SI. Animal models of cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis 2019; 1865:982-992. [PMID: 29627364 PMCID: PMC6177316 DOI: 10.1016/j.bbadis.2018.03.026] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 03/23/2018] [Accepted: 03/29/2018] [Indexed: 12/18/2022]
Abstract
Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with a poor overall prognosis. There is a critical need to develop effective targeted therapies for the treatment of this lethal disease. In an effort to address this challenge, preclinical in vivo studies have become paramount in understanding CCA carcinogenesis, progression, and therapy. Various CCA animal models exist including carcinogen-based models in which animals develop CCA after exposure to a carcinogen, genetically engineered mouse models in which genetic changes are induced in mice leading to CCA, murine syngeneic orthotopic models, as well as xenograft tumors derived from xenotransplantation of CCA cells, organoids, and patient-derived tissue. Each type has distinct advantages as well as shortcomings. In the ideal animal model of CCA, the tumor arises from the biliary tract in an immunocompetent host with a species-matched tumor microenvironment. Such a model would also be time-efficient, recapitulate the genetic and histopathological features of human CCA, and predict therapeutic response in humans. Recently developed biliary tract transduction and orthotopic syngeneic transplant mouse models encompass several of these elements. Herein, we review the different animal models of CCA, their advantages and deficiencies, as well as features which mimic human CCA.
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Affiliation(s)
- Emilien Loeuillard
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Samantha R Fischbach
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
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Crawford DR, Ilic Z, Guest I, Milne GL, Hayes JD, Sell S. Characterization of liver injury, oval cell proliferation and cholangiocarcinogenesis in glutathione S-transferase A3 knockout mice. Carcinogenesis 2017; 38:717-727. [PMID: 28535182 DOI: 10.1093/carcin/bgx048] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
We recently generated glutathione S-transferase (GST) A3 knockout (KO) mice as a novel model to study the risk factors for liver cancer. GSTA3 KO mice are sensitive to the acute cytotoxic and genotoxic effects of aflatoxin B1 (AFB1), confirming the crucial role of GSTA3 in resistance to AFB1. We now report histopathological changes, tumor formation, biochemical changes and gender response following AFB1 treatment as well as the contribution of oxidative stress. Using a protocol of weekly 0.5 mg AFB1/kg administration, we observed extensive oval (liver stem) cell (OC) proliferation within 1-3 weeks followed by microvesicular lipidosis, megahepatocytes, nuclear inclusions, cholangiomas and small nodules. Male and female GSTA3 KO mice treated with 12 and 24 weekly AFB1 injections followed by a rest period of 12 and 6 months, respectively, all had grossly distorted livers with macro- and microscopic cysts, hepatocellular nodules, cholangiomas and cholangiocarcinomas and OC proliferation. We postulate that the prolonged AFB1 treatment leads to inhibition of hepatocyte proliferation, which is compensated by OC proliferation and eventually formation of cholangiocarcinoma (CCA). At low-dose AFB1, male KO mice showed less extensive acute liver injury, OC proliferation and AFB1-DNA adducts than female KO mice. There were no significant compensatory changes in KO mice GST subunits, GST enzymatic activity, epoxide hydrolase, or CYP1A2 and CYP3A11 levels. Finally, there was a modest increase in F2-isoprostane and isofuran in KO mice that confirmed putative GSTA3 hydroperoxidase activity in vivo for the first time.
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Affiliation(s)
- Dana R Crawford
- Albany Medical Center, Department of Immunology and Microbial Disease, 43 New Scotland Avenue, Albany, NY 12208, USA
| | - Zoran Ilic
- Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA
| | - Ian Guest
- Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA
| | - Ginger L Milne
- Vanderbilt University School of Medicine, Department of Medicine and Pharmacology, Nashville, TN 37323, USA
| | - John D Hayes
- Division of Cancer Research, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK
| | - Stewart Sell
- Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA
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Shi Y, Jiang Z, Yang Y, Zheng P, Wei H, Lin Y, Lv G, Yang Q. Clonorchis sinensis infection and co-infection with the hepatitis B virus are important factors associated with cholangiocarcinoma and hepatocellular carcinoma. Parasitol Res 2017; 116:2645-2649. [PMID: 28801696 PMCID: PMC5599464 DOI: 10.1007/s00436-017-5572-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 07/26/2017] [Indexed: 01/08/2023]
Abstract
To evaluate the contributions of Clonorchis sinensis and hepatitis B virus to the development of cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), C. sinensis and hepatitis B virus infections in 20 clinical liver cancer cases from a C. sinensis- and hepatitis B virus-epidemic region were detected. Eight cases of ICC, 11 cases of HCC and one mixed ICC and HCC case were verified by CT, pathological section and (or) observations during surgery. The C. sinensis infection was detected by stool microscopy and ELISA, and the worms and eggs found during surgery and in pathological sections also allowed for diagnoses. Hepatitis B virus infections were detected by ELISA. In the 20 cases, 18 patients were diagnosed with C. sinensis infections. Eight of the 20 patients were infected with the hepatitis B virus, and seven were co-infected with C. sinensis. In the eight ICC patients, seven were diagnosed with C. sinensis infection, and two had mixed infections with the hepatitis B virus. In the 11 HCC patients, 10 were diagnosed with C. sinensis, four had mixed infections with the hepatitis B virus, and only one HCC patient presented a single infection by the hepatitis B virus. These clinical observations revealed that C. sinensis infection and C. sinensis co-infection with the hepatitis B virus are important factors in ICC and HCC.
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Affiliation(s)
- Yunliang Shi
- Institute of Parasitic Disease Prevention and Control, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, 18, Jinzhou Rd, Nanning, Guangxi, 530028, China
| | - Zhihua Jiang
- Institute of Parasitic Disease Prevention and Control, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, 18, Jinzhou Rd, Nanning, Guangxi, 530028, China
| | - Yichao Yang
- Institute of Parasitic Disease Prevention and Control, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, 18, Jinzhou Rd, Nanning, Guangxi, 530028, China.
| | - Peiqiu Zheng
- Hengxian People's Hospital, Nanning, 530300, China
| | - Haiyan Wei
- Institute of Parasitic Disease Prevention and Control, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, 18, Jinzhou Rd, Nanning, Guangxi, 530028, China
| | - Yuan Lin
- Institute of Parasitic Disease Prevention and Control, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, 18, Jinzhou Rd, Nanning, Guangxi, 530028, China
| | - Guoli Lv
- Institute of Parasitic Disease Prevention and Control, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, 18, Jinzhou Rd, Nanning, Guangxi, 530028, China
| | - Qingli Yang
- Institute of Parasitic Disease Prevention and Control, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, 18, Jinzhou Rd, Nanning, Guangxi, 530028, China
- Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning, 530028, China
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Woo H, Han JK, Kim JH, Hong ST, Uddin MH, Jang JJ. In-vivo monitoring of development of cholangiocarcinoma induced with C. sinensis and N-nitrosodimethylamine in Syrian golen hamsters using ultrasonography and magnetic resonance imaging: a preliminary study. Eur Radiol 2016; 27:1740-1747. [PMID: 27510623 DOI: 10.1007/s00330-016-4510-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 07/14/2016] [Accepted: 07/18/2016] [Indexed: 01/31/2023]
Abstract
OBJECTIVES The purpose of this study is to evaluate high-resolution ultrasound and magnetic resonance imaging (MRI) in monitoring of cholangiocarcinoma in the hamsters with C. sinensis infection and N-nitrosodimethylamine (NDMA). MATERIALS AND METHODS Twenty-four male Syrian golden hamsters of were divided into four groups composed of five hamsters as control, five hamsters receiving 30 metacercariae of C. sinensis per each hamster, five hamsters receiving NDMA in drinking water, and nine hamsters receiving both metacercariae and NDMA. Ultrasound was performed every other week from baseline to the 12th week of infection. MRI and histopathologic examination was done from the 4th week to 12th week. RESULTS Cholangiocarcinomas appeared as early as the 6th week of infection. There were 12 cholangiocarcinomas, nine and ten of which were demonstrated by ultrasound and MRI, respectively. Ultrasound and MRI findings of cholangiocarcinomas in the hamsters were similar to those of the mass-forming intrahepatic cholangiocarcinomas in humans. Ultrasound and MRI also showed other findings of disease progression such as periductal increased echogenicity or signal intensity, ductal dilatation, complicated cysts, and sludges in the gallbladder. CONCLUSIONS High-resolution ultrasound and MRI can monitor and detect the occurrence of cholangiocarcinoma in the hamsters non-invasively. KEY POINTS • High-resolution ultrasound and MRI can monitor occurrence of cholangiocarcinoma in the hamsters. • Cholangiocarcinomas were detected as early as the 6th week after C. sinensis infection. • Axial T2-weighted MRI demonstrated cholangiocarcinomas and various inflammatory findings in the hamsters.
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Affiliation(s)
- Hyunsik Woo
- Department of Radiology, SMG-SNU Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, Korea
| | - Joon Koo Han
- Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
| | - Jung Hoon Kim
- Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Sung-Tae Hong
- Department of Parasitology, College of Medicine, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Md Hafiz Uddin
- Adult Stem Cell Research Center, Laboratory of Stem Cell and Tumor Biology, Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea
| | - Ja-June Jang
- Department of Pathology, College of Medicine, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
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Wang X, Hu F, Hu X, Chen W, Huang Y, Yu X. Proteomic identification of potential Clonorchis sinensis excretory/secretory products capable of binding and activating human hepatic stellate cells. Parasitol Res 2014; 113:3063-71. [PMID: 24894083 DOI: 10.1007/s00436-014-3972-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 05/25/2014] [Indexed: 01/21/2023]
Abstract
Epidemiological and experimental evidence demonstrated that Clonorchis sinensis is an important risk factor of hepatic fibrosis and cholangiocarcinoma. C. sinensis excretory/secretory products (CsESPs) are protein complex including proteases, antioxidant enzymes, and metabolic enzymes, which may contribute to pathogenesis of liver fluke-associated hepatobiliary diseases. However, potential CsESP candidates involved into hepatic fibrosis and cholangiocarcinoma still remain to be elucidated. In the present study, we performed proteomic identification of CsESP candidates capable of binding and activating human hepatic stellate cell line LX-2. Immunofluorescence analysis confirmed the interaction of CsESPs with LX-2 cell membrane. LX-2 cells could be stimulated by CsESPs from 24 h post incubation (p < 0.05). Specifically, 50 μg/ml of CsESPs showed the strongest effect on cell proliferation in methyl thiazolyl tetrazolium (MTT) assay which could also be demonstrated by flow cytometry analysis (p < 0.01). Furthermore, expression level of human type III collagen in LX-2 cells treated with CsESPs was significantly higher than that in control cells measured by molecular beacon and semiquantitative reverse transcription (RT)-PCR approaches (p < 0.01). Finally, CsESPs before and after incubation with LX-2 cells were subjected to two-dimensional gel electrophoresis (2-DE) analysis and matrix associated laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry analysis. Nine proteins with abundance change above threefold were Rho GTPase-activating protein, mitochondrial cytochrome c oxidase subunit Va, α-enolase, phospholipase C, interleukin-15, insect-derived growth factor, cytochrome c oxidase subunit VI, DNAH1 protein, and kinesin light chain. Taken together, we identified potential CsESP candidates capable of binding and activating human hepatic stellate cells, providing more direct evidences that are previously unknown to accelerate strategies for C. sinensis prevention.
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Affiliation(s)
- Xiaoyun Wang
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, Guangdong Province, People's Republic of China
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13
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Oishi N, Kumar MR, Roessler S, Ji J, Forgues M, Budhu A, Zhao X, Andersen JB, Ye QH, Jia HL, Qin LX, Yamashita T, Woo HG, Kim YJ, Kaneko S, Tang ZY, Thorgeirsson SS, Wang XW. Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma. Hepatology 2012; 56:1792-803. [PMID: 22707408 PMCID: PMC3458130 DOI: 10.1002/hep.25890] [Citation(s) in RCA: 190] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2011] [Accepted: 05/19/2012] [Indexed: 12/14/2022]
Abstract
UNLABELLED Intrahepatic cholangiocellular carcinoma (ICC) is the second most common type of primary liver cancer. However, its tumor heterogeneity and molecular characteristics are largely unknown. In this study, we conducted transcriptomic profiling of 23 ICC and combined hepatocellular cholangiocarcinoma tumor specimens from Asian patients using Affymetrix messenger RNA (mRNA) and NanoString microRNA microarrays to search for unique gene signatures linked to tumor subtypes and patient prognosis. We validated the signatures in an additional 68 ICC cases derived from Caucasian patients. We found that both mRNA and microRNA expression profiles could independently classify Asian ICC cases into two main subgroups, one of which shared gene expression signatures with previously identified hepatocellular carcinoma (HCC) with stem cell gene expression traits. ICC-specific gene signatures could predict survival in Asian HCC cases and independently in Caucasian ICC cases. Integrative analyses of the ICC-specific mRNA and microRNA expression profiles revealed that a common signaling pathway linking miR-200c signaling to epithelial-mesenchymal transition (EMT) was preferentially activated in ICC with stem cell gene expression traits. Inactivation of miR-200c resulted in an induction of EMT, whereas activation of miR-200c led to a reduction of EMT including a reduced cell migration and invasion in ICC cells. We also found that miR-200c and neural cell adhesion molecule 1 (NCAM1) expression were negatively correlated and their expression levels were predictive of survival in ICC samples. NCAM1, a known hepatic stem/progenitor cell marker, was experimentally demonstrated to be a direct target of miR-200c. CONCLUSION Our results indicate that ICC and HCC share common stem-like molecular characteristics and poor prognosis. We suggest that the specific components of EMT may be exploited as critical biomarkers and clinically relevant therapeutic targets for an aggressive form of stem cell-like ICC.
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Affiliation(s)
- Naoki Oishi
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Mia R. Kumar
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Stephanie Roessler
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Junfang Ji
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Marshonna Forgues
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Anuradha Budhu
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Xuelian Zhao
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jesper B. Andersen
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Qing-Hai Ye
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Hu-Liang Jia
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Lun-Xiu Qin
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Taro Yamashita
- Liver Disease Center and Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan
| | - Hyun Goo Woo
- Department of Physiology, Ajou University School of Medicine, Suwon
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Shuichi Kaneko
- Liver Disease Center and Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan
| | - Zhao-You Tang
- Liver Cancer Institute, Fudan University, Shanghai, China
| | - Snorri S. Thorgeirsson
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA,Address reprint request to: Xin Wei Wang, National Cancer Institute, 37 Convent Drive, Building 37, Room 3044A, Bethesda, MD 20892;
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14
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Uddin MH, Li S, Bae YM, Choi MH, Hong ST. Strain variation in the susceptibility and immune response to Clonorchis sinensis infection in mice. Parasitol Int 2011; 61:118-23. [PMID: 21763454 DOI: 10.1016/j.parint.2011.07.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Revised: 06/29/2011] [Accepted: 07/01/2011] [Indexed: 10/18/2022]
Abstract
Mice have shown various susceptibility to infection by Clonorchis sinensis. To compare the intra-specific variation in the host-parasite relationship of C. sinensis, 6 strains of mice (ICR, BALB/c, C57BL/6, DDY, CBA/N, and C3H/HeN) with 3 different haplotypes were evaluated on their susceptibility. The worm recovery rate and immunological responses were observed after 4 and 8 weeks of infection with 30 metacercariae. The highest worm recovery rate was observed as 20.7% in the C3H/HeN strain after 4 weeks of infection along with histopathological changes. The rate was 10.0% in C57BL/6 mice after 8 weeks. ICR, BALB/c, and CBA/N showed elevated levels of IgE at both time points when compared to the rest of the strains. The serum IgG1 and IgG2a levels were elevated in most of the strains; however, the C57BL/6 strain showed a lower level of IgG2a that indicated the IgG1 predominance over IgG2a. The production of IL-4 after concanavalin-A stimulation of splenocytes slightly increased among the mouse strains except C3H/HeN after 4 or 8 weeks of infection, but each strain produced high levels of IFN-γ after 8 weeks, which implied mixed Th1/Th2 responses. ICR, DDY, CBA/N, and C3H/HeN strains showed a significantly increased level of IL-10 after 8 weeks as compared to C57BL/6. All of the strains showed an increased level of IL-13 and suggested fibrotic changes in the mice. In conclusion, mice are insusceptible to infection with C. sinensis; however, the C57BL/6, BALB/c and ICR strains are relatively susceptible after 8 weeks of infection among the six strains. Worm expulsion may be one of the causes of low susceptibility of C3H/HeN mice strain at the 8th week. Elevated IgE, IFN-γ, and IL-13 of infected mice suggest both Th1 and Th2 responses that may be related to the low host susceptibility.
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Affiliation(s)
- Md Hafiz Uddin
- Department of Parasitology and Tropical Medicine, Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
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15
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Yoo WG, Kim DW, Ju JW, Cho PY, Kim TI, Cho SH, Choi SH, Park HS, Kim TS, Hong SJ. Developmental transcriptomic features of the carcinogenic liver fluke, Clonorchis sinensis. PLoS Negl Trop Dis 2011; 5:e1208. [PMID: 21738807 PMCID: PMC3125140 DOI: 10.1371/journal.pntd.0001208] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2011] [Accepted: 04/17/2011] [Indexed: 02/06/2023] Open
Abstract
Clonorchis sinensis is the causative agent of the life-threatening disease endemic to China, Korea, and Vietnam. It is estimated that about 15 million people are infected with this fluke. C. sinensis provokes inflammation, epithelial hyperplasia, and periductal fibrosis in bile ducts, and may cause cholangiocarcinoma in chronically infected individuals. Accumulation of a large amount of biological information about the adult stage of this liver fluke in recent years has advanced our understanding of the pathological interplay between this parasite and its hosts. However, no developmental gene expression profiles of C. sinensis have been published. In this study, we generated gene expression profiles of three developmental stages of C. sinensis by analyzing expressed sequence tags (ESTs). Complementary DNA libraries were constructed from the adult, metacercaria, and egg developmental stages of C. sinensis. A total of 52,745 ESTs were generated and assembled into 12,830 C. sinensis assembled EST sequences, and then these assemblies were further categorized into groups according to biological functions and developmental stages. Most of the genes that were differentially expressed in the different stages were consistent with the biological and physical features of the particular developmental stage; high energy metabolism, motility and reproduction genes were differentially expressed in adults, minimal metabolism and final host adaptation genes were differentially expressed in metacercariae, and embryonic genes were differentially expressed in eggs. The higher expression of glucose transporters, proteases, and antioxidant enzymes in the adults accounts for active uptake of nutrients and defense against host immune attacks. The types of ion channels present in C. sinensis are consistent with its parasitic nature and phylogenetic placement in the tree of life. We anticipate that the transcriptomic information on essential regulators of development, bile chemotaxis, and physico-metabolic pathways in C. sinensis that presented in this study will guide further studies to identify novel drug targets and diagnostic antigens.
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Affiliation(s)
- Won Gi Yoo
- Department of Medical Environmental Biology and Research Center for Biomolecules and Biosystems, Chung-Ang University College of Medicine, Seoul, Republic of Korea
- Division of Malaria and Parasitic Diseases, National Institute of Health, Korea Centers for Disease Control and Prevention, Osong, Chungbuk, Republic of Korea
| | - Dae-Won Kim
- Division of Malaria and Parasitic Diseases, National Institute of Health, Korea Centers for Disease Control and Prevention, Osong, Chungbuk, Republic of Korea
- Genome Research Center, Korea Research Institute of Bioscience and Biotechnology and University of Science and Technology, Daejeon, Republic of Korea
| | - Jung-Won Ju
- Division of Malaria and Parasitic Diseases, National Institute of Health, Korea Centers for Disease Control and Prevention, Osong, Chungbuk, Republic of Korea
| | - Pyo Yun Cho
- Department of Infection Biology, Zoonosis Research Center, Wonkwang University School of Medicine, Chonbuk, Republic of Korea
| | - Tae Im Kim
- Department of Medical Environmental Biology and Research Center for Biomolecules and Biosystems, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Shin-Hyeong Cho
- Division of Malaria and Parasitic Diseases, National Institute of Health, Korea Centers for Disease Control and Prevention, Osong, Chungbuk, Republic of Korea
| | - Sang-Haeng Choi
- Genome Research Center, Korea Research Institute of Bioscience and Biotechnology and University of Science and Technology, Daejeon, Republic of Korea
| | - Hong-Seog Park
- Genome Research Center, Korea Research Institute of Bioscience and Biotechnology and University of Science and Technology, Daejeon, Republic of Korea
- * E-mail: (H-SP); (T-SK); (S-JH)
| | - Tong-Soo Kim
- Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea
- * E-mail: (H-SP); (T-SK); (S-JH)
| | - Sung-Jong Hong
- Department of Medical Environmental Biology and Research Center for Biomolecules and Biosystems, Chung-Ang University College of Medicine, Seoul, Republic of Korea
- * E-mail: (H-SP); (T-SK); (S-JH)
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16
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Oishi N, Wang XW. Novel therapeutic strategies for targeting liver cancer stem cells. Int J Biol Sci 2011; 7:517-35. [PMID: 21552419 PMCID: PMC3088875 DOI: 10.7150/ijbs.7.517] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2011] [Accepted: 04/14/2011] [Indexed: 12/15/2022] Open
Abstract
The cancer stem cell (CSC) hypothesis was first proposed over 40 years ago. Advances in CSC isolation were first achieved in hematological malignancies, with the first CSC demonstrated in acute myeloid leukemia. However, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been more recently demonstrated in a growing range of epithelial and other solid organ malignancies, suggesting that the majority of malignancies are dependent on such a compartment.Primary liver cancer consists predominantly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It is believed that hepatic progenitor cells (HPCs) could be the origin of some HCCs and ICCs. Furthermore, stem cell activators such as Wnt/β-catenin, TGF-β, Notch and Hedgehog signaling pathways also expedite tumorigenesis, and these pathways could serve as molecular targets to assist in designing cancer prevention strategies. Recent studies indicate that additional factors such as EpCAM, Lin28 or miR-181 may also contribute to HCC progression by targeting HCC CSCs. Various therapeutic drugs that directly modulate CSCs have been examined in vivo and in vitro. However, CSCs clearly have a complex pathogenesis, with a considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit for treatment. Many of the key signaling molecules are shared by both CSCs and normal stem cells, which add further challenges for designing molecularly targeted strategies specific to CSCs but sparing normal stem cells to avoid side effects. In addition to the direct control of CSCs, many other factors that are needed for the maintenance of CSCs, such as angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance, should be taken into consideration when designing therapeutic strategies for HCC. Here we provide a brief review of molecular signaling in liver CSCs and present insights into new therapeutic strategies for targeting liver CSCs.
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Affiliation(s)
| | - Xin Wei Wang
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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17
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Abstract
The association of cancer with preceding parasitic infections has been observed for over 200 years. Some such cancers arise from infection of tissue stem cells by viruses with insertion of viral oncogenes into the host DNA (mouse polyoma virus, mouse mammary tumor virus). In other cases the virus does not insert its DNA into the host cells, but rather commandeers the metabolism of the infected cells, so that the cells continue to proliferate and do not differentiate (human papilloma virus and cervical cancer). Cytoplasmic Epstein Barr virus infection is associated with a specific gene translocation (Ig/c-myc) that activates proliferation of affected cells (Burkitt lymphoma). In chronic osteomyelitis an inflammatory reaction to the infection appears to act through production of inflammatory cytokines and oxygen radical formation to induce epithelial cancers. Infection with Helicobacter pylori leads to epigenetic changes in methylation and infection by a parasite. Clonorchis sinensis also acts as a promoter of cancer of the bile ducts of the liver (cholaniocarcinoma). The common thread among these diverse pathways is that the infections act to alter tissue stem cell signaling with continued proliferation of tumor transit amplifying cells.
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Affiliation(s)
- S Sell
- Wadsworth Center and Ordway Research Institute, Empire State Plaza, Albany, NY 12201, USA.
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18
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Shupe T, Petersen BE. Potential applications for cell regulatory factors in liver progenitor cell therapy. Int J Biochem Cell Biol 2011; 43:214-21. [PMID: 20851776 PMCID: PMC3022095 DOI: 10.1016/j.biocel.2010.09.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2009] [Revised: 08/24/2010] [Accepted: 09/06/2010] [Indexed: 12/18/2022]
Abstract
Orthotopic liver transplant represent the state of the art treatment for terminal liver pathologies such as cirrhosis in adults and hemochromatosis in neonates. A limited supply of transplantable organs in relationship to the demand means that many patients will succumb to disease before an organ becomes available. One promising alternative to liver transplant is therapy based on the transplant of liver progenitor cells. These cells may be derived from the patient, expanded in vitro, and transplanted back to the diseased liver. Inborn metabolic disorders represent the most attractive target for liver progenitor cell therapy, as many of these disorders may be corrected by repopulation of only a portion of the liver by healthy cells. Another potential application for liver progenitor cell therapy is the seeding of bio-artificial liver matrix. These ex vivo bioreactors may someday be used to bridge critically ill patients to other treatments. Conferring a selective growth advantage to the progenitor cell population remains an obstacle to therapy development. Understanding the molecular signaling mechanisms and micro-environmental cues that govern liver progenitor cell phenotype may someday lead to strategies for providing this selective growth advantage. The discovery of a population of cells within the bone marrow possessing the ability to differentiate into hepatocytes may provide an easily accessible source of cells for liver therapies.
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Affiliation(s)
- Thomas Shupe
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, College of Medicine, Gainesville, FL 32610-0275, USA.
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19
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Benhamouche S, Curto M, Saotome I, Gladden AB, Liu CH, Giovannini M, McClatchey AI. Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev 2010; 24:1718-30. [PMID: 20675406 PMCID: PMC2922501 DOI: 10.1101/gad.1938710] [Citation(s) in RCA: 222] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2010] [Accepted: 06/18/2010] [Indexed: 12/13/2022]
Abstract
The molecular signals that control the maintenance and activation of liver stem/progenitor cells are poorly understood, and the role of liver progenitor cells in hepatic tumorigenesis is unclear. We report here that liver-specific deletion of the neurofibromatosis type 2 (Nf2) tumor suppressor gene in the developing or adult mouse specifically yields a dramatic, progressive expansion of progenitor cells throughout the liver without affecting differentiated hepatocytes. All surviving mice eventually developed both cholangiocellular and hepatocellular carcinoma, suggesting that Nf2(-/-) progenitors can be a cell of origin for these tumors. Despite the suggested link between Nf2 and the Hpo/Wts/Yki signaling pathway in Drosophila, and recent studies linking the corresponding Mst/Lats/Yap pathway to mammalian liver tumorigenesis, our molecular studies suggest that Merlin is not a major regulator of YAP in liver progenitors, and that the overproliferation of Nf2(-/-) liver progenitors is instead driven by aberrant epidermal growth factor receptor (EGFR) activity. Indeed, pharmacologic inhibition of EGFR blocks the proliferation of Nf2(-/-) liver progenitors in vitro and in vivo, consistent with recent studies indicating that the Nf2-encoded protein Merlin can control the abundance and signaling of membrane receptors such as EGFR. Together, our findings uncover a critical role for Nf2/Merlin in controlling homeostasis of the liver stem cell niche.
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Affiliation(s)
- Samira Benhamouche
- Department of Pathology, Massachusetts General Hospital Center for Cancer Research, Harvard Medical School, Charlestown, Massachusetts 02129, USA
| | - Marcello Curto
- Department of Pathology, Massachusetts General Hospital Center for Cancer Research, Harvard Medical School, Charlestown, Massachusetts 02129, USA
| | - Ichiko Saotome
- Department of Pathology, Massachusetts General Hospital Center for Cancer Research, Harvard Medical School, Charlestown, Massachusetts 02129, USA
| | - Andrew B. Gladden
- Department of Pathology, Massachusetts General Hospital Center for Cancer Research, Harvard Medical School, Charlestown, Massachusetts 02129, USA
| | - Ching-Hui Liu
- Department of Pathology, Massachusetts General Hospital Center for Cancer Research, Harvard Medical School, Charlestown, Massachusetts 02129, USA
| | - Marco Giovannini
- Center for Neural Tumor Research, House Ear Institute, Los Angeles California 90057, USA
| | - Andrea I. McClatchey
- Department of Pathology, Massachusetts General Hospital Center for Cancer Research, Harvard Medical School, Charlestown, Massachusetts 02129, USA
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20
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Jeen YM, Jin SY. [Intrahepatic cholangiocarcinoma associated with Clonorchis sinensis infection]. THE KOREAN JOURNAL OF HEPATOLOGY 2010; 15:524-7. [PMID: 20037272 DOI: 10.3350/kjhep.2009.15.4.524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Yoon Mi Jeen
- Department of Pathology, Soonchunhyang University Hospital, Seoul, Korea
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21
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Aravalli RN. Progress in stem cell-derived technologies for hepatocellular carcinoma. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2010; 3:81-92. [PMID: 24198513 PMCID: PMC3781728 DOI: 10.2147/sccaa.s6886] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Primary hepatocellular carcinoma (HCC) is a common malignancy that has a poor prognosis because it is often diagnosed at an advanced stage. HCC normally develops as a consequence of underlying liver disease and is most often associated with cirrhosis. Surgical resection and liver transplantation are the current best options to treat liver cancer. However, problems associated with liver transplantation, such as shortage of donors, risk of immune rejection, and tissue damage following surgery provided the impetus for development of alternative therapies. The emerging field of stem cell therapy has raised hopes for finding curative options for liver cancer. Stem cells have the ability not only to proliferate after transplantation but also to differentiate into most mammalian cell types in vivo. In this review, progress on stem cell-derived technologies for the treatment of liver cancer is discussed.
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Affiliation(s)
- Rajagopal N Aravalli
- Department of Radiology, University of Minnesota Medical School, Minneapolis, MN, USA
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22
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Abstract
BACKGROUND The liver is the largest gland and chief metabolic organ of the human body possessing a unique ability to regenerate. The general interest of primary liver tumors is noteworthy because of their increasing worldwide incidence and mortality. Recent studies have focused on the ancestors of mature hepatocytes, which are capable of proliferating, differentiating and self-renewing. OBJECTIVE To provide a brief and up-to-date review on the cellular origin of primary liver tumors and to examine the use of stem cells in potential future therapeutic attempts. METHODS A review of relevant literature. RESULTS It is clear that hepatic progenitor cells (HPCs) could be the basis of some hepatocellular carcinomas (HCC), cholangiocarcinomas (CHC), hepatocellular adenomas and hepatoblastomas. Cancer stem cell (CSC) theory emphasizes the role of hepatic stem cells in the development and progression of liver tumors. CONCLUSION The expression of HPCs markers may be used as new independent prognostic factors in HCC. Conventional treatments for HCC do not seem to be beneficial for the majority of patients and new therapeutic approaches such as gene therapy and targeted drug therapy are of great clinical interest.
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Affiliation(s)
- Michail Papoulas
- University of Athens, Medical School, Department of Forensic Medicine and Toxicology, Goudi, Athens, GR11527, Greece
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23
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Yoon BI, Kim YH, Yi JY, Kang MS, Jang JJ, Joo KH, Kim Y, McHugh Law J, Kim DY. Expression of thioredoxin during progression of hamster and human cholangiocarcinoma. Cancer Sci 2010; 101:281-8. [PMID: 19799607 PMCID: PMC11159955 DOI: 10.1111/j.1349-7006.2009.01353.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Thioredoxin (Trx) is a multifunctional redox protein that has growth-promoting and anti-apoptotic effects on cells and protects cells from endogenous and exogenous free radicals. Recently, altered expression of Trx has been reported in various cancers. In the present study, we investigated altered expression of Trx at the precancerous and carcinogenic phases during cholangiocarcinogenesis in a hamster cholangiocarcinoma (ChC) model, using semiquantitative immunohistochemical and Western blot analyses. Moreover, to determine if the results correlated well with those in human ChCs, we carried out a comparative immunohistochemical study for Trx in tissue-arrayed human ChCs with different grades of tumor cell differentiation. Trx was found highly expressed in the cytoplasm of dysplastic bile ducts with highly abnormal growth patterns and ChCs irrespective of tumor type or tumor cell differentiation. Overexpression of Trx at the precancerous and carcinogenic phases was further supported by significant elevation of Trx protein in Western blotting. The results from the hamster ChCs were in good agreement with those from human ChCs. Our results strongly suggested that the redox regulatory function of Trx plays an important role in bile duct cell transformation and tumor progression during cholangiocarcinogenesis.
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Affiliation(s)
- Byung-Il Yoon
- School of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Korea
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24
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Choi D, Jeon YH, Lee GC, Choi MH, Hong ST. Changes in sonographic findings after treatment of patients with clonorchiasis in a heavy endemic area. THE KOREAN JOURNAL OF PARASITOLOGY 2009; 47:19-23. [PMID: 19290087 DOI: 10.3347/kjp.2009.47.1.19] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2008] [Revised: 01/30/2009] [Accepted: 02/06/2009] [Indexed: 11/23/2022]
Abstract
We measured changes in sonographic findings of patients with clonorchiasis after a treatment in a highly endemic area. A total of 347 residents showed positive stool results for Clonorchis sinensis eggs in a village in northeastern China, and were treated with praziquantel. Of them, 132 patients underwent abdominal sonography both before and 1 year after treatment, and the changes in sonographic findings of 83 cured subjects were compared. Diffuse dilatation of intrahepatic bile ducts (DDIHD) was found in 82 patients (98.2%) before and 80 (96.4%) after treatment, which was improved in 3, aggravated in 1, and unchanged in 79 patients. Increased periductal echogenicity (IPDE) was observed in 42 patients (50.6%) before and 45 (54.2%) after treatment, which was improved in 5, aggravated in 8, and unchanged in 70 patients. Floating echogenic foci in the gallbladder (FEFGB) was detected in 32 patients (38.6%) before and 17 (20.5%) after treatment, which was improved in 20, aggravated in 5, and unchanged in 58 patients. Improvement of FEFGB only was statistically significantly (P = 0.004). The present results confirm that DDIHD and IPDE persist but FEFGB decreases significantly at 1 year after treatment. In a heavy endemic area, the sonographic finding of FEFGB may suggest active clonorchiasis 1 year after treatment.
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Affiliation(s)
- Dongil Choi
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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25
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Sirica AE. Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J Gastroenterol 2008; 14:7033-58. [PMID: 19084911 PMCID: PMC2776834 DOI: 10.3748/wjg.14.7033] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2008] [Revised: 10/21/2008] [Accepted: 10/28/2008] [Indexed: 02/06/2023] Open
Abstract
Aberrant expression and signaling of epidermal growth factor receptor (ErbB) family receptor tyrosine kinases, most notably that of ErbB2 and ErbB1, have been implicated in the molecular pathogenesis of intrahepatic cholangiocarcinoma. Constitutive overexpression of ErbB2 and/or ErbB1 in malignant cholangiocytes has raised interest in the possibility that agents which selectively target these receptors could potentially be effective in cholangiocarcinoma therapy. However, current experience with such ErbB-directed therapies have at best produced only modest responses in patients with biliary tract cancers. This review provides a comprehensive and critical analysis of both preclinical and clinical studies aimed at assessing the role of altered ErbB2 and/or ErbB1 expression, genetic modifications, and dysregulated signaling on cholangiocarcinoma development and progression. Specific limitations in experimental approaches that have been used to assess human cholangiocarcinoma specimens for ErbB2 and/or ErbB1 overexpression and gene amplification are discussed. In addition, current rodent models of intrahepatic cholangiocarcinogenesis associated with constitutive ErbB2 overexpression are reviewed. Select interactive relationships between ErbB2 or ErbB1 with other relevant molecular signaling pathways associated with intrahepatic cholangiocarcinoma development and progression are also detailed, including those linking ErbB receptors to bile acid, cyclooxygenase-2, interleukin-6/gp130, transmembrane mucins, hepatocyte growth factor/Met, and vascular endothelial growth factor signaling. Lastly, various factors that can limit therapeutic efficacy of ErbB-targeted agents against cholangiocarcinoma are considered.
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Kim YJ, Choi MH, Hong ST, Bae YM. Resistance of cholangiocarcinoma cells to parthenolide-induced apoptosis by the excretory-secretory products of Clonorchis sinensis. Parasitol Res 2008; 104:1011-6. [PMID: 19066964 DOI: 10.1007/s00436-008-1283-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2008] [Accepted: 11/07/2008] [Indexed: 11/25/2022]
Abstract
Infection by Clonorchis sinensis, the Chinese or oriental liver fluke, is a significant risk factor for the development of cholangiocarcinoma, a human epithelial carcinoma of the intrahepatic bile duct. Parthenolide is a sesquiterpene lactone that has strong anticancer properties and is also known to induce apoptosis in cholangiocarcinoma cells. Many investigators have reported that excretory-secretory (ES) products of C. sinensis as well as Opisthorchis viverrini promote the development of cholangiocarcinomas. However, the intrinsic mechanism is not clearly understood. Therefore, we investigated the biological roles of the ES products in a cholangiocarcinoma cell line, HuCCT1. The ES products of C. sinensis increased proliferation of HuCCT1 cells and augmented the expression of cyclooxygenase (COX)-2. To determine whether cells treated with ES products would respond differently to parthenolide, HuCCT1 cells were treated with parthenolide alone or parthenolide after pretreatment with ES products. Cells pretreated with ES products were resistant to parthenolide-induced apoptosis. Because parthenolide has been reported to be a COX-2 inhibitor, we hypothesize that COX-2 might be a key factor that promotes resistance of cholangiocarcinoma cancer cells to parthenolide-induced apoptosis. These results suggest that chemotherapy treatment regimens in cholangiocarcinoma patients with C. sinensis infection should be modulated to account for ES products excreted by the liver fluke.
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Affiliation(s)
- Young Ju Kim
- Department of Parasitology and Tropical Medicine, Seoul National University College of Medicine, 28 Yeongeon-dong, Jongro-gu, Seoul, 110-799, South Korea
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Abstract
Hepatocellular carcinoma (HCC) typically has poor prognosis, because it is often diagnosed at an advanced stage. Heterogeneous phenotypic and genetic traits of affected individuals and a wide range of risk factors have classified it a complex disease. HCC is not amenable to standard chemotherapy and is resistant to radiotherapy. In most cases, surgical resection and liver transplantation remain the only curative treatment options. Therefore, development of novel, effective therapies is of prime importance. Extensive research over the past decade has identified a number of molecular biomarkers as well as cellular networks and signaling pathways affected in liver cancer. Recent studies using a combination of "omics" technologies, microRNA studies, combinatorial chemistry, and bioinformatics are providing new insights into the gene expression and protein profiles during various stages of the disease. In this review, we discuss the contribution of these newer approaches toward an understanding of molecular mechanisms of HCC and for the development of novel cancer therapeutics.
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Affiliation(s)
- Rajagopal N Aravalli
- Department of Radiology, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, MN, USA.
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Choi D, Lim JH, Lee KT, Lee JK, Choi SH, Heo JS, Choi DW, Jang KT, Lee NY, Kim S, Hong ST. Gallstones and Clonorchis sinensis infection: a hospital-based case-control study in Korea. J Gastroenterol Hepatol 2008; 23:e399-e404. [PMID: 18070015 DOI: 10.1111/j.1440-1746.2007.05242.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND AND AIM A high prevalence of intrahepatic stones in some areas of East Asia has been believed to be related with Clonorchis sinensis infection. The authors conducted a hospital-based case-control study to evaluate the role of Clonorchis sinensis infection as a risk factor for the development of gallstones in Korea. METHODS The cases of 138 patients with gallstones (intrahepatic 44, gallbladder 67, and extrahepatic 27) and matched controls underwent microscopy for C. sinensis, serological tests for C. sinensis using enzyme-linked immunosorbent assay, radiological examinations, and interviews concerning the history of eating raw freshwater fish. We assessed a relationship of three types of gallstones and variables regarding C. sinensis by using univariate and multivariate statistical analyses. RESULTS Univariate statistical analyses showed that radiological evidence of C. sinensis and recent history of eating raw freshwater fish were related to an increased risk of intrahepatic stones (P = 0.0002 and 0.0039, respectively). According to multivariate statistical analyses, radiological evidence of C. sinensis was the only risk factor for intrahepatic stones (odds ratio = 7.835; 95% confidence interval = 1.671-36.724). Any evidence regarding C. sinensis was not related to an increased risk of either gallbladder or extrahepatic stones. CONCLUSION Radiological evidence of C. sinensis was significantly associated with intrahepatic stones.
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Affiliation(s)
- Dongil Choi
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Lee SO. [Physiologic and pathologic experimental models for studying cholangiocytes]. THE KOREAN JOURNAL OF HEPATOLOGY 2008; 14:139-49. [PMID: 18617761 DOI: 10.3350/kjhep.2008.14.2.139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Cholangiocytes (epithelial cells lining the intra- and extrahepatic bile ducts) and hepatocytes are two major components of liver epithelia. Although cholangiocytes are less numerous than hepatocytes, they are involved in both bile secretion and diverse cellular processes such as cell-cycle phenomena, cell signaling, and interactions with other cells, matrix components, foreign organisms, and xenobiotics. Cholangiocytes are also targets in several human diseases including cholangiocarcinoma, primary sclerosing cholangitis, autoimmune cholangitis, and vanishing bile-duct syndrome. The rapid advances in experimental biology technologies are greatly expanding interest in and knowledge of the physiology and pathophysiology of cholangiocytes. This review focuses on the progress of in vivo and in vitro experimental models in elucidating the physiologic functions of cholangiocytes and the pathophysiology of various cholangiopathies. The following aspects are reviewed: isolation of cholangiocytes from the liver and their heterogeneity, various culture systems, establishment of cholangiocyte cell lines, isolation and usage of intrahepatic bile-duct units, three-dimensional modeling of the bile duct, experimental models for inducing cholangiocyte proliferation, and various cholangiopathies such as cholangiocarcinoma, primary sclerosing cholangitis, and autoimmune cholangitis.
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Affiliation(s)
- Seung-Ok Lee
- Division of Gatroenterology and Hepatology, Department of Internal Medicine, Chonbuk National University Hospital and Medical School, Jeonju, Korea.
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Biliary parasitic diseases including clonorchiasis, opisthorchiasis and fascioliasis. ACTA ACUST UNITED AC 2008; 33:157-65. [PMID: 17934771 DOI: 10.1007/s00261-007-9326-x] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Parasitic infection of the biliary tree is caused by liver flukes, namely Clonorchis sinensis and Opisthorchis viverrini. These flukes reside in the peripheral small bile ducts of the liver and produce chronic inflammation of the bile duct, bile duct dilatation, mechanical obstruction, and bile duct wall thickening. On imaging, peripheral small intrahepatic bile ducts are dilated, but the large bile ducts and extrahepatic bile ducts are not dilated or slightly dilated. There is no visible caused of obstruction. Sometimes, in heavy infection, adult flukes are demonstrated on sonography, CT or MR cholangiography as small intraluminal lesions. The flukes in the gallbladder may appear as floating, small objects on sonography. Chronic infection may result in cholangiocarcinoma of the liver parenchyma or along the bile ducts. Human infection of Fasciola hepatica, a cattle flukes, may occur inadvertently, and the flukes migrate in the liver (hepatic phase) and reside the bile ducts (biliary phase). Image findings in the hepatic phase present with multiple, small, clustered, necrotic cavities or abscesses in the peripheral parts of the liver, showing "tunnels and caves" sign, reflecting parasite migration in the liver parenchyma. In the biliary phase, the flukes are demonstrated in the intra- and extrahepatic bile ducts and the gallbladder as small intraluminal flat objects, sometimes moving spontaneously. Bile ducts are dilated.
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Mayer DA, Fried B. The role of helminth infections in carcinogenesis. ADVANCES IN PARASITOLOGY 2008; 65:239-96. [PMID: 18063098 DOI: 10.1016/s0065-308x(07)65004-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This review examines the significant literature on the role of helminth infections in carcinogenesis. Both parasitic infections and cancer have complex natural histories and long latent periods during which numerous exogenous and endogenous factors interact to obfuscate causality. Although only two helminths, Schistosoma haematobium and Opisthorchis viverrini, have been proven to be definitely carcinogenic to humans, others have been implicated in facilitating malignant transformation. The known mechanisms of helminth-induced cancer include chronic inflammation, modulation of the host immune system, inhibition of intracellular communication, disruption of proliferation-antiproliferation pathways, induction of genomic instability and stimulation of malignant stem cell progeny. Approximately 16% of all cancer cases worldwide are attributable to pathogenic agents, including schistosomes and liver flukes. This equates to 1,375,000 preventable cancer deaths per year. Means to reduce the incidence of helminth-associated malignancies are discussed.
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Affiliation(s)
- David A Mayer
- Department of Surgery, New York Medical College, Valhalla, New York 10595, USA
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Kim YJ, Choi MH, Hong ST, Bae YM. Proliferative effects of excretory/secretory products from Clonorchis sinensis on the human epithelial cell line HEK293 via regulation of the transcription factor E2F1. Parasitol Res 2007; 102:411-7. [PMID: 18026993 DOI: 10.1007/s00436-007-0778-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2007] [Accepted: 10/24/2007] [Indexed: 11/26/2022]
Abstract
Clonorchis sinensis is one of the most prevalent parasitic helminths of humans in East Asia. Although several complications in bile duct epithelial cells are caused by C. sinensis infection, the mechanism is not clearly understood. To clarify the effects of C. sinensis excretory-secretory products (ES products) on bile duct epithelial cells, we investigated their effects on the human embryonic kidney epithelial cell line HEK293 in vitro. Our results show that ES products alter the proportion of cells in each stage of the cell cycle and induce HEK293 cell proliferation. Among cell cycle-related proteins, the expression of cyclin E increased markedly after treatment with ES products, indicating that the G1/S transition occurred. In addition, the expression of the transcription factor E2F1 was up-regulated by the addition of ES products. Small interfering RNA (siRNA) was used to demonstrate that the transcription factor E2F1 is a key factor in the control of cell proliferation in HEK293 cells. The present results demonstrate that ES products from C. sinensis stimulate cell proliferation by inducing E2F1 expression. We suggest that the ES products released from C. sinensis during infection may play an important role in the development of cholangiocarcinoma via the overgrowth of the bile duct epithelium.
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Affiliation(s)
- Young Ju Kim
- Department of Parasitology and Tropical Medicine, Seoul National University College of Medicine, 103 Daehangno, Jongno-gu, Seoul 110-799, South Korea
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Abstract
Among several diagnostic tools for clonorchiasis (Clonorchis sinensis infection), radiologic examinations are commonly used in clinical practices. During the 2 past decades, many reports regarding imaging findings of clonorchiasis were introduced. The basic imaging finding of clonorchiasis is diffuse dilatation of the peripheral intrahepatic bile ducts, without dilation of the large intrahepatic or extrahepatic bile ducts. By this finding, however, active clonorchiasis cannot be differentiated from cured infection. Some recent radiologic studies suggested specific findings of active clonorchiasis. Besides direct demonstration of worms, increased periductal echogenicity on sonography and periductal enhancement on dynamic contrast-enhanced CT or MR imaging possibly represent active clonorchiasis. Those images of the liver clonorchiasis are known to be correlated with worm burdens (EPG counts) in their frequency and also severity. The images of cholangiocarcinoma associated with clonorchiasis show both the tumor with obstruction images and diffuse dilatation of the peripheral intrahepatic bile ducts. Radiological images can be a good practical alternative diagnostic method of clonorchiasis.
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Affiliation(s)
- Dongil Choi
- Department of Radiology, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea
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Yoon BI, Kim DY, Jang JJ, Han JH. Altered expression of thioredoxin reductase-1 in dysplastic bile ducts and cholangiocarcinoma in a hamster model. J Vet Sci 2006; 7:211-6. [PMID: 16871013 PMCID: PMC3242118 DOI: 10.4142/jvs.2006.7.3.211] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Thioredoxin reductase 1 (TrxR) is a homodimeric selenoenzyme catalyzing thioredoxin (Trx) in an NADPH-dependent manner. With regard to carcinogenesis, these redox proteins have been implicated in cell proliferation, transformation and anti-apoptosis. In the present study, using a hamster cholangiocarcinoma (ChC) model, we evaluated the immunohistochemical expression pattern of TrxR in precancerous lesions and ChCs as well as in normal bile ducts. The goal of this study was to determine the potential role and importance of TrxR in cholangiocarcinogenesis. For the ChC model, we obtained liver tissue specimens with dysplastic bile ducts prior to the development of ChC 8 weeks after initiation of the experiment and ChC samples at 27 weeks. The immunohistochemical analysis showed diffuse cytoplasmic overexpression of TrxR in the dysplastic bile duct epithelial cells as well as in cholangiocarcinoma; this was comparable to the negative or weakly positive in normal and type 1 hyperplastic bile ducts. However, TrxR appeared to be considerably down-regulated in the ChCs when compared to the higher expression observed in the dysplastic bile ducts. Therefore, these results suggest that TrxR overexpression followed by down-regulation might be an important event in cholangiocarcinogenesis, especially at early stages including the cellular transformation of candidate bile ducts. Further studies are however required to determine whether TrxR may be a potential target molecule for chemoprevention against cholangiocarcinogenesis. In addition, the molecular mechanism as well as the importance of the loss of TrxR in the development of cholangiocarcinoma, following dysplastic transformation of bile duct cells, also remains to be clarified.
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Affiliation(s)
- Byung Il Yoon
- School of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 200-701, Korea.
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35
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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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Ramalho FS, Ramalho LNZ, Della Porta L, Zucoloto S. Comparative immunohistochemical expression of p63 in human cholangiocarcinoma and hepatocellular carcinoma. J Gastroenterol Hepatol 2006; 21:1276-80. [PMID: 16872309 DOI: 10.1111/j.1440-1746.2006.04309.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND p63 helps regulate differentiation and proliferation in epithelial progenitor cells. Its expression is often higher in malignant tissue compared with normal tissue, and poorly differentiated carcinomas often show a larger number of p63-positive cells than well-differentiated tumors. The aim of the present study was to investigate the immunohistochemical expression of p63 in human cholangiocarcinomas (CC) and hepatocellular carcinomas (HCC). METHODS Sixteen cases of CC and 37 cases of HCC were selected for the present study. Paraffin-embedded sections were submitted to immunohistochemical double-staining to identify p63 and cytokeratin 19. RESULTS p63 was diffusely expressed in 100% of CC, while it was negative in all HCC. In addition, cytokeratin 19, a marker for hepatic progenitor cells, was colocalized in all p63-positive cells. CONCLUSIONS The nuclear immunostaining for p63 in all CC cases indicates that the p63 protein can act to promote neoplastic growth in bile duct epithelium, but it is not important for hepatocellular carcinogenesis. Co-localization of p63 and cytokeratin 19 in CC cells suggests that CC may be derived from undifferentiated progenitor cells (hepatic oval cells). Furthermore, p63 can be useful in the differential diagnosis between CC and HCC in biopsy samples.
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Affiliation(s)
- Fernando S Ramalho
- Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
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Marzioni M, Fava G, Benedetti A. Nervous and Neuroendocrine regulation of the pathophysiology of cholestasis and of biliary carcinogenesis. World J Gastroenterol 2006; 12:3471-3480. [PMID: 16773704 PMCID: PMC4087563 DOI: 10.3748/wjg.v12.i22.3471] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2006] [Revised: 02/06/2006] [Accepted: 02/18/2006] [Indexed: 02/06/2023] Open
Abstract
Cholangiocytes, the epithelial cells lining the biliary ducts, are the target cells in several liver diseases. Cholangiopathies and cholangiocarcinoma generate interest in many scientists since the genesis. The developing mechanisms, and the therapeutic tools of these diseases are still undefined. Several studies demonstrate that many hormones, neuropeptides and neurotransmitters regulate malignant and non-malignant cholangiocyte pathophysiology in the course of chronic biliary diseases. The aim of this review is to present the findings of several studies published in the recent years that contributed to clarifying the role of nervous and neuroendocrine regulation of the pathophysiologic events associated with cholestasis and cholangiocarcinoma development. This manuscript is organized into two parts. The first part offers an overview of the innervation of the liver and the origin of neuroendocrine hormones, neurotransmitters and neuropeptides affecting cholangiocyte function and metabolism. The first section also reviews the effects played by several neuroendocrine hormones and nervous system on cholangiocyte growth, survival and functional activity in the course of cholestasis. In the second section, we summarize the results of some studies describing the role of nervous system and neuroendocrine hormones in the regulation of malignant cholangiocyte growth.
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Affiliation(s)
- Marco Marzioni
- Department of Gastroenterology, Università Politecnica delle Marche, Nuovo Polo Didattico, III piano, Via Tronto 10, 60020 Ancona, Italy.
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Choi D, Lim JH, Lee KT, Lee JK, Choi SH, Heo JS, Jang KT, Lee NY, Kim S, Hong ST. Cholangiocarcinoma and Clonorchis sinensis infection: a case-control study in Korea. J Hepatol 2006; 44:1066-1073. [PMID: 16480786 DOI: 10.1016/j.jhep.2005.11.040] [Citation(s) in RCA: 122] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2005] [Revised: 11/15/2005] [Accepted: 11/16/2005] [Indexed: 01/01/2023]
Abstract
BACKGROUND/AIMS The authors conducted a hospital-based case-control study to evaluate the role of Clonorchis sinensis infection as a risk factor for the development of cholangiocarcinoma (CC), including extrahepatic CC, in Korea. METHODS Cases of 185 patients with CC (intrahepatic, 51; hilar, 53; and distal extrahepatic, 81) and matched controls underwent stool microscopy, pathological examinations, serologic test for C. sinensis using ELISA, skin test for C. sinensis, radiologic examinations, and interview concerning history of eating raw freshwater fish. RESULTS Radiologic evidence of C. sinensis, history of eating raw freshwater fish, and positive serologic result for C. sinensis were found to be related to an increased risk of CC, with the odds ratios (OR)=8.615 (95% confidence interval [CI]=5.045-16.062), OR=2.385 (95% CI=1.527-3.832), and OR=2.272 (95% CI=1.147-4.811), respectively. The risk factors for distal extrahepatic CC were radiologic evidence of C. sinensis (OR=6.571; 95% CI=3.170-15.943) and history of eating raw freshwater fish (OR=2.6; 95% CI=1.294-5.66). CONCLUSIONS Radiologic evidence of C. sinensis, history of eating raw freshwater fish and positive serologic result for C. sinensis were significantly associated with CC, including extrahepatic CC.
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Affiliation(s)
- Dongil Choi
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710, South Korea
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Corcelle V, Stieger B, Gjinovci A, Wollheim CB, Gauthier BR. Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins. Exp Cell Res 2006; 312:2826-36. [PMID: 16781709 DOI: 10.1016/j.yexcr.2006.05.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2006] [Revised: 04/07/2006] [Accepted: 05/16/2006] [Indexed: 01/02/2023]
Abstract
Despite extensive studies, the hematopoietic versus hepatic origin of liver progenitor oval cells remains controversial. The aim of this study was to determine the origin of such cells after liver injury and to establish an oval cell line. Rat liver injury was induced by subcutaneous insertion of 2-AAF pellets for 7 days with subsequent injection of CCl(4). Livers were removed 9 to 13 days post-CCl(4) treatment. Immunohistochemistry was performed using anti-c-kit, OV6, Thy1, CK19, AFP, vWF and Rab3b. Isolated non-parenchymal cells were grown on mouse embryonic fibroblast, and their gene expression profile was characterized by RT-PCR. We identified a subpopulation of OV6/CK19/Rab3b-expressing cells that was activated in the periportal region of traumatized livers. We also characterized a second subpopulation that expressed the HSCs marker c-kit but not Thy1. Although we successfully isolated both cell types, OV6/CK19/Rab3b(+) cells fail to propagate while c-kit(+)-HSCs appeared to proliferate for up to 7 weeks. Cells formed clusters which expressed c-kit, Thy1 and albumin. Our results indicate that a bona fide oval progenitor cell population resides within the liver and is distinct from c-kit(+)-HSCs. Oval cells require the hepatic niche to proliferate, while cells mobilized from the circulation proliferate and transdifferentiate into hepatocytes without evidence of cell fusion.
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Affiliation(s)
- V Corcelle
- Department of Cell Physiology and Metabolism, University Medical Center, 1211 Geneva 4, Switzerland
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Sicklick JK, Li YX, Melhem A, Schmelzer E, Zdanowicz M, Huang J, Caballero M, Fair JH, Ludlow JW, McClelland RE, Reid LM, Diehl AM. Hedgehog signaling maintains resident hepatic progenitors throughout life. Am J Physiol Gastrointest Liver Physiol 2006; 290:G859-70. [PMID: 16322088 DOI: 10.1152/ajpgi.00456.2005] [Citation(s) in RCA: 158] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hedgehog signaling through its receptor, Patched, activates transcription of genes, including Patched, that regulate the fate of various progenitors. Although Hedgehog signaling is required for endodermal commitment and hepatogenesis, the possibility that it regulates liver turnover in adults had not been considered because mature liver epithelial cells lack Hedgehog signaling. Herein, we show that this pathway is essential throughout life for maintaining hepatic progenitors. Patched-expressing cells have been identified among endodermally lineage-restricted, murine embryonic stem cells as well as in livers of fetal and adult Ptc-lacZ mice. An adult-derived, murine hepatic progenitor cell line expresses Patched, and Hedgehog-responsive cells exist in stem cell compartments of fetal and adult human livers. In both species, manipulation of Hedgehog activity influences hepatic progenitor cell survival. Therefore, Hedgehog signaling is conserved in hepatic progenitors from fetal development through adulthood and may be a new therapeutic target in patients with liver damage.
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Affiliation(s)
- Jason K Sicklick
- Division of Gastroenterology, Duke University Medical Center, Snyderman-GSRB I, Suite 1073, 595 LaSalle St., Box 3256, Durham, NC 27710, USA
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Shan YF, Zhou WP, Fu XY, Yan HX, Yang W, Liu SQ, Cao HF, Kang B, Wu MC, Wang HY. The role of p28GANK in rat oval cells activation and proliferation. Liver Int 2006; 26:240-7. [PMID: 16448463 DOI: 10.1111/j.1478-3231.2005.01203.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Human gankyrin gene product (p28GANK) is a novel oncogenic protein ubiquitously overexpressed in hepatocellular carcinoma and also plays a role in cell cycle progression in normal hepatocytes and liver regeneration. However, little is known about the physiological role of p28GANK in the liver oval cell activation and proliferation. We investigated the possible involvement of p28GANK in oval cell-mediated liver regeneration and cell cycle progression. METHODS We examined the different p28GANK expression in 2-acetylaminofuorene/partial heptectomy (2-AAF/PH) rats, as a model of oval cell activation, and PH rats by Western blot and immunohistochemistry. Oval cells isolated from 2-AAF/PH rat model were cultured in our study. p28GANK expression was examined in the oval cells after mitogenic stimulation. RESULTS In 2-AAF/PH rats, p28GANK was expressed in the activated oval cells and located in the nucleus. p28GANK protein expression was increased in 2-AFF/PH rats after hepatectomy lasting for 96 h when retinoblastoma maintained hyperphosphorylation status at Ser-795. The isolated oval cells express AFP, OV6, CK19, CD34, CD45, c-kit and albumin. After epidermal growth factor stimulation, p28GANK protein was up-regulated in oval cells from 24 to 72 h, which coincided with increased expression of CyclinD1, CDK4 and decreased of Rb protein. CONCLUSIONS p28GANK expression was increased in oval cell-mediated liver regeneration and oval cells after mitogenic stimulation. Thus, p28GANK may play a role in oval cell-mediated liver regeneration and liver oval cell cycle progression.
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Affiliation(s)
- Yun-Feng Shan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Shanghai, China
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Abstract
Clonorchis sinensis, the Chinese or oriental liver fluke, is an important human parasite and is widely distributed in southern Korea, China (including Taiwan), Japan, northern Vietnam and the far eastern part of Russia. Clonorchiasis occurs in all parts of the world where there are Asian immigrants from endemic areas. The human and animal reservoir hosts (dogs, pigs, cats and rats) acquire the infection from the ingestion of raw fish containing infectious metacercariae. The first intermediate snail hosts are mainly species of Parafossarulus and Bithynia. Numerous species of freshwater fish serve as the second intermediate hosts of C. sinensis. Extensive studies of clonorchiasis during several decades in Japan, Korea, China and other countries have shown much progress in proving its morphological features including ultrastructure, biology, pathogenesis, epidemiology, clinical manifestations and chemotherapy. The present review deals with mainly current results obtained on the epidemiological, pathological and clinical aspects, as well as control measures in endemic areas. As for the complications of clonorchiasis, formation of calculi in the intrahepatic biliary passages is one of the most characteristic pathological features. It is sometimes accompanied by suppurative cholangitis, cholecystitis, cholangiohepatitis and ultimately can cause cholangiocarcinoma. Experimental results on the relationship to the occurrence of cholangiocarcinoma are presented. Clinical diagnosis by radiological findings including cholangiography, sonography and computerized tomography as well as magnetic resonance imaging for biliary or pancreatic ducts are outlined. Current studies on immunology and molecular biology of C. sinensis were introduced. Praziquantel is the drug of choice for clonorchiasis. The most effective regimen is 25 mg kg(-1) three times daily (total dose, 75 mg kg(-1)) administered orally at 5- to 6-h intervals over a single day. Prevention and control measures are also discussed.
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Affiliation(s)
- H-J Rim
- Department of Paraitology, College of Medicine, Korea university, Seoul 136-705, Korea.
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Kofman AV, Morgan G, Kirschenbaum A, Osbeck J, Hussain M, Swenson S, Theise ND. Dose- and time-dependent oval cell reaction in acetaminophen-induced murine liver injury. Hepatology 2005; 41:1252-61. [PMID: 15880565 DOI: 10.1002/hep.20696] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
We examined the response of murine oval cells, that is, the putative liver progenitor cells, to acetaminophen. Female C57BL/6J mice were injected intraperitoneally with varying doses of N-acetyl-paraaminophen (APAP) (250, 500, 750, and 1,000 mg/kg of weight) and sacrificed at 3, 6, 9, 24, and 48 hours. In preliminary studies, we showed that anticytokeratin antibodies detected A6-positive cells with a sensitivity and specificity of greater than 99%. The oval cell reaction was quantified, on immunostaining for biliary-type cytokeratins, as both number and density of oval cells per portal tract, analyzed by size of portal tract. Acetaminophen injury was followed by periportal oval cell accumulation displaying a moderate degree of morphological homogeneity. Oval cell response was biphasic, not temporally correlating with the single wave of injury seen histologically. Increases in oval cells were largely confined to the smallest portal tracts, in keeping with their primary derivation from the canals of Hering, and increased in a dose-dependent fashion. The timing of the two peaks of the oval cell reaction also changed with increasing dose, the first becoming earlier and the second later. In conclusion, our studies indicate a marked oval cell activation during the height of hepatic injury. Oval cells appear to be resistant to acetaminophen injury. The close fidelity of mechanism and histology of acetaminophen injury between mouse and human livers makes it a useful model for investigating liver regeneration and the participation of stem/progenitor cells in that process.
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Affiliation(s)
- Alexander V Kofman
- Department of Medicine, Division of Digestive Diseases, Liver & Stem Cell Research Laboratory, Beth Israel Medical Center, New York, NY 10003, USA
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Nam KT, Kim DY, Park MS, Jang DD, Yang KH, Han JH, Yoon BI. Suppression of Cholangiocarcinoma Development by Aminoguanidine in the Liver Fluke-infested Hamster. J Toxicol Pathol 2005. [DOI: 10.1293/tox.18.65] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Ki-Taek Nam
- National Institute of Toxicological Research, KFDA
| | - Dae-Yong Kim
- Department of Veterinary Pathology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University
| | - Mi-Sun Park
- Department of Veterinary Pathology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University
| | | | - Ki-Hwa Yang
- National Institute of Toxicological Research, KFDA
| | - Jeong-Hee Han
- Department of Veterinary Medicine, Kangwon National University
| | - Byung-Il Yoon
- Department of Veterinary Medicine, Kangwon National University
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Yoon BI, Choi YK, Kim DY. Differentiation processes of oval cells into hepatocytes: proposals based on morphological and phenotypical traits in carcinogen-treated hamster liver. J Comp Pathol 2004; 131:1-9. [PMID: 15144794 DOI: 10.1016/j.jcpa.2003.12.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2003] [Accepted: 12/09/2003] [Indexed: 12/13/2022]
Abstract
Hepatic stem cells participate in the recovery process of liver with severe injury or impaired hepatocyte regeneration. Oval cells (an oval-shaped liver cell population newly emerging from the portal or periportal zones following severe hepatic cellular damage) are believed to be the progeny of liver stem cells and precursor cells of both hepatocytes and bile duct cells. An attempt was made to define the differentiation processes of hepatic oval cells into mature hepatocytes in hamsters fed a choline-deficient diet and treated with diethylnitrosamine and 2-acetyl aminofluorene, on the basis of histopathological, electron microscopical, histochemical and immunohistochemical characterization of hepatic cell components. Two putative differentiation pathways of oval cells toward mature hepatocytes are proposed, namely (1) the differentiation of ductular-like oval cells via ductular/acinar-type hepatocytes, and (2) the differentiation of individual oval cells via small hepatocytes. Those proposals were strongly supported by consistent immunoreactivity of the cells for OV-6, an oval cell marker, and differential expression patterns for CK19 and PAS-positive cytoplasmic glycogen granules.
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Affiliation(s)
- B-I Yoon
- Department of Veterinary Pathology, School of Agricultural Biotechnology and Xenotransplantation Research Center, College of Veterinary Medicine, Seoul National University, San 56-1, Shillim-dong, Kwanak-gu, Seoul 151-742, South Korea
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Abstract
AIM: To investigate the expression of CD34 and c-kit (receptor of stem cell factor) in cholangiocarcinoma.
METHODS: Fifteen cases of intrahepatic cholangiocarcinoma and 17 cases of extrahepatic cholangiocarcinoma were studied in this experiment. Using Envision detection system, paraffin-embedded sections of the resected cholangiocarcinoma tissue were stained with antibodies against CD34 and c-kit, respectively. The sections were counterstained with hematoxylin, and the results were examined under light microscope. Normal tonsil and mammary tissues were used as positive controls for CD34 and c-kit, respectively.
RESULTS: CD34 was positive in all sections, but only in capillary endothelial cells of tumor tissue. No cholangiocarcinoma cells were positive for CD34. In one case of extrahepatic cholangiocarcinoma, a few tumor cells (about 5%) were immunoreactive with c-kit.
CONCLUSION: CD34 or c-kit positive cells in liver tissue may represent liver stem cells, as they can differentiate into mature biliary cells in vitro. The expression of c-kit by some cholangiocarcinoma cells suggests that cholangiocarcinoma might originate from liver stem cells. However, other mechanisms of hepatocarcinogenesis, such as de-differentiation of mature cholangiocytes, may also exist.
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Affiliation(s)
- Chao Liu
- Department of General Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
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Choi BI, Han JK, Hong ST, Lee KH. Clonorchiasis and cholangiocarcinoma: etiologic relationship and imaging diagnosis. Clin Microbiol Rev 2004; 17:540-52, table of contents. [PMID: 15258092 PMCID: PMC452546 DOI: 10.1128/cmr.17.3.540-552.2004] [Citation(s) in RCA: 170] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Despite a gradual decrease in prevalence, clonorchiasis is still prevalent in East Asia. A large and compelling body of evidence links clonorchiasis and cholangiocarcinoma, although the mechanisms involved are not completely understood. Clonorchiasis induces biliary epithelial hyperplasia and metaplasia, and this could facilitate at least one stage of the carcinogenesis, which is promoting effect. In areas of endemic infection, more clonorchiasis cases are now diagnosed incidentally during radiological examinations such as cholangiography, ultrasonography, and computed tomography. Radiological findings are regarded as pathognomonic for clonorchiasis since they reflect the unique pathological changes of this disorder. These radiological examinations currently play important roles in the diagnosis, staging, and decision-making process involved in the treatment of cholangiocarcinoma. The morphological features and radiological findings of clonorchiasis-associated cholangiocarcinoma are essentially combinations of the findings for the two diseases. The morphological features of clonorchiasis- associated cholangiocarcinoma, observed in radiological examinations, do not differ from those of the usual cholangiocarcinoma. In patients diagnosed with or suspected to have clonorchiasis, radiological findings should be carefully scrutinized for occult cholangiocarcinoma.
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Affiliation(s)
- Byung Ihn Choi
- Department of Radiology and Institute of Radiation Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea.
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Chung BS, Zhang H, Choi MH, Jeon D, Li S, Lee M, Hong ST. Development of resistance to reinfection by Clonorchis sinensis in rats. THE KOREAN JOURNAL OF PARASITOLOGY 2004; 42:19-26. [PMID: 15060336 PMCID: PMC2717335 DOI: 10.3347/kjp.2004.42.1.19] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
We investigated the induction of resistance to Clonorchis sinensis infection by prior infection in rat and hamster models. Animals were challenged with C. sinensis metacercariae, then treated with praziquantel and reinfected. Worm recovery rate in reinfected animals was used to estimate resistance to reinfection. The determined resistance rates to reinfection in rats and hamsters were 97.7% and 10.3%, respectively. In rats, cure from the primary infection of C. sinensis increased resistant to reinfection, and the greater the worm burden and the longer the duration of primary infection, the higher was the resistance rate. For primary infection doses of 10, 40 and 100 metacercariae per rat, the resistance rates were 87.4%, 93.8% and 98.4%, respectively. The resistance rates in rats after 2 or 8-week primary infection were 78.7% and 95.3%, respectively. All worms recovered from reinfected rats were immature. When cured rats were administered with methylprednisolone, resistance to reinfection became impaired. These findings indicate that rats develop a high degree of resistance to reinfection by C. sinensis after cure. The growths and maturations of reinfected worms were also impaired.
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Affiliation(s)
- Byung-Suk Chung
- Department of Parasitology and Tropical Medicine, Institute of Endemic Diseases, Seoul National University College of Medicine, Medical Research Center, Seoul 110-799, Republic of Korea
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Newsome PN, Hussain MA, Theise ND. Hepatic Oval Cells: Helping Redefine a Paradigm in Stem Cell Biology. Curr Top Dev Biol 2004; 61:1-28. [PMID: 15350395 DOI: 10.1016/s0070-2153(04)61001-5] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- P N Newsome
- Department of Hepatology, University of Edinburgh Edinburgh EH16 4SB, United Kingdom, UK
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Choi YK, Yoon BI, Won YS, Lee CH, Hyun BH, Kim HC, Oh GT, Kim DY. Cytokine responses in mice infected with Clonorchis sinensis. Parasitol Res 2003; 91:87-93. [PMID: 12898229 DOI: 10.1007/s00436-003-0934-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2003] [Accepted: 05/27/2003] [Indexed: 01/24/2023]
Abstract
FVB and BALB/c mice show different morbidity, development of Clonorchis sinensis, and pathological changes following C. sinensis infection. FVB mice are susceptible and BALB/c mice are relatively more resistant to C. sinensis infection. To investigate the relationship between cytokine reaction and susceptibility to C. sinensis infection in FVB and BALB/c mice, we described both the patterns and kinetics of Th1 cytokines and Th2 cytokines in spleen cell culture. Interleukin (IL)-4 and IL-10 cytokine production in the culture supernatants of the concanavalin-A-stimulated spleen cells increased at 2-3 weeks post-infection in both strains. IL-5 production increased between 2 and 5 weeks post-infection in both strains, and reached a peak level at 2 weeks post-infection in BALB/c mice and 4 weeks post-infection in FVB mice. In contrast, gamma interferon (IFN-gamma) production decreased between 2 and 4 weeks in both strains. IL-2 production increased slightly in BALB/c mice following infection, but was unchanged in FVB mice. IL-4 production over preinfection levels was significantly higher in FVB mice, whereas IFN-gamma, IL-2, and IL-10 production were significantly higher in BALB/c mice. The levels of serum immunoglobulin E (IgE) and blood eosinophils in both mouse strains significantly increased between 3 and 6 weeks postinfection. Serum IgE levels were significantly higher in FVB mice than in BALB/c mice. The results of this study suggest that susceptibility to C. sinensis infection is associated with Th2 cytokine production, especially IL-4 which is predominant in relatively susceptible FVB mice.
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Affiliation(s)
- Yang Kyu Choi
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
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