Hepatitis C Virus Infection and Cholangiocarcinoma
2019; Elsevier BV; Volume: 189; Issue: 6 Linguagem: Inglês
10.1016/j.ajpath.2019.01.018
ISSN1525-2191
AutoresMaría Cristina Navas, Shannon Glaser, Harshil Dhruv, Scott Celinski, Gianfranco Alpini, Fanyin Meng,
Tópico(s)Hepatitis C virus research
ResumoHepatitis C virus (HCV) infection is a global public health problem because it is a main cause of liver cirrhosis and hepatocellular carcinoma. This human oncogenic virus is also associated with the development of non-Hodgkin lymphoma and cholangiocarcinoma (CCA). The association between HCV infection and CCA has been examined in a number of epidemiologic studies. However, in vivo and in vitro results demonstrating the oncogenic mechanisms of HCV in CCA development and progression are insufficient. Here, we review the epidemiologic association of HCV and CCA and recent publications of studies of HCV infection of cholangiocytes and CCA cell lines as well as studies of viral infection performed with liver samples obtained from patients. In addition, we also discuss the preliminary results of in vitro assays of HCV protein expression in CCA cell lines. Finally, we discuss the hypothetical role of HCV infection in CCA development by induction of epithelial–mesenchymal transition and up-regulation of hedgehog signaling, and consequently biliary tree inflammation and liver fibrosis. Further studies are required to demonstrate these hypotheses and therefore to elucidate the mechanisms of HCV as a risk factor for CCA. Hepatitis C virus (HCV) infection is a global public health problem because it is a main cause of liver cirrhosis and hepatocellular carcinoma. This human oncogenic virus is also associated with the development of non-Hodgkin lymphoma and cholangiocarcinoma (CCA). The association between HCV infection and CCA has been examined in a number of epidemiologic studies. However, in vivo and in vitro results demonstrating the oncogenic mechanisms of HCV in CCA development and progression are insufficient. Here, we review the epidemiologic association of HCV and CCA and recent publications of studies of HCV infection of cholangiocytes and CCA cell lines as well as studies of viral infection performed with liver samples obtained from patients. In addition, we also discuss the preliminary results of in vitro assays of HCV protein expression in CCA cell lines. Finally, we discuss the hypothetical role of HCV infection in CCA development by induction of epithelial–mesenchymal transition and up-regulation of hedgehog signaling, and consequently biliary tree inflammation and liver fibrosis. Further studies are required to demonstrate these hypotheses and therefore to elucidate the mechanisms of HCV as a risk factor for CCA. Hepatitis C Virus (HCV) is remarkably efficient in the establishment of persistent infection. More than 60% of infected individuals experience chronic hepatitis C that is a main cause of liver cirrhosis and primary liver cancer.1Westbrook R.H. Dusheiko G. Natural history of hepatitis C.J Hepatol. 2014; 61: S58-S68Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar Globally, 30% of hepatocellular carcinoma (HCC) cases, the most important primary liver cancer, are associated with persistent HCV infection, representing a significant public health problem.2Plummer M. de Martel C. Vignat J. Ferlay J. Bray F. Franceschi S. Global burden of cancers attributable to infections in 2012: a synthetic analysis.Lancet Glob Health. 2016; 4: e609-e616Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar The HCV oncoproteins and the molecular mechanisms of carcinogenesis are well identified in the development of HCC associated with HCV infection as well as the role of chronic liver inflammation.3Vescovo T. Refolo G. Vitagliano G. Fimia G.M. Piacentini M. Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma.Clin Microbiol Infect. 2016; 22: 853-861Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar One of the HCV oncoproteins is Core (21 kDa), the subunit of the viral capsid. This structural protein also has regulatory functions in processes such as cell growth, apoptosis, oxidative stress, senescence, mitochondrial functions, innate immune response, steatosis, signal transduction, and, in particular, cell transformation.4Kao C.C. Yi G. Huang H.-C. The core of hepatitis C virus pathogenesis.Curr Opin Virol. 2016; 17: 66-73Crossref PubMed Scopus (20) Google Scholar This human oncogenic virus is also associated with the development of B-cell non-Hodgkin lymphoma, and recent epidemiologic studies have reported a link between HCV infection and cholangiocarcinoma (CCA).5Allison R.D. Tong X. Moorman A.C. Ly K.N. Rupp L. Xu F. Gordon S.C. Holmberg S.D. 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Hruban R.H. Lillemoe K.D. Yeo C.J. Cameron J.L. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors.Ann Surg. 1996; 224: 463-475Crossref PubMed Scopus (1030) Google Scholar, 9Bosman F.T. Carneiro F. Hruban R.H. Theise N.D. WHO Classification of Tumours of the Digestive System.ed 4. WHO, Geneva, Switzerland2010Google Scholar, 10Sobin L.H. Wittekind C. TNM Classification of Malignant Tumours, 7th Edition.in: Sobin L.H. Gospodarowicz M.K. Wittekind C. Wiley-Blackwell, Hoboken, NJ2011Google Scholar However, considering the heterogeneity of biliary tumors a new classification of CCA has been proposed: intrahepatic (iCCA), perihilar, and distal biliary tree. In addition, these tumors differ in their epidemiologic pattern, prognosis, pathogenesis, clinical management, and treatment.11Banales J.M. Cardinale V. Carpino G. Marzioni M. Andersen J.B. Invernizzi P. Lind G.E. Folseraas T. Forbes S.J. Fouassier L. Geier A. Calvisi D.F. Mertens J.C. Trauner M. Benedetti A. 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Current controversies in cholangiocarcinoma.Biochim Biophys Acta Mol Basis Dis. 2018; 1864: 1461-1467Crossref Scopus (25) Google Scholar The incidence of iCCA has increased in the past decades in different regions such as Western and Central Europe, North America, Asia, and Oceania, whereas the incidence of ECC has not changed during the past decade.14Petrick J.L. Braunlin M. Laversanne M. Valery P.C. Bray F. McGlynn K.A. International trends in liver cancer incidence, overall and by histologic subtype, 1978-2007.Int J Cancer. 2016; 139: 1534-1545Crossref PubMed Scopus (223) Google Scholar, 15Khan S.A. Toledano M.B. Taylor-Robinson S.D. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma.HPB (Oxford). 2008; 10: 77-82Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar Indeed, the estimated incidence of iCCA increased to 128% between 1973 and 2012 (0.44 to 1.18 cases/100,000) in the United States, whereas the rank of ECC incidence was between 0.96 and 1.02 cases/100,000 during the same period.16Saha S.K. Zhu A.X. Fuchs C.S. Brooks G.A. Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise.Oncologist. 2016; 21: 594-599Crossref PubMed Scopus (407) Google Scholar Moreover, the trends in mortality from iCCA showed a significant increase in mortality in some countries such as Australia, Canada, France, Germany, Japan, Ireland, Sweden, Portugal, Slovenia, and Spain.15Khan S.A. Toledano M.B. Taylor-Robinson S.D. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma.HPB (Oxford). 2008; 10: 77-82Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar The increased incidence of iCCA could be associated with the epidemiologic pattern of chronic liver diseases such as viral hepatitis.17Shaib Y.H. El-Serag H.B. Davila J.A. Morgan R. McGlynn K.A. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study.Gastroenterology. 2005; 128: 620-626Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar However, the quality of cancer registry in some countries as well as differences in resources available for diagnosis, classification, and treatment of CCA have to be considered to establish the trends on incidence of this biliary epithelial tumor.7Forman D. Bray F. Brewster D.H. Gombe Mbalawa C. Kohler B. Piñeros M. Steliarova-Foucher E. Swaminathan R. Ferlay J. Cancer Incidence in Five Continents Vol. X. IARC Scientific Publications, Lyon, France2014Google Scholar, 13Hoyos S. Navas M.C. Restrepo J.C. Botero R.C. Current controversies in cholangiocarcinoma.Biochim Biophys Acta Mol Basis Dis. 2018; 1864: 1461-1467Crossref Scopus (25) Google Scholar iCCA is a tumor developed by the transformation of the epithelial cells lining small and large intrahepatic bile ducts, the cholangiocytes. Two histologic subtypes of iCCA have been characterized, mucinous (bile duct type) and mixed (bile ductular type). The mucinous iCCA appears in large bile ducts that are characterized by mucin-producing cylindrical cells, similar to the perihilar extrahepatic bile duct. Mucinous iCCA and perihilar CCA have similar clinical, pathologic, and molecular profiles,18Komuta M. Govaere O. Vandecaveye V. Akiba J. Van Steenbergen W. Verslype C. Laleman W. Pirenne J. Aerts R. Yano H. Nevens F. Topal B. Roskams T. Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes.Hepatology. 2012; 55: 1876-1888Crossref PubMed Scopus (233) Google Scholar whereas mixed iCCA arises from small intrahepatic bile ducts, such as interlobular bile ducts, and ductules that are characterized by mucin-negative cuboidal cholangiocytes.11Banales J.M. Cardinale V. Carpino G. Marzioni M. Andersen J.B. Invernizzi P. Lind G.E. Folseraas T. Forbes S.J. Fouassier L. Geier A. Calvisi D.F. Mertens J.C. Trauner M. Benedetti A. Maroni L. Vaquero J. Macias R.I.R. Raggi C. Perugorria M.J. Gaudio E. Boberg K.M. Marin J.J.G. Alvaro D. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA).Nat Rev Gastroenterol Hepatol. 2016; 13: 261-280Crossref PubMed Scopus (735) Google Scholar, 19Patel T. 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Moreover, hepatic stem cells located at the portal region could be activated, generating oval cells that have qualities of both liver epithelial cells and then could be differentiate into mature hepatocytes. Interestingly, the ductular plasticity of mature hepatocytes has been found in chronic liver injury. Indeed, ductal epithelium could be derived from hepatocytes that exhibit the characteristics of oval cells.22Kopp J.L. Grompe M. Sander M. Stem cells versus plasticity in liver and pancreas regeneration.Nat Cell Biol. 2016; 18: 238-245Crossref PubMed Scopus (120) Google Scholar The hepatic progenitor cell could be the cell of origin of iCCA by transformation of cholangiocytes and/or hepatocytes during their differentiation.14Petrick J.L. Braunlin M. Laversanne M. Valery P.C. Bray F. McGlynn K.A. International trends in liver cancer incidence, overall and by histologic subtype, 1978-2007.Int J Cancer. 2016; 139: 1534-1545Crossref PubMed Scopus (223) Google Scholar, 23Roskams T. van den Oord J.J. De Vos R. Desmet V.J. Neuroendocrine features of reactive bile ductules in cholestatic liver disease.Am J Pathol. 1990; 137: 1019-1025PubMed Google Scholar The tumors derived from hepatic progenitor cells (mixed iCCA and cholangiocellular carcinoma) can present different histologic characteristics with focal hepatocyte differentiation and/or ductular areas and diverse clinicopathologic features while they display similar gene expression profiles.18Komuta M. Govaere O. Vandecaveye V. Akiba J. Van Steenbergen W. Verslype C. Laleman W. Pirenne J. Aerts R. Yano H. Nevens F. Topal B. Roskams T. Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes.Hepatology. 2012; 55: 1876-1888Crossref PubMed Scopus (233) Google Scholar As described before, the ductular plasticity of mature hepatocytes is a characteristic that could be important in oncogenesis. Indeed, normal human hepatocytes have been recently proposed as another cell type of origin for iCCA.22Kopp J.L. Grompe M. Sander M. Stem cells versus plasticity in liver and pancreas regeneration.Nat Cell Biol. 2016; 18: 238-245Crossref PubMed Scopus (120) Google Scholar The transdifferentiation and conversion of normal hepatocytes into cholangiocyte precursors was demonstrated in a mouse model by overexpression of Notch1 and thymoma viral proto-oncogene (AKT). Moreover, the Notch-mediated conversion of normal hepatocytes into cholangiocytes preceded the development of iCCA and macronodular cirrhosis in the mouse model.24Fan B. Malato Y. Calvisi D.F. Naqvi S. Razumilava N. Ribback S. 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According to the International Agency for Research on Cancer, infection with C. sinensis or O. viverrinin with subsequent development of chronic bile duct inflammation is recognized as carcinogen type I and is probably carcinogenic to humans, respectively.28Boyle P. Levin B. Liver cancer. World Cancer Report. IARC, Lyon, France2008Google Scholar Primary sclerosing cholangitis has been established as a risk factor for CCA in developed countries, especially in Europe. The lifetime incidence of CCA in patients, predominantly men, with primary sclerosing cholangitis is 5% to 10%. This disease is characterized by chronic inflammation of bile ducts and consequently biliary strictures that could evolve to cirrhosis and the development of CCA, mainly mucinous iCCA.26Gupta A. Dixon E. Epidemiology and risk factors: intrahepatic cholangiocarcinoma.Hepatobiliary Surg Nutr. 2017; 6: 101-104Crossref PubMed Google Scholar, 29Rizvi S. Gores G.J. 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Andersen J.B. Invernizzi P. Lind G.E. Folseraas T. Forbes S.J. Fouassier L. Geier A. Calvisi D.F. Mertens J.C. Trauner M. Benedetti A. Maroni L. Vaquero J. Macias R.I.R. Raggi C. Perugorria M.J. Gaudio E. Boberg K.M. Marin J.J.G. Alvaro D. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA).Nat Rev Gastroenterol Hepatol. 2016; 13: 261-280Crossref PubMed Scopus (735) Google Scholar, 26Gupta A. Dixon E. Epidemiology and risk factors: intrahepatic cholangiocarcinoma.Hepatobiliary Surg Nutr. 2017; 6: 101-104Crossref PubMed Google Scholar, 27Welzel T.M. Graubard B.I. El-Serag H.B. Shaib Y.H. Hsing A.W. Davila J.A. McGlynn K.A. 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