title: Epithelial Transforming Growth Factor-β Signaling Does Not Contribute to Liver Fibrosis but Protects Mice From Cholangiocarcinoma.
abstract: OBJECTIVE
  Transforming growth factor-β (TGFβ) exerts key functions in fibrogenic cells, promoting fibrosis development in the liver and other organs. In contrast, the functions of TGFβ in liver epithelial cells are not well understood, despite their high level of responsiveness to TGFβ. We sought to determine the contribution of epithelial TGFβ signaling to hepatic fibrogenesis and carcinogenesis.
  
  
  METHODS
  TGFβ signaling in liver epithelial cells was inhibited by albumin-Cre-, K19-CreERT-, Prom1-CreERT2-, or AAV8-TBG-Cre-mediated deletion of the floxed TGFβ receptor II gene (Tgfbr2). Liver fibrosis was induced by carbon tetrachloride, bile duct ligation, or disruption of the multidrug-resistance transporter 2 gene (Mdr2). Hepatocarcinogenesis was induced by diethylnitrosamine or hepatic deletion of PTEN.
  
  
  RESULTS
  Deletion of Tgfbr2 from liver epithelial cells did not alter liver injury, toxin-induced or biliary fibrosis, or diethylnitrosamine-induced hepatocarcinogenesis. In contrast, epithelial deletion of Tgfbr2 promoted tumorigenesis and reduced survival of mice with concomitant hepatic deletion of Pten, accompanied by an increase in tumor number and a shift from hepatocellular carcinoma to cholangiocarcinoma. Surprisingly, both hepatocyte- and cholangiocyte-specific deletion of Pten and Tgfbr2 promoted the development of cholangiocarcinoma, but with different latencies. The prolonged latency and the presence of hepatocyte-derived cholangiocytes after AAV8-TBG-Cre-mediated deletion of Tgfbr2 and Pten indicated that cholangiocarcinoma might arise from hepatocyte-derived cholangiocytes in this model. Pten deletion resulted in up-regulation of Tgfbr2, and deletion of Tgfbr2 increased cholangiocyte but not hepatocyte proliferation, indicating that the main function of epithelial TGFBR2 is to restrict cholangiocyte proliferation.
  
  
  CONCLUSIONS
  Epithelial TGFβ signaling does not contribute to the development of liver fibrosis or formation of hepatocellular carcinomas in mice, but restricts cholangiocyte proliferation to prevent cholangiocarcinoma development, regardless of its cellular origin.
authors.affiliation: Department of Medicine, Columbia University, New York, New York; Institute of Oncology, Provincial Hospital, Shandong University, Jinan, China.
authors.forename: Xueru
authors.initials: X
authors.lastname: Mu
authors.affiliation: Department of Medicine, Columbia University, New York, New York.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pradere
authors.affiliation: Department of Medicine, Columbia University, New York, New York.
authors.forename: Silvia
authors.initials: S
authors.lastname: Affò
authors.affiliation: Institute of Human Nutrition, Columbia University, New York, New York.
authors.forename: Dianne H
authors.initials: DH
authors.lastname: Dapito
authors.affiliation: Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, Columbia University, New York, New York.
authors.forename: Richard
authors.initials: R
authors.lastname: Friedman
authors.affiliation: Department of Pathology, Columbia University, New York, New York.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lefkovitch
authors.affiliation: Department of Medicine, Columbia University, New York, New York; Institute of Human Nutrition, Columbia University, New York, New York. Electronic address: rfs2102@cumc.columbia.edu.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001650:Bile Duct Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D001652:Bile Ducts / Q000378:metabolism* / Q000473:pathology; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018281:Cholangiocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004052:Diethylnitrosamine; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D002251:Carbon Tetrachloride; D004052:Diethylnitrosamine; D051059:PTEN Phosphohydrolase; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C487757:Pten protein, mouse
keywords: Liver Cancer; Mouse Model; Signal Transduction; TGFβ