title: erbB-2/neu transformed rat cholangiocytes recapitulate key cellular and molecular features of human bile duct cancer.
abstract: OBJECTIVE
  Cholangiocarcinomas appear to arise from the malignant transformation of cholangiocytes lining the biliary tract. Because the development of an in vitro model of malignant transformation can provide a powerful new tool for establishing critical events governing the molecular pathogenesis of cholangiocarcinoma, we investigated the potential of achieving malignant transformation of cultured rat cholangiocytes in relation to aberrant overexpression of mutationally activated erbB-2/neu.
  
  
  METHODS
  Malignant neoplastic transformation was achieved after infection of the rat cholangiocyte cell line, designated BDE1, with the retrovirus Glu664-neu, containing the transforming rat erbB-2/neu oncogene.
  
  
  RESULTS
  Compared with untransformed control cells, malignant transformants carrying the activating erbB-2/neu mutation prominently overexpressed p185neu receptor protein, which was phosphorylated strongly at its major autophosphorylation site at tyrosine 1248. Moreover, erbB-2/neu transformation of BDE1 cells resulted in increased telomerase activity, up-regulation of cyclooxygenase-2 with overproduction of prostaglandin E(2), enhanced phosphorylation of mitogen-activated protein kinase and of serine/threonine kinase Akt/PKB, overexpression of vascular endothelial growth factor, and increased mucin 1 messenger RNA expression. Only erbB-2/neu transformants were tumorigenic when transplanted into isogeneic rats, yielding a 100% incidence of tumors closely resembling human desmoplastic ductal cholangiocarcinomas in their morphology. Malignant cholangiocytes in the tumors were strongly immunoreactive for biliary cytokeratin 19, p185neu, and cyclooxygenase-2.
  
  
  CONCLUSIONS
  This unique malignant transformation model recapitulates key molecular features of the human disease and appears to be well suited for testing novel molecular therapeutic strategies against cholangiocarcinoma.
authors.affiliation: Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, Medical College of Virginia Campus, Richmond, Virginia 23298-0297, USA.
authors.forename: Guan-Hua
authors.initials: GH
authors.lastname: Lai
authors.forename: Zichen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.forename: Deanna J
authors.initials: DJ
authors.lastname: Ward
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Dewitt
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Holt
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Rozich
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Hixson
authors.forename: Alphonse E
authors.initials: AE
authors.lastname: Sirica
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology; D001652:Bile Ducts / Q000166:cytology*; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D019098:Telomerase / Q000378:metabolism
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D019098:Telomerase