An improved intrahepatic biliary cell culture/in vivo transplantation system has been established with an essentially pure population of hyperplastic bile ductular epithelial cells isolated from cholestatic rat liver at six or more weeks after bile duct ligation. Based on an extended characterization of this unique cell system, it is now apparent that it possesses features which make it quite attractive for use in the analysis of hyperplastic bile ductular epithelial cell function, growth control, and carcinogenesis. Moreover, this system has been developed to a point where it now can be used to effectively investigate the relationship of the hyperplastic bile ductular epithelial cells to proliferating """"""""biliary oval cells"""""""" that have been isolated and cultured from preneoplastic rat livers during the early stages of hepatocarcinogenesis. In this regard, this continuation proposal focuses on achieving neoplastic transformation of pure cultures of bile ductular epithelial cells from bile duct-ligated rats (i.e., by in vitro treatments with the direct-acting carcinogen N-methyl- N'-nitro-N-nitrosoquanidine or by transfection with the H-ras oncogene, according to established procedure). Particular attention will then be paid to assessing the tumorigenicity of the biliary cell transformants following inoculation of defined populations into the interscapular fat pads or liver (via the portal vein) of syngeneic rats and/or nude mice. Resulting tumors will be classified according to their type and level of differentiation, as well as by their positive and negative expressions of such phenotypic traits as cytokeratin 19, mucin production, alpha- fetoprotein, hepatocyte antigen 368.7, gamma-glutamyl transpeptidase, and glutathione S-transferase-P. In addition, an effort will be made to develop a novel multistage model of cholangiocarcinogenesis in rats, using Furan as the initial carcinogenic stimulus. A number of potential biliary cell tumor promoters will then be evaluated for their ability to specifically enhance the development of cholangiocellular carcinomas in these animals. It is anticipated that these studies will provide further insight into the differentiation potential of the hyperplastic bile ductular epithelial cell and its relationship to the """"""""multipotential oval cell"""""""", as well as lead to the development of valuable new models of in vivo and in vitro cholangiocarcinogenesis.
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