Evidence was previously obtained from novel in vivo rat models of severe liver injury and intrahepatic cholangiocarcinogenesis induced by furan to strongly suggest that typical hyperplastic bile ductular epithelial cells can alter their commitment to differentiate along the biliary cell lineage so as to act as facultative cell progenitors of either metaplastic small intestinal-like glands or of unique ductular hepatocytic-like cells. Moreover, a very high incidence of biliary cell-derived """"""""intestinal- type"""""""" adenocarcinomas preferentially developed in the livers of the furan treated rats. To more definitively establish if typical hyperplastic bile ductular epithelial cells are capable of acting as a facultative pluripotent stem-like cell during cholangiocarcinogenesis and in certain types of severe hepatic injury, the following specific aims will be pursued: (1) Achieve neoplastic transformation of cultured populations of rat hyperplastic bile ductular epithelial cells that are clearly distinct from proliferating rat liver oval cell populations for the purpose of establishing for the first time the differentiation potential of these more typical bile ductular cells when converted to their tumorigenic phenotype by selected in vitro transforming treatments; (2) Based on the preliminary findings, determine if (a) cotransfection of both the c-met protooncogene, which encodes the receptor for hepatocyte growth factor/scatter factor (HGF/SF), and the HGF/SF growth factor gene into cultured populations of rat hyperplastic bile ductular epithelial cells in tumorigenic, and (b) if the overexpression of these respective genes may correlate with a preferential differentiation of transformed biliary cells along the small intestinal lineage; and (3) Use gap junction genes as molecular biomarkers to further establish the temporal lineage relationship between hyperplastic bile ductular epithelial cell types and ductular hepatocytes that form in the rat liver in response to severe hepatic injury induced by furan. It is anticipated that the results generated by the proposed research are likely to contribute in a significant way to furthering our current understanding of the hepatic stem cell hypothesis, as well as to add considerably to our present knowledge of the cellular origins and histogenesis of hepatobiliary cancers.
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