BILIARY PROLIFERATION AND ADAPTATION IN FURAN-INDUCED RAT-LIVER INJURY AND CARCINOGENESIS

Distinctive intrahepatic biliary adaptation responses occur in the liv er of rats subjected to select hepatotoxic and/or carcinogenic treatme nts with the nongenotoxic cholangiocarcinogenic agent furan. Specifica lly, metaplastic small intestinal-like glands closely resembling in th eir cellular composition the crypts of Lieberkuhn of normal rat small intestine were selectively derived from putative hyperplastic bile duc tule-like progenitor structures in the right and caudate liver lobes o f young adult Fischer-344 male rats given furan by gavage at a daily d ose of 30-45 mg/kg body weight, 5 times weekly, over a 2-6-wk treatmen t period. Longer term chronic administration of furan at 30 mg/kg/day for 9-19 wk resulted in the preferential development of primary hepati c adenocarcinomas, which arose at 70-100% incidences from right/caudat e liver lobes and which were characterized by small intestine mucosal cell differentiation. Interestingly, the neoplastic glands of these '' intestinal-type'' hepatic tumors demonstrated strongly positive immuno chemical reactions for both hepatocyte growth factor/scatter factor an d its c-met encoded receptor and were immunohistochemically positive f or transforming growth factor beta(1) (TGF-beta(1)) and for mannose-6- phosphate/insulin-like growth factor II receptor, implicated in the ac tivation of latent TGF-beta(1). In contrast, a different pattern of ab errant bile ductular cell differentiation was noted to occur in the at rophied right liver lobe of moribund Fischer-344 male rats that were c hronically exposed over a 10-14-day period to a severely hepatotoxic d ose of furan (60 mg/kg/day). Under this latter experimental condition, rare yet distinct cholangiolar-like structures composed of biliary ep ithelial cells and typically a single ductular hepatocytic cell in var ious stages of maturation specifically formed in association with an e xtensive hyperplastic bile ductular reaction. Very similar cholangiola r-like structures also appeared in areas of preexisting hyperplastic b ile ductule tissue at 3-5 days following the administration of a singl e hepatonecrogenic dose of CCl4 to rats that 4-6 wk earlier had been s ubjected to a bile duct ligation. In addition, a novel rat model was d eveloped in which furan combined in a unique synergistic manner with b ile duct ligation to induce the replacement of almost all of liver wit h well-differentiated hyperplastic bile ductules without evidence of d ifferentiation along either metaplastic small intestine mucosal cell o r ductular hepatocyte lineages. Bile ductular epithelial cell isolates from bile duct-ligated/furan-treated rats were further observed to be organized in the form of bile duct-like structures in vitro under spe cific conditions of primary cell culture and in vivo following their c ell transplantation into the inguinal fat pads of syngeneic recipient rats. Overall, these findings serve to exemplify the remarkable plasti city that may be exhibited by certain proliferating biliary cell popul ations in liver in response to specific types of severe hepatic injury and/or during cholangiocarcinogenesis.