Primary biliary cancer in liver (cholangiocarcinoma) is a highly malignant disease of which there is no effective treatment. While characterized by high mortality and morbidity, little is actually known about the cellular and molecular pathogenesis of differentiation and growth regulation, which appear to be relevant to the development of cholangiocarcinoma in furan-treated rats. The tumors induced in this unique animal model of cholangiocarcingenesis closely resemble in their morphology and phenotypic features mucin-producing tubular or """"""""intestinal-type"""""""" cholangiocarcinomas of human liver. During the previous grant period, we have demonstrated that neoplastic epithelium of furan-induced rat cholangiocarcinomas exhibit prominent overexpression and activation of the growth factor receptor tyrosine kinase. Neu, the rat homologue of human ErbB-2, when compared to hyperplastic and normal intrahepatic biliary ephithelial cells. in addition, we have recently observed that cyclooxygenase-2 (COX-2) is markedly up-regulated in a novel rat cholangiocarcinoma cell line overexpressing Neu, as well as in tumorigenic neu-transformd rat liver epithelial stem-like cells, but is not detected in untransformed control cells. Moreover, we have presented data strongly suggesting that CDX1, a homeobox intestine-specific transcription factor, may be playing a critical role in controlling cellular differentiation along the intestinal lineage in the pathogenesis of intestinal-type chalongiocarcinoma formed in the liver of furan-treated rats. Based on these recent findings, and because ErbB-2 and COX-2 have been shown to be overexpressed in significant percentages of human cholangiocarcinoma development, has now prompted us to focus on accomplishing the following specific aims: (1) to selectively target Neu and COX-2 as a potentially important preclinical therapeutic strategy for inhibiting cholangiocarcinoma development, growth, and/or progression in the furan model, (2) to directly determine the role played by homeobox intestine-specific transcription factors, such as CDX1 and CDX2, in regulating differentiation in hepatobiliary neoplasia. Overall, the findings generated by the proposed studies will not only provide useful new basic information about the pathogenesis of cholangiocarcinoma development in the furan model, but are also anticipated to yield important preclinical information potentially quite relevant for the prevention and/or therapy of human cholagiocarcinogenesis.
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