Intrahepatic cholangiocarcinoma (ChC) is a highly lethal cancer arising from biliary epithelium (cholangiocytes) of liver, possibly from """"""""stem-like"""""""" cells associated with the hepatic biliary tract. Recent epidemiological studies have shown an increase in the worldwide incidence of ChC, including in the United States. However, ChC remains a clinical and biological challenge, since mortality rates continue to be very high, the cellular and molecular pathogenesis of ChC is still unclear, and there are to date no effective chemotherapeutic strategies for this devastating cancer. A major limitation to advancing our understanding of critical molecular mechanisms underlying the development of ChC has been the inability to achieve neoplastic transformation of cultured cholangiocytes. During the previous funding period, we have provided data supporting overexpression of constitutively activated ERBB-2 together with up-regulation of COX-2 as playing a potentially significant role in the molecular pathogenesis of ChC. We also very recently achieved neoplastic transformation of a novel rat biliary epithelial cell line following retroviral infection with the mutated rat erbB-2 oncogene, and determined COX-2 to be up-regulated in the malignant transformants. These cells gave rise to ChC when transplanted into syngeneic rats. In order to expand upon these exciting results, we now propose to (1) further establish and characterize novel in vitro models of genetically-mediated and spontaneous transformed rat cholangiocytes based on dysregulation of ErbB signaling and defined by discreet stages; (2) determine if aberrant ErbB-2 signaling linked to up-regulated COX-2 serves as a molecular switch for activating the angiogenic tumor cell phenotype as a function of malignant transformation of cholangiocytes; (3) test if the homeobox transcription factor CDX1 regulates mucin gland histogenesis by in vitro transformed cholangiocytes; and (4) assess the potential therapeutic effects of GW572016, a dual ErbB1/ErbB-2 tyrosine kinase inhibitor currently in clinical trials, against malignant cholangiocytes in vitro and in vivo. Powerful new experimental models of cholangiocyte malignant transformation and selective therapeutic targeting of ChC in novel preclinical assays are anticipated from these studies.
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