Biliary cancer growth factor pathways, cyclo-oxygenase-2 and potential therapeutic strategies

Cholangiocarcinoma is a hepatic biliary cancer of high morbidity and mortality, whose molecular pathogenesis is unknown. However, there is increasing evidence to suggest that alterations in selected growth factor pathways, including an overexpression of the growth factor receptor tyrosine kinases c-ErbB-2/c-Neu and c-Met, together with possible aberrant autocrine expression of hepatocyte growth factor/scatter factor, the ligand for c-Met, may be playing important roles associated with the development of cholangiocarcinoma in both the human liver and in the furan rat model of cholangiocarcinogenesis. Cyclo-oxygenase-2, whose regulation has been experimentally related to c-ErbB-2/c-Neu as well as to hepatocyte growth factor/scatter factor, and which has been demonstrated to be overexpressed in other cancers of the gastrointestinal tract, has also been observed in preliminary studies to be upregulated in human biliary cancers and in cholangiocarcinoma induced in the furan rat model. Moreover, new data from our laboratory have demonstrated the cyclo-oxygenase-2 inhibitor NS-398 to produce a significant dose-dependent growth inhibition of rat cholangiocarcinoma cells in vitro, as well as to suppress anchorage-independent growth of these cells in soft agar. Based on the data reviewed, we propose that the selective therapeutic targeting of aberrant growth factor receptor tyrosine kinase signaling and of cyclo-oxygenase-2, alone or in combination, has potential to become a useful new approach for the treatment and/or chemoprevention of cholangiocarcinoma. We further propose that the furan rat model may serve as a powerful preclinical model for testing therapeutic and chemopreventative strategies that selectively target c-ErbB-2/c-Neu, cyclo-oxygenase-2, and/or autocrine hepatocyte growth factor/c-Met, aberrantly expressed in cholangiocarcinogenesis.