Cyclooxygenase-2 and ERBB-2 in cholangiocarcinoma: potential therapeutic targets.

Cholangiocarcinoma is a rare but highly malignant primary hepatobiliary cancer with a high rate of mortality. Early diagnosis is difficult and current therapies are ineffective for the advanced disease. Although the molecular pathogenesis of cholangiocarcinoma is still poorly understood, there is increasing evidence to suggest that overexpression of the proto-oncogene-encoded receptor tyrosine kinase ERBB-2 together with upregulation of cyclooxygenase-2 (COX-2) may be an important feature of cholangiocarcinogenesis in both the human and the experimental rodent models. Evidence presented supports a strong positive correlation between ERBB-2 overexpression and cyclooxygenase upregulation in human cholangiocarcinogenesis. Combination drug targeting of ERBB-2 and of COX-2 was also found to act synergistically to suppress anchorage-independent growth and activate caspase-3 in cultured rat cholangiocarcinoma cells overexpressing both proteins. These findings suggest that aberrant expression of ERBB-2 and COX-2 is a common feature of human and rat cholangiocarcinomas and that targeting of both proteins may prove useful as a therapeutic strategy for this lethal cancer.