Mechanisms of biliary carcinogenesis: A pathogenetic multi-stage cascade towards cholangiocarcinoma

Carcinomas of the biliary tract are rare cancers developing from the epithe lial or blast-like cells lining the bile ducts. A variety of known predispo sing factors and recent experimental models of biliary carcinogenesis (e.g. , infection with the liver fluke Opisthorchis viverrini, models of chemical ly induced carcinogenesis and experimental models of pancreaticobiliary mal junction) have elucidated different stages of this complex system of biliar y tumorigenesis. Chronic inflammatory processes, generation of active oxyge n radicals, altered cellular detoxification mechanisms, activation of oncog enes, functional loss of tumor-suppressor genes and dysregulation of cell p roliferation and cell apoptotic mechanisms have been identified as importan t contributors in the development of cholangiocarcinomas. In this review, t he known mechanisms involved in the carcinogenesis of biliary epithelium ar e addressed. We will divide the topic into four stages: 1) Predisposition a nd risk factors of biliary cancer. 2) Genotoxic events and alterations lend ing to specific DNA damage and mutation patterns. 3) Dysregulation of DNA r epair mechanisms and apoptosis, permitting survival of mutated cells and 4) Morphological evolution from premalignant biliary lesions to cholangiocarc inoma. Finally, established and hypothetical future therapeutic strategies directed towards specific pathogenetic events during biliary carcinogenesis will be addressed.