Multistage carcinogenesis of liver-fluke-associated cholangiocarcinoma in Thailand

In northeast Thailand, the traditional habit of eating ground, raw freshwater and salt-fermented fish on a daily basis results in a local population repeatedly exposed to both liver fluke (Opisthorchis viverrini) infection and consuming nitrosamine-contaminated food from early in life. Epidemiological studies have revealed a coincident high prevalence of cholangiocarcinoma in this region and we have demonstrated in animal models that dietary contamination with nitrosamines and Opisthorchiasis are strong predisposing factors for cholangiocarcinogenesis. Thus all Syrian golden hamsters receiving a combination of subcarcinogenic doses of dimethylnitrosamine (DMN) and infection with flukes developed cholangiocarcinomas, while chemical administration or fluke infection alone did not cause cancer. Synergistic induction by chemical carcinogens and liver fluke infection was found to be related to levels of exposure to both. In this two-stage carcinogenesis model, nitrosamines are considered to act as genotoxicants exerting carcinogenic effects, while the liver flukes are assumed to play epigenetic roles. In our studies of biliary pathology related to worm burden in humans we found that while most of the subjects had worms, only a minority (25%) demonstrated a pathology of adenomatous hyperplasia, which is believed to predispose bile ducts to subsequent development of carcinomas, indicating the possible role of flukes as promoters. Biliary changes in nontumorous areas of hepatectomy specimens, including fibrosis (with or without adenomatous hyperplasia) which is found in most cases, and dysplasia in the fibrotic ducts indicate a conversion event in carcinogenesis: other factors may be required to aggravate the simple proliferation lesion so that they subsequently change to carcinomas. Furthermore, commonality in tumor phenotypes and expressions of ras p21 in both fluke related and non-fluke-related cholangiocarcinomas suggest that some similar mechanisms might be operating, at least in the relatively late stages of this multistage carcinogenesis involving the bile ducts.