Hepatocarcinogenesis in mice with a conditional knockout of the hepatocyte growth factor receptor c-Met

The receptor for the hepatocyte growth factor/scatter factor (HGF/SF), c-Met, plays a role in tuinour promotion, progression and metastasis. In this study, we analysed chemically induced hepatocarcinogenesis in mice lacking a functional HGF receptor in their liver. Control and c-Met deficient mice were injected with a single dose of N-nitrosodiethylamine (DEN, 90 mu g/g b.wt.) at 6 weeks of age and mice were subsequently kept on a phenobarbital (PB) containing diet (0.05%) for 35 weeks or on control diet. At the end of the experiment, the carcinogenic response in liver of the animals was monitored. Conditional c-met knockout (KO) mice showed a higher prevalence of macroscopically visible liver tumours and of glutamine synthetase positive and glucose-6-phosphatase deficient lesions in liver. Tumour promotion by PB led to significant increases in the number of preneoplastic and neoplastic lesions in liver of both wild-type and c-met knockout mice, with only minor differences in response. Our results indicate that a defect in c-Met-mediated signaling increases chemically induced tumour initiation in liver but does not significantly affect PB-mediated tumour promotion. (C) Wiley-Liss, Inc.