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 tumour promotion, progressionand metastasis. In this study, we analysed chemically induced hepatocarcinogenesisin mice lacking a functional HGF receptor intheir liver. Control and c-Met deficient mice were injected with asingle dose of N-nitrosodiethylamine (DEN, 90 lg/g b.wt.) at 6weeks of age and mice were subsequently kept on a phenobarbital(PB) containing diet (0.05%) for 35 weeks or on control diet. Atthe end of the experiment, the carcinogenic response in liver of theanimals was monitored. Conditional c-met knockout (KO) miceshowed a higher prevalence of macroscopically visible livertumours and of glutamine synthetase positive and glucose-6-phosphatasedeficient lesions in liver. Tumour promotion by PB led tosignificant increases in the number of preneoplastic and neoplasticlesions in liver of both wild-type and c-met knockout mice, withonly minor differences in response. Our results indicate that adefect in c-Met-mediated signaling increases chemically inducedtumour initiation in liver but does not significantly affect PBmediatedtumour promotion.