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, 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 mICROg/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.
Marx-Stoelting
Philip
P
Department of Toxicology, Institute of Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany.
Borowiak
Malgorzata
M
Knorpp
Thomas
T
Birchmeier
Carmen
C
Buchmann
Albrecht
A
Schwarz
Michael
M
D000818:Animals; D004052:Diethylnitrosamine / Q000494:pharmacology; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010634:Phenobarbital / Q000633:toxicity; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D004052:Diethylnitrosamine; D019859:Proto-Oncogene Proteins c-met; D005952:Glucose-6-Phosphatase; D005974:Glutamate-Ammonia Ligase; D010634:Phenobarbital