Abstract
Tumor promoters are nonmutagenic chemicals that increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. The molecular mechanisms underlying this process are only partly understood but interference with signaling pathways regulating cell division and/or cell death is likely to be important. Ras- and β-Catenin-dependent signaling is important for both of these processes and ras and β-catenin genes are known mutational targets in mouse hepatocarcinogenesis. About 80% of liver tumors generated in mice by a promotional regimen including phenobarbital (PB) as tumor promoter and N-nitrosodiethylamine (DEN) as initiator showed β-catenin mutations whereas Ha-ras mutations were not detected. By contrast, tumors from mice treated with DEN alone showed a ~30% Ha-ras mutation prevalence but no β-catenin mutations. This result suggests that PB-mediated promotion in mouse liver consists in a positive selection for hepatocytes harboring mutations in β-catenin. The gap junction protein connexin 32 (Cx32) was also found to be involved in tumor promotion by PB because Cx32 gene knockout mice were almost entirely resistent to the promotional effects of the barbiturate. The link between β-catenin-signaling and Cx32-dependent gap junctional intercellular communication, if existent, remains obscure.