Hepatocellular expression of a dominant-negative mutant TGF-beta type II receptor accelerates chemically induced hepatocarcinogenesis

The potent growth-inhibitory activity of cytokines of the transforming grow th factor-beta (TGF-beta) superfamily and their widespread expression in ep ithelia suggest that they may play an important role in the maintenance of epithetial homeostasis. To analyse TGF-beta mediated tumor suppressor activ ity in the liver, we generated transgenic mice overexpressing a dominant ne gative type II TGF-beta receptor in hepatocytes under control of the regula tory elements of the human C-reactive protein gene promoter. Transgenic ani mals exhibited constitutive and liver-specific transgene expression. The fu nctional inactivation of the TGF-beta signaling pathway in transgenic hepat ocytes was shown by reduced TGF-beta induced inhibition of DNA synthesis in primary hepatocyte cultures. Liver morphology and spontaneous tumorigenesi s were unchanged in transgenic mice suggesting that interruption of the sig naling of all three isoforms of TGF-beta in hepatocytes does not disturb ti ssue homeostasis in the liver under physiological conditions. However, foll owing initiation with the carcinogen diethylnitrosamine and tumor-promotion with phenobarbital transgenic mice exhibited a moderate albeit significant increase in the incidence, size and multiplicity of both preneoplastic tis sue lesions in the liver and of hepatocellular carcinomas. These results gi ve in vivo evidence for a tumor suppressor activity of the endogeneous TGF- beta system in the liver during chemical hepatocarcinogenesis.