Heterozygous mice for the transforming growth factor-beta type II receptorgene have increased susceptibility to hepatocellular carcinogenesis

The transforming growth factor-13 (TGF-13) receptor complex and its downstr eam signaling intermediates constitute a tumor suppressor pathway. In many cancers, expression of TGF-beta type 11 receptor (T betaR-II) is markedly d ecreased. In the present study, we show that the hepatocytes isolated from 15-day-old, but not 9-month-old, mice heterozygous for the deletion of the T betaR-II gene are slightly less sensitive to the growth-inhibitory effect of TGF-beta when compared with wild-type littermates of same age. In addit ion, the proliferation index of hepatocytes as indicated by bromodeoxyuridi ne incorporation is mildly increased in the heterozygous mice. These subtle changes in cellular phenotype did not result in either gross or microscopi c abnormality of the liver. The treatment of these mice with the chemical c arcinogen, diethyinitrosamine, results in a significantly enhanced tumorige nesis in the liver when compared with the wild-type littermates. Our result s demonstrate the gene-dosage effect of T betaR-11 and indicate that the re duced expression of T betaR-11 in mice increases susceptibility to tumorige nesis in the liver.