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Heterozygous Mice for the Transforming Growth Factor-ß Type II Receptor Gene Have Increased Susceptibility to Hepatocellular Carcinogenesis

Laboratory of Cell Regulation and Carcinogenesis [Y-H. I., H. T. K., I. Y. K., K-B. H., M. A., J-J. J., K. F., S-J. K.] and Laboratory of Experimental Carcinogenesis [V. M. F., S. S. T.], National Cancer Institute, Bethesda, Maryland 20892; Pathology/Histotechnology Laboratory, SAIC-Frederick Cancer Research and Development Center, Frederick, Maryland 21702 [D. C. H.]; and Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria 3050, Australia [A. S.]

The transforming growth factor-ß (TGF-ß) receptor complex and its downstream signaling intermediates constitute a tumor suppressor pathway. In many cancers, expression of TGF-ß type II receptor (TßR-II) is markedly decreased. 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 TßR-II gene are slightly less sensitive to the growth-inhibitory effect of TGF-ß when compared with wild-type littermates of same age. In addition, the proliferation index of hepatocytes as indicated by bromodeoxyuridine incorporation is mildly increased in the heterozygous mice. These subtle changes in cellular phenotype did not result in either gross or microscopic abnormality of the liver. The treatment of these mice with the chemical carcinogen, diethylnitrosamine, results in a significantly enhanced tumorigenesis in the liver when compared with the wild-type littermates. Our results demonstrate the gene-dosage effect of TßR-II and indicate that the reduced expression of TßR-II in mice increases susceptibility to tumorigenesis in the liver.

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