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Laboratory of Experimental Carcinogenesis, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892
Transforming growth factor ß-1 (TGF-ß1) is a potent inhibitor of hepatocyte growth both in vivo and in vitro. In this study, we analyzed the effects of TGF-ß1 on both naturally occurring and diethylnitrosamine-induced hepatocarcinogenesis using single transgenic TGF-ß1 and double transgenic c-myc/TGF-ß1 mice in which the expression of both transgenes was targeted to the liver. Hepatocellular tumors developed spontaneously in 59% (10 of 17) of the TGF-ß1 mice by 16–18 months of age. Coexpression of TGF-ß1 and c-myc transgenes in the liver accelerated hepatic tumor growth in both the presence and absence of carcinogenic treatment. Moreover, diethylnitrosamine-initiated tumors in the c-myc/TGF-ß1 mice showed a high rate of malignant conversion associated with a reduced expression or lack of TGF-ß receptor type II. The results suggest that overexpression of TGF-ß1 may contribute to liver carcinogenesis and that loss of TGF-ß receptor type II transduced inhibitory growth signals and up-regulation of c-myc are critical steps in liver tumor progression.
1 Supported by a grant from the Danish Cancer Society.
2 To whom requests for reprints should be addressed, at National Cancer Institute, Building 37, Room 3C28, 37 Convent Drive MSC4255, Bethesda, MD 20892-4255. Phone: (301) 496-5688; Fax: (301) 496-0734.
Received 1/28/97. Accepted 4/17/97.
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