CONSTITUTIVE EXPRESSION OF MATURE TRANSFORMING-GROWTH-FACTOR BETA-1 IN THE LIVER ACCELERATES HEPATOCARCINOGENESIS IN TRANSGENIC MICE

Transforming growth factor beta-1 (TGF-beta 1) is a potent inhibitor o f hepatocyte growth both in vivo and in vitro. In this study, we analy zed the effects of TGF-beta 1 on both naturally occurring and diethyln itrosamine-induced hepatocarcinogenesis using single transgenic TGF-be ta 1 and double transgenic c-myc/TGF-beta 1 mice in which the expressi on of both transgenes was targeted to the liver. Hepatocellular tumors developed spontaneously in 59% (10 of 17) of the TGF-beta 1 mice by 1 6-18 months of age, Coexpression of TGF-beta 1 and c-myc transgenes in the liver accelerated hepatic tumor growth in both the presence and a bsence of carcinogenic treatment, Moreover, diethylnitrosamine-initiat ed tumors in the c-myc/TGF-beta 1 mice showed a high rate of malignant conversion associated with a reduced expression or lack of TGF-beta r eceptor type II, The results suggest that overexpression of TGF-beta 1 may contribute to liver carcinogenesis and that loss of TGF-beta rece ptor type II transduced inhibitory growth signals and up-regulation of c-myc are critical steps in Liver tumor progression.