To investigate the interaction of the nuclear oncogene c-myc with different growth factors acting via tyrosine kinase kinase receptors, we have analyzed the mechanism of hepatocarcinogenesis in three lines of transgenic mice overexpressing c-myc alone and coexpressed with transforming growth factor-alpha (TGFalpha) or hepatocyte growth factor (HGF). We demonstrate that sustained overexpression of c-myc in the liver leads to cancer through highly abnormal cell proliferation. Coexpression of TGFalpha dramatically accelerated c-myc-associated hepatocarcinogenesis and provided a selective growth advantage to the tumor cells by both increasing their proliferation and reducing their susceptibility to apoptosis. Clusters of cells in preneoplastic lesions produced higher levels of TGFalpha suggesting a mechanism for clonal growth. Although there was high coexpression of TGFbeta1 and urokinase-plasminogen activator (uPA) in the liver of c-myc/TGFalpha mice, the neoplastic tissues showed very low levels of BAX and TGFbeta receptor type I and II, all proteins related to apoptosis and growth inhibition. Despite high levels of p53 and p21/WAF1, the tumors overexpressed cyclin D1, PCNA, cyclin B, cdc2 and showed changes in the phosphorylation state of Rb protein, suggesting a lack of checkpoints in the cell cycle as a cause of abnormal cell proliferation. Tumors arising in c-myc and c-myc/TGFalpha displayed increased levels of endogenous TGFalpha, confirming the importance of this growth factor for tumor promotion. In contrast, coexpression of HGF and c-myc in double transgenic mice decreased c-myc-induced cell proliferation, delayed the neoplastic process, and prevented malignant conversions of the preneoplastic lesions. These lesions exhibited decreased levels of HGF receptor, implying a mechanism of escape from the HGF modulation. Furthermore, tumor promotion by phenobarbital (PB) was completely inhibited in the c-myc/HGF transgenic line, while PB was an effective tumor promoter in the c-myc single transgenic mice. Taken together, our data indicate that HGF may act as liver tumor suppressor by preventing the growth of initiated hepatocytes.