Interactive effects of c-myc and transforming growth factor alpha transgenes on liver tumor development in simian virus 40 T antigen transgenic mice.

To analyze the effects of c-myc and transforming growth factor alpha (TGFalpha) on hepatocarcinogenesis induced by simian virus 40 T antigen (TAg), livers from single and bitransgenic mice, 3 to 11 mice per line, were examined morphologically 1 to 8 weeks after birth. Mice carrying c-myc or TGFalpha alone exhibited centrilobular hypertrophy and increased apoptosis (c-myc mice only) of hepatocytes after 3 or 4 weeks of age, but no detectable changes in cell proliferation or proliferative lesions were observed in either line during the 8 weeks. Mice carrying TAg alone exhibited increased cell proliferation, apoptosis, and dysplasia of hepatocytes with notably high mitotic and apoptotic indices as major changes before development of putative preneoplastic lesions after 4 weeks of age and neoplastic lesions after 6 weeks. In bitransgenic mice coexpressing c-myc or TGFalpha with TAg, nonproliferative lesions and mitotic and apoptotic indices were similar to those in mice carrying TAg alone. In TAg x c-myc bitransgenic mice, however, both preneoplastic and neoplastic lesions developed sooner and grew more rapidly than those in TAg mice, whereas in TAg x TGFalpha bitransgenic mice, rapid tumor growth was the principle observation. Because of the effects of transgene coexpression, livers from TAg x c-myc and TAg x TGFalpha mice had multiple tumors as early as 3 and 6 weeks of age, respectively. The results indicate cooperative functions of c-myc and TGFalpha with TAg during development and/or growth of liver tumors in vivo.