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 (TGF a lpha) on hepatocarcinogenesis induced by simian virus 40 T antigen (TAg), l ivers from single and bitransgenic mice, 3 to 11 mice per line, were examin ed morphologically 1 to 8 weeks after birth. Mice carrying c-myc or TGF alp ha alone exhibited centrilobular hypertrophy and increased apoptosis (c-myc mice only) of hepatocytes after 3 or 4 weeks of age, but no detectable cha nges 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 mi totic 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 TGF alpha with TAg, nonpr oliferative lesions and mitotic and apoptotic indices were similar to those in mice carrying TAg alone. In TAg X c-myc bitransgenic mice, however, bot h preneoplastic and neoplastic lesions developed sooner and grew more rapid ly than those in TAg mice, whereas in TAg x TGF alpha bitransgenic mice, ra pid tumor growth was the principle observation. Because of the effects of t ransgene coexpression, livers from TAg x c-myc and TAg x TGF alpha mice had multiple tumors as early as 3 and 6 weeks of age, respectively. The result s indicate cooperative functions of c-myc and TGF alpha with TAg during dev elopment and/or growth of liver tumors in vivo.