Molecular analyses of liver tumors in c-myc transgenic mice and c-myc and TGF-α double transgenic mice

It has been demonstrated that co-expression of c-myc and transforming growth factor α (TGF-α) as transgenes in the mouse liver results in a tremendous acceleration of neoplastic development in this organ as compared to expression of either transgene alone [Murakami, H., et al. (1993) Cancer Res., 53, 1719–1723]. In order to clarify the roles of transgenes and additional other genetic alterations during hepatocarcinogenesis, we analyzed liver tumors developed in albumin/c-myc transgenic mice and albumin/c-myc and MT-1/TGF-α double transgenic mice. High expression of TGF-α transgene was found in nine of 14 (64%) liver tumors in double transgenic mice, suggesting that TGF-α overexpression confers growth advantage during hepatocarcinogenesis. Only one of 14 (7%) liver tumors in double transgenic mice and none of 13 liver tumors in cmyc transgenic mice showed overexpression of insulin-like growth factor II (IGF-II). This result was in contrast to the report by Takagi et al. [Takagi, H., et al. (1992) Cancer Res., 52, 5171–5177] which showed overexpression of IGF-II in 75% of liver tumors in TGF-α transgenic mice and suggested that the presence of c-myc transgenes together with TGF-α from an early stage of hepatocarcinogenesis may lead to different carcinogenic pathways which are independent of IGF-II overexpression. Expression of c-myc transgene was found in most of the liver tumors, but at lower levels than non-tumorous parts of the liver in c-myc and double transgenic mice. These results suggest that c-myc transgene expression cooperates with TGF-α in the early stages of hepatocarcinogenesis but has growth disadvantage in later stages of hepatocarcinogenesis. There was no evidence of mutational activation of the H-ras gene or mutational inactivation of the p53 gene in any liver tumors developed in c-myc or double transgenic mice.