Molecular analyses of liver tumors in c-myc transgenic mice and c-myc and TGF-alpha double transgenic mice.
It has been demonstrated that co-expression of c-myc and transforming growth factor alpha (TGF-alpha) 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-alpha double transgenic mice. High expression of TGF-alpha transgene was found in nine of 14 (64%) liver tumors in double transgenic mice, suggesting that TGF-alpha overexpression confers growth advantage during hepatocarcinogenesis. Only one of 14 (7%) liver tumors in double transgenic mice and none of 13 liver tumors in c-myc 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-alpha transgenic mice and suggested that the presence of c-myc transgenes together with TGF-alpha 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-alpha 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.
Ohgaki
H
H
Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Sanderson
N D
ND
Ton
P
P
Thorgeirsson
S S
SS
D000818:Animals; D001483:Base Sequence; D003433:Crosses, Genetic; D017931:DNA Primers; D005091:Exons; D005260:Female; D016259:Genes, myc; D016158:Genes, p53; D011905:Genes, ras; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D011995:Recombination, Genetic; D012709:Serum Albumin / Q000096:biosynthesis / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics*
D017931:DNA Primers; D016271:Proto-Oncogene Proteins c-myc; D012709:Serum Albumin; D016211:Transforming Growth Factor alpha; D007335:Insulin-Like Growth Factor II