Rare activation of the human c-Ha-ras transgene of mice in hemangioendothelial sarcomas and liver tumors induced by Glu-P-1.
A transgenic mouse (Tg), having the human c-Ha-ras proto-oncogene, has been demonstrated to develop hemangioendothelial sarcomas (HESs) which are associated with the transgene mutation, but not to develop liver tumors. In this study, we examined the effects of 2-amino-6-methyldipyrido [1,2-a:3',2'-d] imidazole (Glu-P-1), a food-borne carcinogen, which has been demonstrated to induce HESs and liver tumors in CDF1 mice, on Tg mice. Chronic administration of 0.05% Glu-P-1 in the diet induced HESs in Tg (7/17), but not in 18 non-transgenic mice (N-Tg). With basal diet, two out of 17 Tg but none of 22 N-Tg, developed HESs. In contrast, Glu-P-1 administration induced liver tumors, both in Tg and in N-Tg; 16/17 in Tg and 13/18 in N-Tg. The incidence of hepatocellular carcinomas in Tg was higher than that in N-Tg (8/17 versus 3/18). With basal diet, only one out of 17 Tg and none of 22 N-Tg developed liver tumors. The Ha-ras mutation in tumors developed by the groups administered Glu-P-1, was examined. No mutations were detected in the transgene and mouse c-Ha-ras genes in all three HESs examined. In contrast, when 29 liver tumors taken from Tg were examined, two mutations of the transgene were detected in two HCCs. No mouse c-Ha-ras gene mutations were detected in any of the 47 liver tumors examined, which had developed in Tg and N-Tg mice. These results suggest that the transgene plays a role in the development of HESs induced by Glu-P-1, but not as a result of its mutation. Further, the transgene plays no significant role in the development of liver tumors induced by Glu-P-1, but does play a role in the malignant conversion of some liver tumors, as a result of its mutation.
Inoue
R
R
Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan.
Ushijima
T
T
Katami
M
M
Kushida
H
H
Wakabayashi
K
K
Sato
H
H
Asamoto
M
M
Katsuki
M
M
Sugimura
T
T
Nagao
M
M
D000818:Animals; D001483:Base Sequence; D004273:DNA, Neoplasm / Q000737:chemistry; D005260:Female; D011905:Genes, ras / Q000187:drug effects* / Q000235:genetics; D006394:Hemangiosarcoma / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009153:Mutagens / Q000494:pharmacology*; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D000090063:Proto-Oncogene Mas
D004273:DNA, Neoplasm; D007093:Imidazoles; C000715470:MAS1 protein, human; D009153:Mutagens; D000090063:Proto-Oncogene Mas; C023785:2-amino-6-methyldipyrido(1,2-a-3',2'-d)imidazole