R. Inoue et al., RARE ACTIVATION OF THE HUMAN C-HA-RAS TRANSGENE OF MICE IN HEMANGIOENDOTHELIAL SARCOMAS AND LIVER-TUMORS INDUCED BY GLU-P-1, Japanese journal of cancer research, 87(6), 1996, pp. 583-588
A transgenic mouse (Tg), having the human c-Ha-ras proto-oncogene, has
been demonstrated to develop hemangioendothelial sarcomas (HESs) whic
h are associated with the transgene mutation, but not to develop liver
tumors. In this study, we examined the effects of 2-amino-6-methyldip
yrido [1,2-a:3',2'-d] imidazole (Glu-P-1), a food-borne carcinogen, wh
ich has been demonstrated to induce HESs and liver tumors in CDS mice,
on Tg mice. Chronic administration of 0.05% Glu-P-1 in the diet induc
ed HESs in Tg (7/17), but not in 18 non-transgenic mice (N-Tg). With b
asal diet, two out of 17 Tg but none of 22 N-Tg, developed HESs. In co
ntrast, 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 adminis
tered Glu-P-1, was examined. No mutations were detected in the transge
ne and mouse c-Ha-ras genes in all three HESs examined. In contrast, w
hen 29 liver tumors taken from Tg were examined, two mutations of the
transgene were detected in two HCCs. No mouse c-sa-ras gene mutations
were detected in any of the 47 liver tumors examined, which had develo
ped in Tg and N-Tg mice. These results suggest that the transgene play
s a role in the development of HESs induced by Glu-P-1, but not as a r
esult of its mutation. Futher, 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 o
f its mutation.