Rare Activation of the Human c‐Ha‐ras Transgene of Mice in Hemangioendothelial Sarcomas and Liver Tumors Induced by Glu‐P‐1

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Abstract
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. 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 of its mutation.