To clarify the carcinogenic factors--whether it is the kind of
carcinogen or their length of exposure--that determine whether
colorectal cancer develops from an
adenoma or develops de novo in the absence of an
adenoma, we histopathologically analyzed a total of 229 rat colon
tumors induced by administration of
1,2-dimethyl-hydrazine (
DMH) or
N-methyl-N'-nitro-N-nitrosoguanidine (
MNNG) for three or 15 weeks. In the three-week-exposure groups, 71% of
DMH-induced
carcinomas and 82% of
MNNG-induced
carcinomas coexisted with low-grade dysplasia (adenomatous remnant). However, in the 15-week-exposure groups, lowgrade dysplasia was observed in only 10% of
DMH-induced and 27% of
MNNG-induced
carcinomas. Even in the
tumors smaller than 20 mm3, it was observed in only 10% of
DMH-induced and 32% of
MNNG-induced
carcinomas. Furthermore,
carcinomas without low-grade dysplasia predominated from the initial period of
tumor occurrence. Next, we investigated association of K-ras and APC gene mutations with these
carcinogenesis patterns in 80
tumors. K-ras mutations were not detected in any
tumors induced by three weeks of exposure. However, in the 15-week-exposure groups, this mutation was observed in 57% of
DMH-induced
tumors and 13% of
MNNG-induced
tumors. APC mutations in the region homologous to the human mutation cluster region were observed in only 6% of
tumors. Thus, our results suggest that the
carcinogenesis patterns in rat colon are dependent on the length of exposure to
carcinogen and that K-ras mutations were partly involved in a subset of them.