Differences in carcinogenesis by the length of carcinogen exposure period in rat colon

• Published in: Digestive diseases and sciences Vol. 46; no. 1; pp. 109 - 117
• Main Authors: ENDO, Tetsu, OOKAWA, Keizou, TANAKA, Masanori, NAKAJI, Shigeyuki, TSUCHIDA, Shigeki, SUGAWARA, Kazuo
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 2001; Springer Nature B.V
• Subjects: 1,2-Dimethylhydrazine - administration & dosage; Animals; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - administration & dosage; Carcinoma - chemically induced; Carcinoma - genetics; Carcinoma - pathology; Chemical agents; Colonic Neoplasms - chemically induced; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Genes, APC - genetics; Genes, ras - genetics; Medical sciences; Methylnitronitrosoguanidine; Mutation; Rats; Rats, Inbred F344; Time Factors; Tumors; Rat; Rodentia; Malignant tumor; Carcinogenesis; Colonic disease; Carcinogen; Vertebrata; Experimental disease; Mammalia; Animal; Risk factor; Digestive diseases; Genetics; Intestinal disease; Colon; Mutation; Exposure time; Onc gene
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1023/A:1005613926089

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.