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Department of Pathology, Gifu University School of Medicine, Gifu 500-8705, Japan
Activating mutations in the ß-catenin gene is thought to be responsible for the excessive ß-catenin signaling involved in the majority of carcinogen-induced colonic carcinomas. To determine whether ß-catenin signaling is involved in the initial stage of colon carcinogenesis, mutational analysis of the gene and immunohistochemistry for ß-catenin protein were performed in the early appearing lesions, including aberrant crypt foci (ACF), of colonic mucosa in rats given azoxymethane. Male F344 rats received s.c. injections of azoxymethane at a dose of 15 mg/kg body weight, once weekly for 3 weeks, and they were sacrificed 10 weeks after the carcinogen treatment. The colonic mucosa was examined in en face preparations and in serial sections after the observation in whole mount preparations. Microscopical observations in the cross sections have shown two populations of histologically altered crypts. The first type had a macroscopic feature resembling ACF [histologically altered crypts with ACF appearance (HACAs)]. The second type of altered crypts did not have the ACF-like appearance and could not be clearly distinguished from adjacent normal crypts in whole mount preparations [histologically altered crypts with macroscopically normal-like appearance (HACNs)]. The ß-catenin gene mutations were recognized in 10 of 15 HACNs (67%) and 3 of 15 HACAs (20%). Frequent immunoreactivity of ß-catenin protein was seen in the cytoplasm of HACNs (13 of 15 cases), whereas apparent accumulation was not confirmed in any HACAs analyzed. These results suggest that (a) there are two types of putative preneoplastic lesions in cancer-predisposed colonic mucosa, and ß-catenin signaling may contribute to the initial stage of colon carcinogenesis; and (b) HACNs are more likely to be direct precursors of colon tumors than HACAs in the rat colon carcinogenesis.
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