Role of premalignant lesion and its significance in the promotion/progssion stage of colon carcinogenesis in Apc min mice.

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It is well known that Apc min mice develop intestinal tumors predominantly in the small intestine, but less number in the colon. In previous studies, we have identified the presence of a number of microadenomas in the colon of Apc min mice and showed that loss of heterozygosity of Apc is found in most of such microadenomas. These findings suggest that Apc LOH is responsible for microadenoma development, but is not sufficient for colon tumorigenesis. In order to identify alterations involved in promotion/progression stages of the carcinogenesis, we have performed mutational analysis and examined changes of protein expression in the colon tumors of Apc min mice. None of genetic alterations which are frequently found in human colon cancers, such as K-ras, p53 and B-raf gene mutations or microsatellite instability is not detectable at colon tumors in this model, suggesting that tumorigenesis process of this model is different from that of most human cancers. However, patterns of expression of many cancer-related proteins, such as PLK1, Aurora A, cyclin D1, Smad4, and MGMT which are identified by immunostainings are similar to those in human colon cancers, indicating the similarity of altered expressions between mice and humans. Further analyses are going on using genetically modified mouse models, combined with Apc min allele.