Establishment and Characterisation of Mouse Models for Colorectal Carcinoma

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Cancers of the intestine are among the most frequent tumors in the western countries. The process of colon carcinogenesis involves the stepwise, progressive disruption of cellular signalling cascades which are responsible for regulating cell proliferation, cell death and cellular differentiation. Environmental factors, like dietary components, as well as genetic mutations in tumor suppressor genes or oncogenes are known to mediate the initiation and progression of cancers in the intestinal tract. Recent evidence demonstrates the pivotal importance of the APC (adenomatous polyposis coli) and Ras signalling pathways in these processes, which are found to be misregulated in the vast majority of colon cancer cells (Pennisi, 1998, McCormick,1999). Murine models provide excellent opportunities to identify and define the roles of genes involved in colorectal cancer. The aim of this project is the establishment of mouse models for colon carcinogenesis by tissue-specific expression of transgenes like K-Ras an the APC target ß-catenin, and combination of mutated alleles in several loci by taking use of the already existing transgenic animals that are available in the group of D. Louvard. The resulting transgenic animals will be analyzed with molecular, biochemical and immunohistochemical techniques in order to elucidate the importance of the chosen transgenes for cell number homeostasis and carcinogenesis.