DIETARY INTERACTIONS WITH APC MUTATION IN COLON CANCER

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This application is a collaboration among 3 groups to develop and capitalize upon a unique mouse model in which the interaction of genetics and diet in the genesis of colon cancer can be defined. One of us has constructed the Apc 1638 mouse by inserting a targeted mutation in the Apc gene. This generates a truncated apc protein analogous to a major mutation which causes human familial polyposis. These mice develop multiple intestinal tumors at an early age, but in comparison to the previously reported Min mouse, in which a different mutation was randomly generated in the Apc gene, the Apc 1638 mice produce fewer intestinal tumors and consequently have a longer lifespan, in this model, we have found a dramatic affect of diet on the incidence of colonic neoplasms. A nutritional stress diet induces a large increase in tumors at an early stage in these animals. The diet is formulated on the principle of nutrient density to mimic major nutritional risk factors in the human Western diet - elevated fat and phosphate, decreased calcium and vitamin D. The purpose of the proposed experiments is to exploit this unique system for studies of gastrointestinal cancer etiology, pathogenesis and prevention. First, the model will be better characterized in terms of the kinetics of tumor formation in relation to morphometric parameters and pathology. Second, mutations, deletions and amplifications at loci mechanistically linked to the development and progression of colon cancer - Apc, dcc, p53, Ki-ras, c-myc - will be characterized in the tumors which arise, and carefully related to the pathology and etiological factors (ie targeted Apc mutation, nutritional elements, or both). This has not yet been reported for the Min mouse or other rodent models. Third, alterations of normal cell differentiation in the colon, including number and position of proliferating cells, apoptotic cells, and changes in expression of cellular and molecular markers, will be investigated for their role in initiating tumor formation in the flat mucosa of these animals. Thus, we will complete a description of the model and define the cellular and molecular events which precede and accompany tumor formation initiated by interaction of specific dietary and genetic factors. This model, which mimics the nutritional and genetic factors that underly the etiology of human colon cancer and which avoids the use of chemical carcinogens of unknown relevance to the human disease, should be extremely valuable for future studies in chemo- and nutritional prevention of colon cancer.