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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA067944-02
Application #
2111759
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1995-09-30
Project End
1999-07-31
Budget Start
1996-07-19
Budget End
1996-07-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Strang Cancer Prevention Center
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10021
Kuraguchi, M; Yang, K; Wong, E et al. (2001) The distinct spectra of tumor-associated Apc mutations in mismatch repair-deficient Apc1638N mice define the roles of MSH3 and MSH6 in DNA repair and intestinal tumorigenesis. Cancer Res 61:7934-42
Kuraguchi, M; Edelmann, W; Yang, K et al. (2000) Tumor-associated Apc mutations in Mlh1-/- Apc1638N mice reveal a mutational signature of Mlh1 deficiency. Oncogene 19:5755-63
Mahmoud, N N; Carothers, A M; Grunberger, D et al. (2000) Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis 21:921-7
Edelmann, W; Umar, A; Yang, K et al. (2000) The DNA mismatch repair genes Msh3 and Msh6 cooperate in intestinal tumor suppression. Cancer Res 60:803-7
Mahmoud, N N; Bilinski, R T; Churchill, M R et al. (1999) Genotype-phenotype correlation in murine Apc mutation: differences in enterocyte migration and response to sulindac. Cancer Res 59:353-9
Heyer, J; Escalante-Alcalde, D; Lia, M et al. (1999) Postgastrulation Smad2-deficient embryos show defects in embryo turning and anterior morphogenesis. Proc Natl Acad Sci U S A 96:12595-600
Smits, R; Kielman, M F; Breukel, C et al. (1999) Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes Dev 13:1309-21
Edelmann, W; Yang, K; Kuraguchi, M et al. (1999) Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice. Cancer Res 59:1301-7
Edelmann, W; Cohen, P E; Kneitz, B et al. (1999) Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat Genet 21:123-7
Augenlicht, L H; Anthony, G M; Church, T L et al. (1999) Short-chain fatty acid metabolism, apoptosis, and Apc-initiated tumorigenesis in the mouse gastrointestinal mucosa. Cancer Res 59:6005-9

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