Mucinous carcinoma of the colon in TGFβ1-deficient mice

T Doetschman, PhDa, I Ormsby, MSa, G Boivin, DVMb, J Hoying, PhDa, E Balish, MDc, S Engle, PhDa

aDepartment of Molecular Genetics and bDepartment of Comparative Pathology, University of Cincinnati College of Medicine, Cincinnati, OH, cDepartment of Surgery, University of Wisconsin Medical School, Madison, WI.

Tgfb1+/+ Rag2-/- and Tgfb1-/- Rag2-/- mice develop hyperplastic lesions in colon that are associated with granulocytic inflammatory foci. By 6 months mucinous carcinoma develops in all mutant mice, but rarely do hyperplastic lesions undergo transition to adenoma or carcinoma in control mice, suggesting that TGFbeta1 functions as a tumor suppressor at an early stage of tumorigenesis, namely, the hyperplasia/adenoma transition. Surprisingly, epithelial cell growth, genetic stability and inflammatory activity were the same in mutant and control mice, and the expression patterns of APC, p53 and beta-catenin were also not different. Inflammatory stress is the causative agent since germfree Tgfb1-/- Rag2-/- mice are free of inflammatory lesions, hyperplasia and cancer. Consequently, TGFbeta1 appears to suppress intestinal tumorigenesis at an early stage by maintaining epithelial tissue organization during inflammatory stress. The relationship between colon cancer in this mouse model and ulcerative colitis-associated mucinous carcinoma in human is presently being investigated.

KEY WORDS: Transforming Growth Factor beta, Colon Cancer, Growth Factors, Tumor Suppressor, Knockout, Mouse, Animal Model.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Carcinogenesis.

This presentation was a winner in our poster contest and was recognized with the Symposium Presidents' Award for Scientific Excellence.