Colorectal neoplasia is a leading cause of cancer morbidity and mortality in the United States. Although the genomics revolution has resulted in high profile advances in cancer therapeutics, these have not translated into a definitive improvement in the survival of patients with advanced disease. Thus, it is critical to continue the study of the molecular pathogenesis of colon cancer with the goal of improved diagnosis and treatment. Over the past decade, we have studied the autocrine growth inhibitory factor, transforming growth factor beta(TGFbeta), in normal and aberrant intestinal epithelial growth. During this interval, TGFbet, its receptor, and the Smad signaling pathway have been decisively recognized as a critical axis of tumor suppression in the intestinal epithelium. In certain contexts however, TGFbeta signaling may contribute to tumor promotion, a duality of function that is increasingly recognized in neoplastic disorders. We propose to explore this dual activity of TGFbeta in in vivo and in vitro models of intestinal neoplasia, especially in the context of oncogenic Ras, which we have defined as a key repressor of growth inhibitory Smad-dependent TGFbeta signaling. The overarching hypothesis is that TGFbeta is a tumor suppressor via Smad-dependent signaling early in tumorigenesis. At later stages of disease TGFbeta signaling switches, in part under the influence of oncogenic Ras, to tumor promotion.
The specific aims are to 1) test the hypothesis that histone deacetylases are Smad-binding partners and modulators of Smad-dependent signaling; 2) test the hypothesis, using microarray analysis, that TGFbeta induces a unique transcriptome in Ras-transformed cells and then use the results to further characterize TGFbeta as a tumor promoter; 3) test the hypothesis that TGFbeta will have both tumor suppressing and tumor promoting functions in animal models of TGFbeta signaling and colorectal cancer using genetically engineered mice in which TGFbeta signaling is enhanced. Dissection of the pathways involved in the tumor suppressive versus the tumor promoting effects of TGFbeta will lead to opportunities to selectively inhibit its undesirable effects without compromising its tumor suppressive functions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
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May, Michael K
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Nationwide Children's Hospital
United States
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