There is a growing body of evidence that the Transforming growth factor-p (TGF-beta) family of peptides has critical functions in the gastrointestinal tract. In normal epithelial cells TGF-beta has a predominant growth- inhibitory effect and serves a tumor suppressor role. Neoplastic transformation results in loss of this normal growth-inhibitory response. Several lines of evidence reveal that the responses to TGF-beta may become predominantly tumor-promoting in the context of either prolonged exposure of cells to high levels of TGF-beta or after oncogenic transformation. Based on these observations, we have developed the following central hypothesis: Loss of TGF-beta tumor suppressor effects is a common consequence of neoplastic transformation, and tumor cell responses to TGF-beta promote angiogenesis and tumor growth due to a switch in signal transduction. We further hypothesize that TGF-beta causes a collaborative and synergistic induction of VEGF expression in epithelial cells that express a dominant oncogene such as Ras or cyclin D I . Our short-term goals to be pursued over the next five years are to test this hypothesis and to identify mechanisms for this switch in TGFbetaP responses. A long-term goal is to use this information to identify novel therapeutic strategies that selectively target the tumor promoting effects of TGF-BETA, while preserving the tumor-suppressive actions. Secondary hypotheses that emanate from the central hypothesis will be tested under the following specific aims.
Specific Aim 1 : Determine the mechanism for TGF-BETA regulation of VEGF gene expression, and the role of TGF-BETA-induced VEGF expression on tumor angiogenesis in colorectal cancer.
Specific Aim 2 : To examine the interaction of the Wnt/BETA-catenin signaling pathway with TGF-BETA responsiveness in colonocyte and hepatocyte cells.
Specific Aim 3 : To determine whether loss of TGF-BETA growth-inhibitory responsiveness or TGF-BETA tumor promotion contributes to hepatocellular tumorigenesis in the LFABP-cyclin D1 transgenic mice.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Surgery and Bioengineering Study Section (SB)
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May, Michael K
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Vanderbilt University Medical Center
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United States
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