There is a growing body of evidence that the Transforming growth factor-beta (TGF-beta) family of peptides has critical functions in the gastrointestinal tract. In normal epithelial cells, including intestinal epithelium, 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. Inactivating mutations of TGF-beta receptors and selected TGF-beta signal transduction proteins (Smad family proteins) have been associated with a significant fraction of human colorectal and pancreatic cancers. On the other hand, under selected conditions TGF-beta may actually promote tumorigenesis. 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: Tumor promoting effects of TGF-beta override tumor suppressor effects during transformation of intestinal and other types of epithelial cells, due to a switch in TGF-beta signal transduction. Despite loss of growth inhibitory signaling, the tumor promoting signaling via the TGF-beta receptors remains intact. Secondary hypotheses that emanate from the central hypothesis will be tested under the following specific aims.
Specific Aim 1 : To determine the mechanism of altered TGF-beta signaling in intestinal epithelial cells expressing ras oncogenes.
Under Aim 1 we will determine the mechanism for Smad4 down regulation under conditions of Ras transformation and we will determine the biological significance of this novel observation from our preliminary studies.
Specific Aim 2 : To determine the roles of Smad and Smad-independent signal transduction in tumor-promoting effects of TGF-beta in intestinal epithelial cells. In this Specific Aim we will determine the role of both Smad and Smad-independent signaling pathways in TGF-beta tumor promotion.
Specific Aim 3 : To determine the role of E-cadherin down regulation in the invasive phenotype induced by oncogenic Ras and TGF-beta. Under this aim, we will determine the mechanism and the biological importance of the down regulation of E-cadherin by Ras and TGF-beta for tumor formation and invasiveness. A long-term goal is to identify novel therapeutic strategies that selectively target the tumor promoting effects of TGF-beta, while preserving the tumor-suppressive actions.
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