Colorectal carcinoma currently ranks as the second most frequent form of cancer in the United States, with an estimated 150,000 cases discovered each year, and 56,000 deaths as a result of the disease. In the past several years, remarkably progress has been made toward identifying the genetic changes which lead to the development of the disease. However, this progress has yet to result in the development of new therapies that prolong the survival of patients with late stage colon cancer. A promising area of research that may also lead to the development of novel therapeutic agents is the study of signal transduction pathways in colon tumor cells. My laboratory and others have been studying the expression and activity of the non-receptor tyrosine kinases of the src family and their potential roles in the growth regulation of colonic epithelial cells. Src activation is one of the most frequent epigenetic events in colon cancer, and occurs early in the development of the disease. We have demonstrated that inhibition of Src activity alone decreases tumorigenicity of human colon carcinoma cells. To determine the role of Src activation in tumorigenicity, we have examined the regulation of Src- mediated pathways critical to growth control. We have shown that Src activation directly induces expression of vascular endothelial growth factor (VEGF), and further, through constitutive association with focal adhesion kinase (FAK), inhibits apoptosis. The studies proposed for the renewal of this grant are designed to better understand the molecular basis by which Src activation promotes these biological events. We will test the hypothesis that aberrant Src/FAK signaling complexes deregulate downstream intermediates of a common """"""""Survival"""""""" pathway leading to VEGF expression and inhibition of apoptosis. While Src alone may be important to tumorigenic growth, both Src and Yes activation can occur in hepatic metastases, and with different prognostic results. Therefore, a second hypothesis to be tested in this proposal is that Src and Yes activation play distinct roles in tumor progression from those of tumorigenic growth.
The specific aims of the proposal are to: (1) determine the requirement of interaction with focal adhesion kinase (FAK) for Src/Yes to exhibit their tumorigenic and/or metastatic potentials; (2) determine the role(s) of Src and FAK in mediating a common survival pathway leading to expression of vascular endothelial growth factor and inhibiting apoptosis; and (3) Determine the structural domains of Src required for its tumorigenic phenotype and if specific structural domains of Src and Yes induce differences in metastatic potential of establish colon tumor cell lines. Results from these studies will clarify important signal transduction pathways required for tumorigenic growth and metastasis of colon tumor cells, and intermediates in these pathways may serve as prognostic markers and/or targets for the disease.
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