Recent evidence demonstrates that cell adhesion receptors play an important role in growth regulation of neoplastic cells in vitro, and in the control of tumor development in animals. Individual members of the integrin family of heterodimeric cell surface adhesion receptors have been found to have either positive or negative effects on tumor growth. They have shown that the alpha5 / beta1 integrin, a receptor for fibronectin, can suppress tumor growth when it is over-expressed in human colon carcinoma xenografts. They have also demonstrated that alpha5/beta1 can protect carcinoma cells against apoptosis. They hypothesize that the two effects are inter-related. Thus, the intent of this proposal is to understand the mechanistic basis of these effects. Since it has become clear that integrins are signal transducing receptors, much of the proposal will focus on the question of how alpha5/beta1 expression may affect signaling pathways in carcinoma cells. In this proposal they will explore three major issues. First, they will determine the structural features of the integrin alpha5 subunit that contribute to its signaling, growth suppressive, and anti-apoptotic functions. Second, they will determine how ectopic over-expression of alpha5/beta1 negatively regulates known pathways for signal transduction in carcinoma cells, particularly the Ras pathway. Third, they seek to ascertain the mechanism involved in alpha5/beta1 mediated suppression of apoptosis. These investigations should allow them to elucidate the most critical aspects of the tumor suppressive and anti-apoptotic actions of the alpha5/beta1 integrin in carcinomas. They should also provide important and broad ranging insights into the role of integrins in the regulation of intracellular signaling processes, and in the control of tumor cell growth. They may also open up new opportunities for the design of agents to control tumor growth.
