Oral squamous cell carcinoma (SCC) cells infiltrate into adjacent tissues, degrading basement membranes and extracellular matrix, and display unregulated growth. In contrast to normal mucosa where epithelial proliferation is highly regulated and is restricted to the basal cell layer, SCC cells proliferate rapidly throughout the suprabasal cell layers. Furthermore, the survival and growth of normal epithelial cells require signals generated by integrin-matrix interactions, and the detachment induced apoptosis (anoikis) is followed by induction of terminal differentiation. However, suprabasal oral SCC cells in vivo are devoid of integrin engagement generally escape apoptosis and are able to survive and proliferate. We have identified a novel mechanism by which oral SCC cells enhance their survival through formation of intracellular adhesions in a process we have called """"""""synoikis"""""""". The goal of the proposed research is to define the importance of both matrix and cell-cell adhesion in regulating survival and growth of oral SCC cells. The following specific aims will be addressed: 1) Determine how loss of integrin-ECM adhesion initiates anoikis. 2), Define the molecular basis of cell-cell adhesion-dependent survival in synoikis. 3). Determine how cell adhesion activates growth factor receptors. These studies will help expand our understanding, at the molecular level, of the mechanisms through which cell adhesion regulates survival and uncontrolled intratumoral growth of oral cancer and provide the biological basis for discovery of new therapeutic strategies targeted to this debilitating disease.
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