The purpose of this project is to elucidate the molecular mechanisms of cell adhesion and recognition necessary for growth and migration of neoplastic and supporting cells in squamous cell neoplasms of the upper aerodigestive tract in order to develop approaches for pharmacologic and molecular prevention and therapy. A repertoire of integrin cell adhesion molecules that are overexpressed by squamous cell carcinomas and by the endothelial cells that form the vascular blood supply has been characterized by immunobiochemical and immunohistochemical methods. The ability of specific antibodies and small molecule receptor antagonists of these integrin receptors to inhibit attachment and growth of tumor and endothelial cells in vitro and in vivo has been the subject of ongoing investigations. The attachment of tumor cells to laminin, the extracellular matrix produced by the tumors, was shown to be predominantly due to three integrin receptors using specific antibodies, in vitro. Studies to evaluate whether these receptors play an important role in tumor development and may be suitable targets for therapy await the development of small molecule inhibitors to each of these receptors. In studies using endothelial integrin receptor antagonists, members of the integrin receptor family appear to be important in the growth and migration of endothelial cells during tumor- induced neoangiogenesis. In the past year, endothelial integrin receptor antagonists were identified which inhibit the growth of squamous cell carcinomas in vivo. The inhibitors were shown to directly inhibit proliferation of endothelial but not tumor cells in vitro, consistent with a primary effect upon angiogenesis.
