LAMININ AND ITS RECEPTORS IN ORAL CANCER

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The long term goal of Project I is to understand the adhesive mechanisms that regulate migration and invasion by oral squamous carcinoma (SCC) cells. Epithelial cells use two distinct adhesion systems: (1) the cadherins, a family of membrane proteins that mediate homotypic cell- cell adhesion, and (2) integrins, a family of heterodimeric receptors that form adhesions between cells and their extracellular matrix. Carcinoma invasion requires concurrent changes in both types of adhesion systems. Motility, an essential component of carcinoma invasion, is a continuum of events in which the cell extends pseudopodia, forms nascent attachments via integrin receptors, assembles and contracts the cytoskeleton, and finally, as it translocates forward, disengages distal adhesions. It is now apparent that integrins do not simply bind cells to matrix but also are potent signaling molecules. Initial engagement of integrins induces their condensation into focal contacts, forming anchors to the extracellular matrix and discrete signal-transducing complexes on the cytoplasmic surface. Oral SCC cells, like their normal counterparts, the mucosal keratinocytes, synthesize and adhere to a basement membrane that is rich in extracellular matrix components such as laminins and type IV collagen. Evidence suggests that migrating SCC cells use newly deposited kalinin (laminins) to facilitate their locomotion through the activation of alpha-3-beta-1 and alpha-6-beta-4 integrins. On the other hand, cadherins in oral SCC cells restrain tumor invasion. The hypothesis to be tested is that unregulated secretion and deposition of kalinin by SCC cells provides a migratory pathway promoting invasion through engagement of alpha-3 and alpha-6 integrins. A corollary hypothesis is that the cadherins act to restrict motility induced by integrin-ligand interactions. The specific aims are to (1) identify the laminin isoforms synthesized by oral SCC cells that stimulate cell motility, (2) determine how Beta-1 and Beta-4 integrin expression becomes unregulated in SCC cells, (3) define how cadherins regulate integrin-induced migration/invasion of SCC cells, and (4) assess the expression of kalinin and its receptors in tumor specimens of oral SCC. In summary, these studies will address how activation of specific integrin receptors by kalinin and other ligands induces the motile and invasive response. Other experiments will examine how kalinin-integrin interactions disturb cadherin dependent cell-cell adhesions. Finally, studies in collaboration with the Biostatistics and the Tissue and Histopathology Cores will determine the potential value of kalinin and its receptors as prognostic markers in predicting tumor behavior.