The invasive growth of carcinomas depends not only on soluble growth factors and activation of oncogenes. but also on altered interactions with the extracellular matrix that allow the tumor to spread. A family of cell surface receptors termed integrins, plays a central role in mediating cell responses to the extracellular matrix. Integrins interact with extracellular matrix proteins such as fibronectin, vitronectin, tenascin, collagen, and laminin and transmit signals that regulate gene expression, cell proliferation, survival. and morphology. In human oral cancer specimens, the expression of one major class of integrins, termed b 1 integrins, has been studied in some detail. The importance of another class of integrins termed av integrins, has only recently been recognized. Initial studies showed that at least three different av integrins are up-regulated in different cellular components of squamous cell carcinomas (scc) derived from the oral mucosa. The alpha-v-beta-6 integrin is neo-expressed in carcinoma cells, alphavbeta6 is strongly expressed in tumor-associated stromal cells, and alphavbeta3 is strongly expressed in blood vessels that support the growth and survival of the tumor. Thus, it is conceivable that inhibitors of av integrins could have potent effects on oral cancer growth and survival. It is proposed to extend the initial studies on integrin expression in oral carcinoma by analyzing a larger number of specimen from normal, hyperplastic and malignant oral mucosa, which will be processed and catalogued in conjunction with the oral cancer Tissue and Histopathology Core. The goal of this investigation is to confirm the correlation between oral cancer progression and av integrin expression and to evaluate the potential utility of av integrins as histopathological markers of oral cancer progression and prognosis. Furthermore, factors that regulate alpha-v-beta-6 expression in cultured SCC cells will be analyzed, and the hypothesis that alpha-v-beta-6 expression may be induced by stroma-derived signals will be tested. To assess the function of av integrins in oral carcinoma, we will test the effects of av-blocking antibodies on the growth and invasion of SCC cells in different in vitro models and compare the behavior of b6- negative SCC cell lines will be compared with that of their transfected counterparts overexpressing alpha-v-beta-6. Finally, the hypothesis that av integrins are involved in regulating the expression of proteases, growth factors, and cytokines in SCC cells will be tested. These studies will provide new insights into the role of cell matrix interactions in oral cancer, and will provide the basis for developing novel therapeutics that interfere with oral cancer growth and invasion by interfering with essential cell matrix interaction of SCC cells.
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