The most common type of oral cancer is squamous cell carcinoma, which accounts for approximately nine of every ten oral malignancies. The morbidity these cancers cause--in altered appearance, loss of speech articulation, difficulty in eating, and pain--is out of proportion to their incidence. Most discouraging is the fact that about 50% of all patients with oral cancer die of their disease within five years. Squamous cell carcinoma of the oral cavity spreads by local extension and by lymphatic metastasis, The processes by which carcinoma cells at the primary site invade through the basement membrane, enter the lymphatics, and then arrest and grow in lymph nodes are poorly understood. It is likely that the tumor cell's repertoire of adhesion receptors is crucial in regulating not only cellular invasiveness but also cell proliferation. In the interaction of squamous carcinoma cells with the extracellular matrix, the integrins, a supergene family of heterodimer adhesion receptors, are known to be important. One of the integrins, the alpha6-beta4 complex, is specific to epithelial cells and its expression has been correlated with tumor progression and poor survival in oral squamous cell carcinoma. It has recently been established that this complex is associated with hemidesmosomes. In this proposal, we will address the following questions concerning the development of human oral squamous cell carcinoma: (1) What are the specific changes in the expression of integrin adhesion receptors as normal keratinocytes progress to dysplasia (premalignancy), to malignancy, and finally to nodal metastases? (2) Can in vitro correlations be made between integrin receptor expression on normal mucosal keratinocytes and oral squamous cell carcinoma cell lines and their adhesive and invasive activities toward relevant extracellular matrices? (3) Can the tumorigenic and invasive behavior of oral squamous cell carcinoma be modified by altering the function and/or expression of specific integrin receptors? Initially, we will focus on the alpha6-beta4 complex but eventually we will examine the other major integrins expressed. Using tissue biopsy specimens, we will compare the expression and distribution of integrin receptors in normal cells, dysplastic cells, and oral squamous cell carcinoma in order to establish a possible link between receptor expression and tumor progression. We will assess differences between cultured normal mucosal cells and squamous carcinoma cells in adhesion to extracellular matrix substrates and will search for correlations between adhesive behavior and integrin profiles. Panels of variant tumor cell lines with altered receptor profiles will be selected from parental cell populations by flow cytometry and tested for their invasive behavior. Antibodies that block specific receptor function will be tested for their effects on adhesion, migration, and invasion. Using molecular approaches, we will directly alter the level of integrin expression to further define their role in regulating cell-matrix interactions. These studies should increase our understanding of how alterations in the expression or function of specific integrin adhesion receptors in tumor progression influences the invasive behavior of oral cancer.
