REGULATION OF GROWTH BY ALPHA V INTEGRINS

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The alphavbeta6 integrin is frequently neo-expressed in human oral squamous cell carcinoma (SCCs), and is required for proliferation and migration and migration of SCC cell lines in vitro. The known extracellular matrix ligands that interact with alphavbeta6 are fibronectin and tenascin, which are abundant in the stromal matrix of SCCs. In addition, alphavbeta6 was recently shown to bind and activate latent TGFbeta. Knockout mouse studies strongly suggest that alphavbeta6 is required for activation of TGFbeta1 in the lung. TGFbeta is also known to regulate proliferation and invasion of many types of carcinomas, and to exert either inhibitory or stimulatory effects on carcinoma growth. Thus, alphavbeta6 may influence SCC progression either indirectly via activation of TGFbeta, or directly by transmitting signals through its cytoplasmic domain. Our preliminary data show that the proliferation of two different oral SCC lines strongly depends on alphavbeta6, and that a neutralizing antibody to alphavbeta6 interferes with the growth in nude mice of a highly aggressive oral SCC line, termed HSC-3. To characterize the role of alphav integrins in SCC growth in more detail and under more stringent conditions, we will employ several model systems, including panels of human SCC cell lines and chemically or genetically induced SCCs in mice. Several different experimental approaches will be used to assess alphav integrin function in tumor cell growth. First, we will disrupt alphavbeta6 function, or the function of all alphav integrins, using neutralizing antibodies or ligand analogs. We will also develop neutralizing antibodies with higher in vivo potency, and test their effects on SCC growth in different in vivo models. Second, we will manipulate alphavbeta6 expression in SCC cell lines and study growth of these cell lines in vivo. Third, we will generate transgenic mice that conditionally over-express beta6 in the tongue epithelium, under control of the Tet-On system. In these mice, chemical carcinogenesis in the presence or absence of alphavbeta6 at different stages of progression will be studied. In addition, we will investigate whether alphavbeta6 effects on SCC growth are mediated through activation of TGFbeta or through direct alphavbeta6 signaling.. The long-term goal of these studies is to provide a detailed understanding of the involvement of alphav integrins in the pathways that regulate oral SCC growth, invasion and progression. In addition, we are investigating the possibility of using neutralizing antibodies to alphav integrins for immunotherapy of oral cancer.