Tumor invasion and metastasis is a complex process involving multiple interactions between tumor cells and a variety of extracellular matrix proteins. Many matrix components, such as laminin and fibronectin, have been studied in detail regarding their putative roles in tumor progression. However, it is apparent that other cell-matrix interactions also play a role in this process. In this project it is proposed to investigate the expression of tenascin (-TN) and its receptor, alpha-v- beta-6, during the progression of oral squamous cell carcinoma TN is a large oligomeric glycoprotein which is present transiently in the extracellular matrix during development and is involved in morphogenic movements, tissue patterning and tissue repair. Tenascin has multiple domains, both adhesive and anti-adhesive, that interact with cells, fibronectin, and other extracellular matrix proteins. There are several isoforms of the molecule which result from alternative splicing. The biological significance of the alternatively spliced region of TN has been emphasized by several reports showing that the large TN splice variant is expressed at the onset of important cellular processes that need active cell migration or tissue remodeling. Recently, it has been shown that tenascin expression is upregulated in oral cancer (Tiita et al., 1994). Alpha -v-beta-6, a receptor for tenascin, has also been shown to be upregulated, in oral squamous cell carcinoma, although not expressed in normal oral mucosa (Breuss et al., 1995). So like tenascin, alpha-v-beta-6 is absent from normal tissue but is expressed at significant levels in the neoplastic condition. The hypothesis of this study is that tenascin plays a role in the progression of oral cancer by acting directly as a stimulatory modulator of tumor cell motility, invasion, or gene expression through interactions with the integrin alpha-v-beta-6.
The specific aims of this proposal are as follows: (1) To evaluate the expression of tenascin and its alternatively spliced isoforms and alpha-v-beta-6 in oral cancer, (2) To establish an animal model of oral carcinogenesis using beta-6 and tenascin """"""""knockout"""""""" mice. These studies should enrich our understanding of how the expression of novel matrix proteins like tenascin and its receptor, alpha-v-beta-6, participates in oral cancer progression.
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