An Oral Cancer Research Center (OCRC) is proposed that will focus on gaining an understanding, at the molecular level, of the factors- that control the invasive behavior of oral squamous cell carcinoma (SCC). This neoplasm is characterized by relentless invasion and growth. SCC cells infiltrate into adjacent tissues, degrading basement membranes and extracellular matrix, often disrupting tissue architecture and frequently engendering lymph node involvement and distant metastasis. Cellular activities that lead to invasion include growth factor-induced cell locomotion, interactions of extracellular matrix macromolecules with their receptors, and elaboration of matrix-degrading enzymes. The proposed Center comprises four research laboratories at the University of California, San Francisco that have considerable experience in defining molecules related to tumor invasion. Moreover, this group already established synergistic approaches to the analysis of the complex issues related to highly intricate and sequential processes like invasion. Project I studies the role of basement membrane laminins and cell-surface receptors in promoting cell invasion by disruption of the tumor-suppressor cadherin molecules. Project II addresses the importance of the alphav class of integrin receptors, which bind interstitial connective tissue molecules, in regulating cell growth and invasion. Project III explores regulation of proteinase expression promoted by growth factors produced in response to stromal-SCC invasion. Project IV studies the role of hyaluronic acid and the CD44 receptor in modulating tumor invasion by oral SCC. In addition, two pilot projects will examine (1) genetic alterations in oral SCC, using a new cytogenetic method (comparative genomic hybridization), and (2) the role of extracellular matrix tenascin and its receptor (alpha-v-beta-6) in progression of oral SCC, using receptor-null mice. The Center includes Administrative, Biostatistics, and Histopathology Cores to support the research efforts. It is anticipated that this diverse set of investigators assembled in a highly interactive and interdependent collective will advance our understanding of the underlying biological principles that govern the process of tumor invasion by oral SCC. Finally, although beyond the immediate scope of this proposal, advances in our basic knowledge in this area will suggest development of appropriate treatment modalities for invasive SCC.
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