Oral cancer is characterized by relentless growth and invasion, frequently resulting in distant metastasis. While significant progress has been made in defining the clinical and histopathological characteristics of cancer, the molecular mechanisms of tumor progression remain poorly understood. The major focus of the proposed Program Project is to further define the alterations that occur during the stepwise conversion of normal mucosa to oral dysplasia, and finally to invasive squamous cell carcinoma. The project comprises four interactive research laboratories at the University of California San Francisco. That have considerable experience in defining molecules related to tumor progression, including tumor marked analysis, growth factor and adhesion receptor function, signal transduction, and molecular genetics. Moreover, this group has already initiated approaches to the analysis of the complex issues related to the sequential processes characterizing tumor progression. Project I addresses the mechanism of TGF-alpha processing and its regulation by intracellular signaling pathways during carcinoma development. Project II will examine the importance of he alphav class of integrin receptors, which bind extracellular matrix ligands as well as the latent form of TGF- beta, in regulating cell growth and invasion. Project III will define the importance of specific cell adhesion systems in regulating survival, apoptosis and growth in normal and malignant oral keratinocytes. Project IV will analyze the role of human papillomavirus and MRP-8/14 in oral cancer pathogenesis. In addition, the Program will support intratumoral seed finding of young investigators proposing basic and clinical research projects in oral cancer. The two initial pilot projects will examine (1) p14/ARF status as a molecular predictor of oral cancer development, and (2) the role of fibronectin and its receptors in regulating invasion and growth of oral squamous cell carcinoma. These interactive research and feasibility projects will be supported by an administrative core, a cell culture/animal model core, and a histopathology core. Additional infrastructure support will be provided by the specialized cores of the newly established UCSF Comprehensive Cancer Center.