Oral cancers comprise a significant fraction of human malignancies in the United States. Presently the molecular mechanism of oral carcinogenesis is poorly understood. The long- term objective of this laboratory is to elucidate the molecular pathway leading to the malignant transformation of oral mucosal tissues. This is a five-year research grant application proposing to use the cheek pouch of the Syrian hamster as an experimental model for the molecular study of oral carcinogenesis. The advantage of this animal model is that is allows closely monitoring of the oral mucosal tissues during malignant transformation by carcinogenic chemicals. Carcinoma development in this animal model closely resembles those arising in humans. Experimental evidence will be presented to show that a tumor-specific protein, transforming growth factor-alpha (TGF-alpha), is expressed in both human and hamster oral carcinomas. Since the cellular receptor to TGF- alpha, epidermal growth factor receptor, is also expressed in these tumor cells, we hypothesize that an autocrine growth mechanism is operative in these oral tumor cells. Currently autocrine growth is believed to be important in the pathogenesis of tumors. Therefore elucidating the molecular pathway leading to the tumor-specific expression of TGF-alpha will be of great fundamental importance towards the molecular understanding of carcinoma development, which accounts for more than ninety percent of all human tumors. Experiments are proposed to study both the biological significance and the molecular basis leading to the tumor-specific expression of TGF-alpha. During the first three years, the biological significance of TGF-alpha in the chemical transformation of oral mucosal tissues will be studied. In the first year (Phase I), the kinetics of aberrant TGF-alpha expression will be studied by in situ hybridization. In the second and third years (Phase II), experiments will be performed to verify the involvement of TGF- alpha in the autocrine growth of these chemically-induced oral tumors by gene-transfer techniques. For the last two years (Phase III), experiments are projected to study the genetic basis leading to the tumor-specific expression of TGF-alpha. Molecular cloning of the 5' regulatory region and its sequence analysis will be done to achieve this goal.
