This application is to support the salary of the candidate to ensure him full-time capability to conduct investigations currently supported by a FIRST Award from the National Institute of Dental Research (DE-08680) into the biological roles of transforming growth factor-alpha (TGF-alpha) in the development of oral cancer. The candidate is currently an assistant professor at the Harvard School of Dental Medicine. His laboratory, the Laboratory of Molecular Carcinogenesis, is equipped to perform the experiments proposed in this application. There are currently three post- DMD graduate students and two research assistants in his laboratory. His laboratory has made the observation that expression of TGF-alpha is consistently associated with the onset of malignancy in oral cancers (Wong et al., 1988; Todd et al., 1989). More recently, they made the novel finding that eosinophils can deliver high quantities of TGF-alpha into tumor developing sites (Elovic et al., 1990). In view of the pleuripotential nature of this cytokine, particularly that of angiogenesis and mitogenesis, the following specific aims are designed to test the role of TGF-alpha in the malignant transformation of oral mucosal tissues from this cellular source. First, the hamster TGF-alpha cDNA will be clone to facilitate molecular detection of this gene's activity in the animal model, namely the cheek pouch of the Syrian hamster. A modification of the polymerase chain reaction will be used for this purpose. Second, we hypothesize that human eosinophils can express TGF-alpha and molecular characterization of this cytokine from this leukocyte will be performed. In-situ hybridization, Northern blotting, polymerase chain reaction (PCR) product restriction enzyme analysis, radioimmunoassay, and immunohistochemistry will be used to demonstrate TGF-alpha mRNA and product in eosinophils from patients with the idiopathic hypereosinophilic syndrome. Thirdly, we hypothesize that the eosinophil-derived TGF-alpha is involve in two phenotypes critical to the development of cancer: angiogenesis and mitogenesis. In vitro and in vivo models will be used to test these hypotheses. The investigations should open a new direction to examine the role of TGF- alpha in the tumor development process. The possible participation of this cytokine, as delivered by the eosinophils, in angiogenesis and mitogenesis are of great importance in cancer biology. Furthermore the association of the eosinophil with the expression of TGF-alpha will offer a new level of understanding how this leukocyte can influence epidermal growth factor receptor bearing cells (e.g. keratinocytes, and fibroblasts) in normal and pathological processes.
