The long term objectives of this proposal are to elucidate the role of TPF (for Tumor Promoting Factor), a recently identified secretory molecule which is overexpressed in a wide range of human tumors, in the pathological process of tumorigenesis. Although significant progress has been made in recent years in studies of molecular events associated with tumor progression, much more needs to be done to further our understanding of the molecular mechanisms underlying specific pathological processes, such as angiogenesis, tumor migration and metastasis. It is important to identify and investigate the functions of novel factors associated with these processes. In this context, the investigator's preliminary results strongly suggest that TPF possesses the functional and structural characteristics as such a factor, as non-metastatic tumor cells engineered to overexpress the molecule grow aggressively and form dramatically enlarged tumors in an animal model system. Furthermore, TPF appears to have a significant effect on the survival of microvascular endothelial cells under serum-starved condition. To firmly establish a specific role for TPF in the multistep process of carcinogenesis the investigator will focus studies on two Specific Aims.
For Aim 1, he will define the molecular nature of functional mechanism for TPF under both in vitro and in vivo conditions. He will test if TPF acts to affect the functions of microvascular endothelial cells using established systems assaying for angiogenesis. He will also test the effect of TPF overexpression on tumor progression in a recently established model system using human epithelial cells and nude mice.
For Aim 2, he will identify and isolate the receptor or binding target of TPF using several established approaches and lay the ground work for future studies on the mechanism by which TPF potentiates tumor progression and metastasis. Tumorigenesis is a complex multistep process. To significantly advance the knowledge of molecular events underlying tumor progression and metastasis, novel factors involved in this pathological process need to be identified and characterized. Thus, the accomplishment of these proposed studies will provide further understanding of the molecular mechanism by which TPF promotes tumor progression and contribute to the development of novel therapeutics for the treatment of human cancers.
