Although mortality rates have declined over the past 20 years, cancer remains as one of the most intractable healthcare burdens in the U.S. and is expected to surpass heart disease as the leading cause of death in the next few years. In order for there to be improvements in clinical outcomes, a comprehensive understanding of the molecular mechanisms underlying tumorigenesis and tumor angiogenesis is required. The long-term goal of this project is to uncover novel signal transduction networks that regulate these processes so that new targets can be identified and alternative therapies can be developed. The overall objective of this application is to understand the novel molecular and cellular mechanisms by which the Tnfaip8 gene family regulates tumorigenesis, tumor angiogenesis and inflammation. The central hypothesis of this proposal is that members of Tnfaip8 gene family regulate mechanisms controlling tumorigenesis, tumor angiogenesis, and inflammation through their effects on tumor cells and the microenvironment. To test the central hypothesis, the following specific aims are proposed: (1) characterize the tumor cell-intrinsic roles Tnfaip8 gene family in the promotion of tumor development; (2) characterize the tumor cell-derived and stromal cellderived roles Tnfaip8 gene family members play in promoting angiogenesis; and (3) identify mechanisms by which novel angiogenesis-related genes are regulated by members of the tnfaip8 gene family. To fulfill the specific aims, many of the proposed studies will rely upon comparative functional genomics studies and be performed using zebrafish xenotransplantation models for tumorigenesis and tumor angiogenesis. Additional studies will be performed in in vitro tumor cell models to identify pathways in which members of the TNFAIP8 gene family members participate, both at the transcriptional and protein levels. Fulfillment of these specific aims is expected to yield critical data defining the roles that the TNFAIP8 gene family plays in regulating tumorigenesis in a vertebrate model organism.
The results obtained from the proposed studies are anticipated to have a positive impact because they are likely to uncover novel signal transduction networks that are regulating tumorigenesis, which may ultimately be leveraged by us to develop new anti-tumor and anti-angiogenic therapies. These data are likely to inform other significant biomedical topics, including embryonic development, cardiovascular disease, immunity, degenerative diseases, and aging.