Grantee: University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
Researcher: Shi-Yuan Cheng
Grant Title: Interactions and Distinct Roles of Angiogenic Factors in Human Glioma Angiogenesis
https://doi.org/10.37717/99-52
Program Area: Researching Brain Cancer
Grant Type: Research Award
Amount: $439,364
Year Awarded: 1999
The progressive growth of human glioblastoma is dependent on neovascularization to develop blood vessels that provide nutrients and remove waste products from the interior regions of the neoplasm. In the absence of angiogenesis, glioma generally ceases to grow. Vascular endothelial growth factor-A (VEGF) has different splice variants and plays a major role in glioma angiogenesis. Angiopoietin-1 (Ang-1) involves in a later stage of the angiogenesis, vessel maturation, by activating its endothelial cell (EC) receptor, Tie-2. Ang-2, a natural antagonist of Ang-1, might play a dual role depending on the expression levels of VEGF. There are three current unanswered questions in glioma angiogenesis: 1). How do VEGF and Ang/Tie-2families work in concert during glioma angiogenesis? 2). How does Ang-2 exert its dual role in glioma angiogenesis? 3). Do various VEGF isoforms have distinct functions in glioma angiogenesis?
To test these hypotheses, we propose: 1). To determine the dual role of Ang-2 in VEGF-induced glioma angiogenesis. The dual role of Ang-2 will be determined using our VEGF overexpression system and a regulated VEGF receptor antagonist (truncated Flt-1) expression system to modulate the expression levels of VEGF in vivo. In addition, we also will examine the vessel regressive function of Ang-2 after VEGF expression is suppressed. 2). To determine whether Ang-1is responsible for recruiting mesenchymal cells, and whether such a function is mediated by platelet-derived growth factor B (PDGF-B) in VEGF-induced glioma angiogenesis. 3). To determine the distinct roles of VEGF121 and VEGF189 in glioma angiogenesis.
The effect on the bioactivityof the VEGF isoforms will be examined using EC cells isolated from various tissues purified VEGF proteins and extracellular matrix components from the isolated EC cells. The proposed work would greatly advance our knowledge toward understanding the glioma angiogenic process, and may lead to identification of new molecules that play important roles in glioma angiogenesis; and could have a significant impact in developing anti-angiogenic treatment for glioma. In particular, demonstration of the dual function of Ang-2 in glioma angiogenesis using our unique model system would provide vital information in designing multi-regiment therapies for human glioma.