Abstract B25: Autocrine action of VEGF/VEGFR pathway in human Glioblastomas in addition to the paracrine angiogenic role

Angiogenesis is an important determinant for glioma growth and there is a growing interest in anti-angiogenic therapies as a way of blocking glioma development. To get insights into brain tumor angiogenesis, we have addressed the expression of a panel of angiogenesis regulatory proteins in 34 human Glioblasotmas (GBs) specimens. Methods: Immunohistochemistry (IHC) detection of Vascular endothelial growth factor (VEGF), Phosphorylated VEGF Receptor (PKDR), Hypoxia Inducible Factor (HIF-1) and the hypoxia marker Carbonic Anhydrase IX (CAIX). Results & Discussion: VEGF & PKDR cytoplasmic staining of variable intensity in tumoral cells and vascular endothelium was observed in all cases. The highest levels were seen around necrotic foci and in areas of endothelial proliferation. However, VEGF & PKDR expression by tumoral cells was shown also in non-hypoxic areas far away from necrotic foci. Hypoxia induces FIH expression, which in turn activates VEGF expression by tumoral cells. This is followed by diffusion, and interaction through a paracrine process with endothelial VEGF Receptors (VEGFR). Interaction between VEGF and VEGFR, induces activation and phosphorylation of VEGFR, triggering angiogenesis by the emission of vascular sprouts. Our finding of high levels of PKDR by neoplastic cells indicates that interaction and activation of the VEGF/VEGFR pathway can be as well an autocrine process. As VEGF is a powerful growth factor, this support that in addition to angiogenic induction, VEGF may play an active role in neoplastic cell growth. The strong expression of VEGF & PKDR in non-hypoxic areas suggests that VEGF may be induced by other stimulus than hypoxia. This possibility my have a therapeutic influence in that treatment with VEGF blockers and or inhibitors, aimed at an antiangiogenic effect, could additionally act against neoplastic proliferation on neoplastic cells themselves. Supported by Grant to JCM, Fundacion de Investigacion Mutua Madrilena. Citation Information : Clin Cancer Res 2010;16(7 Suppl):B25