Kužela seminar series
Fri 25 Nov. 2011, 14:00
Title: Autocrine VEGF-VEGFR2/Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth
Speaker: Dr. Petra Hamerlik, Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark
Malignant gliomas, including the most malignant variant glioblastoma multiforme (GBM), are rapidly growing destructive tumors that extensively invade the surrounding brain parenchyma. Robust neoangiogenesis and intratumoral heterogeneity are hallmark features of these brain malignancies, which contribute to their phenotypic plasticity and therapeutic resistance. The latter includes drugs that target the angiogenic interplay between Vascular Endothelial Growth Factor (VEGF) and its receptors, VEGFRs. Recent observations suggest that anti-VEGF compounds (blocking antibodies and tyrosine kinase inhibitors) administered in combination with or before radiation improve the responsiveness of solid tumors through radiosensitizing effects. While Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGF receptors may be expressed by cancer cells. GBMs are characterized by florid vascularization and aberrantly elevated Vascular Endothelial Growth Factor (VEGF). Anti-angiogenic therapy with Bevacizumab reduces GBM tumor growth, however clinical benefits are transient, invariably followed by tumor recurrence. We have found that the limited impact of BevacizumabVmediated VEGF blockage may reflect ongoing autocrine signaling through VEGFVEGFR2/NRP1, associated with VEGFR2/NRP1 recycling and a pool of active VEGFR2 in a cytosolic compartment of human Glioma Initiating Cells (GICs). Whereas Bevacizumab failed to inhibit pro-survival effects of VEGFR2-mediated signaling in our experiments, direct inhibition of VEGFR2 tyrosine kinase activity or shRNA-mediated VEGFR2 or NRP1 knockdown attenuated GIC viability. We propose that direct inhibition of VEGFR2 kinase may block the highly dynamic VEGF-VEGFR2/NRP1 pathway and inspire a GBM treatment strategy complementary to the currently prevalent ligand neutralization approach.