Kužela seminar series

Fri 25 Nov. 2011, 14:00
CH1-222

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.