Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth
Research output: Contribution to journal › Journal article › Research › peer-review
Although vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) is traditionally regarded as an endothelial cell protein, evidence suggests that VEGFRs may be expressed by cancer cells. Glioblastoma multiforme (GBM) is a lethal cancer characterized by florid vascularization and aberrantly elevated VEGF. Antiangiogenic therapy with the humanized VEGF antibody bevacizumab reduces GBM tumor growth; however, the clinical benefits are transient and invariably followed by tumor recurrence. In this study, we show that VEGFR2 is preferentially expressed on the cell surface of the CD133(+) human glioma stem-like cells (GSCs), whose viability, self-renewal, and tumorigenicity rely, at least in part, on signaling through the VEGF-VEGFR2-Neuropilin-1 (NRP1) axis. We find that the limited impact of bevacizumab-mediated VEGF blockage may reflect ongoing autocrine signaling through VEGF-VEGFR2-NRP1, which is associated with VEGFR2-NRP1 recycling and a pool of active VEGFR2 within a cytosolic compartment of a subset of human GBM cells. Whereas bevacizumab failed to inhibit prosurvival effects of VEGFR2-mediated signaling, GSC viability under unperturbed or radiation-evoked stress conditions was attenuated by direct inhibition of VEGFR2 tyrosine kinase activity and/or shRNA-mediated knockdown of VEGFR2 or NRP1. We propose that direct inhibition of VEGFR2 kinase may block the highly dynamic VEGF-VEGFR2-NRP1 pathway and inspire a GBM treatment strategy to complement the currently prevalent ligand neutralization approach.
Original language | English |
---|---|
Journal | The Journal of Experimental Medicine |
Volume | 209 |
Issue number | 3 |
Pages (from-to) | 507-20 |
Number of pages | 14 |
ISSN | 0022-1007 |
DOIs | |
Publication status | Published - 12 Mar 2012 |
- Antibodies, Monoclonal, Humanized, Autocrine Communication, Bevacizumab, Cell Proliferation, Cell Survival, Endosomes, Glioblastoma, Humans, In Vitro Techniques, Neoplastic Stem Cells, Neovascularization, Pathologic, Neuropilin-1, RNA, Small Interfering, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Research areas
ID: 186868265