期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 209, 期 3, 页码 507-520出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20111424
关键词
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资金
- Danish Council for Independent Research/Medical Sciences [ID4765/11-105457]
- Czech Ministry of Education [MSM6198959216]
- Czech Ministry of Health [NT11065-5]
- European Commission [CZ.1.07/2.3.00/20.0019, CZ.1.05/2.1.00/01.0030]
- Danish National Research Foundation
- National Institutes of Health [NS054276, CA129958, CA116659]
- National Research Service Award [CA142159]
- American Brain Tumor Association
- Joelle Syverson Fund
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.
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