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Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth

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DOI

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  • Petra Hamerlik
  • Justin D Lathia
  • Rikke Rasmussen
  • Qiulian Wu
  • Jirina Bartkova
  • MyungHee Lee
  • Pavel Moudry
  • Jiri Bartek
  • Walter Fischer
  • Jiri Lukas
  • Jeremy N Rich
  • Jiri Bartek
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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 languageEnglish
JournalJournal of Experimental Medicine
Volume209
Issue number3
Pages (from-to)507-20
Number of pages14
ISSN0022-1007
DOIs
Publication statusPublished - 12 Mar 2012

    Research areas

  • 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

ID: 49729683