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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftJournal of Experimental Medicine
Vol/bind209
Udgave nummer3
Sider (fra-til)507-20
Antal sider14
ISSN0022-1007
DOI
StatusUdgivet - 12 mar. 2012

ID: 49729683