title: Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth.
abstract: 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.
authors.affiliation: Danish Cancer Society Research Center and Centre for Genotoxic Stress Research, DK-2100 Copenhagen, Denmark.
authors.forename: Petra
authors.initials: P
authors.lastname: Hamerlik
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.forename: Rikke
authors.initials: R
authors.lastname: Rasmussen
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: MyungHee
authors.initials: M
authors.lastname: Lee
authors.forename: Pavel
authors.initials: P
authors.lastname: Moudry
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Walter
authors.initials: W
authors.lastname: Fischer
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D019898:Autocrine Communication; D000068258:Bevacizumab; D049109:Cell Proliferation; D002470:Cell Survival; D011992:Endosomes / Q000502:physiology; D005909:Glioblastoma / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D066298:In Vitro Techniques; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000502:physiology*; D009389:Neovascularization, Pathologic; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D000068258:Bevacizumab; D040301:Vascular Endothelial Growth Factor Receptor-2