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

• Published in: The Journal of experimental medicine 2012-03, Vol.209 (3), p.507-520
• Main Authors: Hamerlik, Petra, Lathia, Justin D, Rasmussen, Rikke, Wu, Qiulian, Bartkova, Jirina, Lee, MyungHee, Moudry, Pavel, Bartek, Jr, Jiri, Fischer, Walter, Lukas, Jiri, Rich, Jeremy N, Bartek, Jiri
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal, Humanized - pharmacology; Autocrine Communication; Bevacizumab; Cell Proliferation; Cell Survival; Endosomes - physiology; Glioblastoma - blood supply; Glioblastoma - pathology; Glioblastoma - physiopathology; Glioblastoma - therapy; Humans; In Vitro Techniques; Medicin och hälsovetenskap; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - physiology; Neovascularization, Pathologic; Neuropilin-1 - antagonists & inhibitors; Neuropilin-1 - genetics; Neuropilin-1 - physiology; RNA, Small Interfering - genetics; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - physiology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - physiology
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20111424

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.