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

0390225 - ÚMG 2013 RIV US eng J - Článek v odborném periodiku
Hamerlik, P. - Lathia, J.D. - Rasmussen, R. - Wu, Q. - Bartkova, J. - Lee, M. - Moudrý, Pavel - Bartek, J. Jr. - Fischer, W. - Lukas, J. - Rich, J.N. - Bártek, Jiří
Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth.
Journal of Experimental Medicine. Roč. 209, č. 3 (2012), s. 507-520. ISSN 0022-1007. E-ISSN 1540-9538
Grant ostatní: Danish Council for Independent Research/Medical Sciences(DK) ID4765/11-105457; MZd(CZ) NT11065; MŠMT(CZ) CZ.1.07/2.3.00/20.0019; MŠMT(CZ) CZ.1.05/2.1.00/01.0030; NIH(US) NS054276; NIH(US) CA129958; NIH(US) CA116659; NRSA(US) CA142159
Program: NT
Výzkumný záměr: CEZ:AV0Z50520514
Institucionální podpora: RVO:68378050
Klíčová slova: VEGFR2 * cancer * GBM
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 13.214, rok: 2012

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.
Trvalý link: http://hdl.handle.net/11104/0219116