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Autocrine VEGFR1 and VEGFR2 signaling in glioblastoma

Emese Szabo, Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland; Hannah Schneider, Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland; Katharina Seystahl, Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland; Elisabeth Jane Rushing, Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland; Frank Herting, Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center, DE-82377 Penzberg, Germany; Michael Weidner, Roche Pharmaceutical Research and Early Development, Oncology DTA, Roche Innovation Center, DE-82377 Penzberg, Germany; Michael Weller, Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland.


Although the vascular endothelial growth factor (VEGF) / VEGF receptor (VEGFR) system has become a prime target of anti-angiogenic treatment, its biological role in glioblastoma beyond angiogenesis has remained controversial.
Using neutralizing antibodies to VEGF or placental growth factor (PlGF) or the tyrosine kinase inhibitor, cediranib, or lentiviral gene silencing, we delineate autocrine signaling in glioma cell lines.
VEGFR1 and VEGFR2 control glioma cell clonogenicity, viability and invasiveness in vitro in a cell line-specific manner. VEGFR1 silencing promoted mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK/ERK) signaling, whereas VEGFR2 silencing resulted in cell-type dependent activation of the protein kinase B (PKB)/AKT and MAPK/ERK pathways. These responses may represent specific escape mechanisms from VEGFR inhibition. The survival of orthotopic glioma-bearing mice was significantly prolonged upon VEGFR1 silencing in the LNT-229 and LN-308 xenograft models and upon VEGFR2 silencing in LN-308 model, associated with decreased tumor size and loss of matrix metalloproteinase 9 (MMP9) immunoreactivity. Neutralizing VEGF and PlGF by specific antibodies was superior to either antibody treatment alone in the VEGFR1-dependent LNT-229 model.
Thus differential dependence on autocrine signaling through VEGFR1 and VEGFR2 may provide a rationale for biomarker-stratified VEGF-based therapeutic approaches to glioblastoma.

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