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Autocrine VEGFR1 and VEGFR2 signaling promotes survival in human glioblastoma models in vitro and in vivo
- Source :
- Neuro-Oncology
- Publication Year :
- 2016
- Publisher :
- Oxford University Press, 2016.
-
Abstract
- BACKGROUND Although the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system has become a prime target for antiangiogenic treatment, its biological role in glioblastoma beyond angiogenesis has remained controversial. METHODS Using neutralizing antibodies to VEGF or placental growth factor (PlGF) or the tyrosine kinase inhibitor, cediranib, or lentiviral gene silencing, we delineated autocrine signaling in glioma cell lines. The in vivo effects of VEGFR1 and VEGFR2 depletion were evaluated in orthotopic glioma xenograft models. RESULTS VEGFR1 and VEGFR2 modulated glioma cell clonogenicity, viability, and invasiveness in vitro in an autocrine, 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 prolonged upon VEGFR1 silencing in the LNT-229, LN-308, and U87MG models and upon VEGFR2 silencing in LN-308 and U87MG. Disruption of VEGFR1 and VEGFR2 signaling was associated with decreased tumor size, increased tumor necrosis, or 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. CONCLUSIONS Differential dependence on autocrine signaling through VEGFR1 and VEGFR2 suggests a need for biomarker-stratified VEGF(R)-based therapeutic approaches to glioblastoma.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Cancer Research
Angiogenesis
Apoptosis
Tyrosine-kinase inhibitor
chemistry.chemical_compound
angiogenesis
Mice
0302 clinical medicine
Basic and Translational Investigation
Tumor Cells, Cultured
1306 Cancer Research
Extracellular Signal-Regulated MAP Kinases
Neovascularization, Pathologic
VEGF
Vascular endothelial growth factor
Autocrine Communication
2728 Neurology (clinical)
Oncology
030220 oncology & carcinogenesis
cardiovascular system
2730 Oncology
Female
Signal transduction
signaling
Signal Transduction
medicine.drug_class
10208 Institute of Neuropathology
Mice, Nude
610 Medicine & health
In Vitro Techniques
03 medical and health sciences
medicine
Animals
Humans
Autocrine signalling
Protein kinase B
Cell Proliferation
Vascular Endothelial Growth Factor Receptor-1
glioblastoma
Kinase insert domain receptor
Vascular Endothelial Growth Factor Receptor-2
Xenograft Model Antitumor Assays
10040 Clinic for Neurology
030104 developmental biology
chemistry
PlGF
Immunology
Cancer research
Neurology (clinical)
Subjects
Details
- Language :
- English
- ISSN :
- 15235866 and 15228517
- Volume :
- 18
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Neuro-Oncology
- Accession number :
- edsair.doi.dedup.....d0fef72e89864690768a92ef6e7108ca