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2. Vascular endothelial growth factor receptor 2 (VEGFR-2) signalling activity in paediatric pilocytic astrocytoma is restricted to tumour endothelial cells

Author

Sikkema, A. H., de Bont, E. S. J. M., Molema, G., Dimberg, A., Zwiers, P. J., Diks, S. H., Hoving, E. W., Kamps, W. A., Peppelenbosch, M. P., den Dunnen, W. F. A., Gastroenterology & Hepatology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Stem Cell Aging Leukemia and Lymphoma (SALL), Faculteit Medische Wetenschappen/UMCG, Nanotechnology and Biophysics in Medicine (NANOBIOMED), Vascular Ageing Programme (VAP), Molecular Neuroscience and Ageing Research (MOLAR), Groningen Kidney Center (GKC), and Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE)

Subjects
ANGIOGENIC PROFILE, kinase activity profiling, GLIOBLASTOMA-MULTIFORME, PROXIMITY LIGATION, SOLID TUMORS, BEVACIZUMAB PLUS IRINOTECAN, angiogenesis, VEGFR-2, RECURRENT GLIOBLASTOMA, YOUNG-ADULTS, embryonic structures, cardiovascular system, laser microdissection, pilocytic astrocytoma, FACTOR-C, PHASE-II TRIAL, IN-VIVO
Abstract

Aims: Tumours depend on angiogenesis for enhanced tumour cell survival and progression. Vascular endothelial growth factor receptor (VEGFR) signalling plays a major part in this process. Previously, we evaluated tyrosine kinase activity in paediatric brain tumour tissue lysates using a peptide microarray containing 144 different tyrosine kinase peptide substrates. When applied to paediatric pilocytic astrocytoma tissue, this analysis revealed extensive phosphorylation of VEGFR-derived peptides. The aim of the current study was to validate this result and determine the presence of VEGFR-2 activity in paediatric pilocytic astrocytoma as the main VEGFR in terms of mitogenic signalling. In addition, the localization of VEGFR1-3 mRNA expression was assessed. Methods: VEGFR-2 phosphorylation was determined by adopting a proximity ligation assay approach. Enrichment of endothelial markers and VEGFRs in tumour endothelium was determined by quantitative polymerase chain reaction (qPCR) analysis of laser-microdissected blood vessels. Results: Proximity ligation assays on tumour cryosections showed the presence of phosphorylation of VEGFR-2, which primarily localized to vascular endothelium. qPCR analysis of endothelial markers and VEGFRs showed a 13.6-fold average enrichment of VEGFR-2 expression in the laser-microdissected endothelium compared to whole tumour. Also the expression of VEGFR-1 and -3 was highly enriched in the endothelium fraction with an average fold-enrichment of 16.5 and 50.8 respectively. Conclusions: Phosphorylated VEGFR-2 is detected on endothelial cells in paediatric pilocytic astrocytoma. Furthermore, endothelial cells are the main source of VEGFR1-3 mRNA expression. This suggests a crucial role for VEGF/VEGFR-induced angiogenesis in the progression and maintenance of these tumours.

Published
2011

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