gms | German Medical Science

63rd Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Japanese Neurosurgical Society (JNS)

German Society of Neurosurgery (DGNC)

13 - 16 June 2012, Leipzig

VEGFR-3 is upregulated in glioblastoma-derived endothelial cells and tumor cells under hypoxic conditions and is a mediator for tumor resistance

Meeting Abstract

  • J. Thorsteinsdottir - Neurochirurgische Klinik und Poliklinik, Klinikum Großhadern, Ludwig-Maximilians-Universität München
  • J. Puymann - Neurochirurgische Klinik und Poliklinik, Klinikum Großhadern, Ludwig-Maximilians-Universität München
  • J.C. Tonn - Neurochirurgische Klinik und Poliklinik, Klinikum Großhadern, Ludwig-Maximilians-Universität München
  • C. Schichor - Neurochirurgische Klinik und Poliklinik, Klinikum Großhadern, Ludwig-Maximilians-Universität München

Deutsche Gesellschaft für Neurochirurgie. Japanische Gesellschaft für Neurochirurgie. 63. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie (JNS). Leipzig, 13.-16.06.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. DocFR.07.04

doi: 10.3205/12dgnc217, urn:nbn:de:0183-12dgnc2171

Published: June 4, 2012

© 2012 Thorsteinsdottir et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.



Objective: Under physiological conditions VEGFR-3 plays a role in early angiogenesis promoting vascular sprouting in embryos and is a key mediator for lymphangiogenesis in adults. Recent studies showed an increasing role of VEGFR-3 in tumorangiogenesis. Especially, in glioma, a grade-dependent expression of VEGFR-3 was detected. New anti-angiogenic therapies target the VEGF-system and cause a transient normalization of the pathological tumor vasculature, but long-term anti-angiogenic therapies showed an increase of hypoxic regions in animal models resulting in tumor resistance. As we could previously show that the ligands of VEGFR-3 (VEGF-C and VEGF-D) serve as an alternative system under anti-VEGF-A-therapy, we investigated the role of VEGFR-3 under hypoxic conditions.

Methods: Influence of hypoxia (0.1% O2 saturation) for 72 h on expression of VEGFR-2, VEGFR-3 and the ligands VEGF-A, VEGF-C and VEGF-D were investigated by PCR and Western Blot analysis in tumor cells (U87) and glioblastoma-derived endothelial cells (gbEC). Under hypoxic conditions and growth factor stimulation, proliferation of tumor and endothelial cells were analyzed by sulforhodamin-B-assay and in-vitro angiogenesis by tube formation assay. Inhibition of VEGFR-3 pathway regarding proliferation was mediated by MAZ51 (VEGFR-3-kinase-inhibitor) and inhibition of VEGFR-2 was mediated by Tyrphostin (tyrosine-kinase-inhibitor).

Results: In hypoxia, expression of VEGFR-3 is upregulated, whereas VEGFR-2 is downregulated on mRNA- and Western Blot-level. Hypoxia reduces proliferation of U87 and gbEC as well as tube formation in gbEC. VEGF-C156, a specific ligand for VEGFR-3, enhances hypoxia-compromised proliferation of gbEC, but not U87. Blocking of VEGFR-2 and VEGFR-3 in gbEC showed significant reduction of proliferation. Under hypoxia the effect of decreased proliferation rate by VEGFR-3-inhibition in gbEC was detectable, but reduced.

Conclusions: Under hypoxic conditions, VEGFR-3 is overexpressed and functionally activated in tumor and endothelial cells in glioblastoma. As experimental models show that long-term anti-angiogenic therapies result in tumor progression accompanied by an increase of hypoxic regions, VEGFR-3 should be considered as an alternative pathway which provides a resistance mechanism especially in the vascular endothelial system.