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61. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC) im Rahmen der Neurowoche 2010
Joint Meeting mit der Brasilianischen Gesellschaft für Neurochirurgie am 20. September 2010

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

21. - 25.09.2010, Mannheim

VEGFR-3 pathway as a possible escape mechanism from anti-VEGF-A therapy in glioblastoma

Meeting Abstract

  • Jun Thorsteinsdottir - Neurochirurgische Klinik und Poliklinik, Klinikum der Universität München-Großhadern, Deutschland
  • Jörg-Christian Tonn - Neurochirurgische Klinik und Poliklinik, Klinikum der Universität München-Großhadern, Deutschland
  • Christian Schichor - Neurochirurgische Klinik und Poliklinik, Klinikum der Universität München-Großhadern, Deutschland
  • Stefan Grau - Neurochirurgische Klinik und Poliklinik, Klinikum der Universität München-Großhadern, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 61. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC) im Rahmen der Neurowoche 2010. Mannheim, 21.-25.09.2010. Düsseldorf: German Medical Science GMS Publishing House; 2010. DocP1713

DOI: 10.3205/10dgnc184, URN: urn:nbn:de:0183-10dgnc1842

Veröffentlicht: 16. September 2010

© 2010 Thorsteinsdottir et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

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Objective: Neo-angiogenesis in gliomas is related to the expression of VEGF-A and its receptor VEGFR-2. Anti-VEGF-A therapy in combination with chemotherapy is an emerging treatment concept for malignant glioma. In various animal glioma models, anti-VEGF-A-therapy, e.g. with bevacizumab, a neutralizing antibody against VEGF-A, normalized pathological architecture of tumor vasculature and increased response to chemotherapy and radiation. However, this phenomenon was transient. The underlying causes for the observed secondary onset of re-angiogenesis are unclear. VEGFR-3, the receptor for VEGF-C and -D, is expressed in glioma endothelium in a tumor grade dependent manner. Thus we investigated the role of this receptor and its ligands in respect to anti-VEGF-A therapy.

Methods: Human glioblastoma cells (U87, U251), endothelial cells (HBMEC) and isolated endothelial cells (EC) from glioblastoma were treated with bevacizumab (Avastin®) for 5 and 14 days respectively. The influence of anti-VEGF-A-therapy regarding the activity of the VEGFR-3 pathway by means of proliferation, secretion of VEGF-A, -C and -D, endothelial tube formation and intracellular signal mechanisms such as MAP kinase phosphorylation were investigated.

Results: Short-time treatment with bevacizumab showed no effect on tumor or endothelial cells. Long-term treatment (10 to 14 days) reduced tumor cell and EC proliferation significantly (p<0.01). The absence of VEGF-A did not affect the phosphorylation status of VEGFR-3, but it induced cellular reactivity of tumor and endothelial cells to VEGF-C, -D and -C156s (a specific ligand for VEGFR-3) by means of increased proliferation and EC tube formation (p<0.01). In tumor cells, bevacizumab induced up-regulation of VEGF-C and -D on the mRNA level and the secretion of VEGF-D, whereas secretion of VEGF-A was down-regulated. Furthermore, anti-VEGF-A treatment changed the activation of intracellular pathways, showing increased activation of p38MAPK in EC and SAPK/JNK in tumor cells.

Conclusions: These findings support the theory of activation of redundant pro-angiogenic signalling systems during anti-VEGF-A treatment. The VEGFR-3 pathway with its ligands and intracellular pathways may (amongst other molecules) serve as an alternative pathway to overcome the impact of anti-VEGF-A treatment. This may help in understanding complex changes observed during anti-VEGF-A therapy.