gms | German Medical Science

59. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
3. Joint Meeting mit der Italienischen Gesellschaft für Neurochirurgie (SINch)

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

01. - 04.06.2008, Würzburg

Tumor-escape from anti-angiogenic therapy? Phenotypic changes induced by anti-VEGF treatment

Die Flucht des Tumors vor anti-angiogener Therapie? Phänotypische Veränderungen von Endothel- und Tumorzellen unter anti-VEGF-Therapie

Meeting Abstract

  • corresponding author S. Grau - Neurochirurgische Klinik, Klinikum Großhadern, LMU München
  • J. Thorsteinsdottir - Neurochirurgische Klinik, Klinikum Großhadern, LMU München
  • F. Winkler - Neurologische Klinik, Klinikum Großhadern, LMU München
  • L. von Baumgarten - Neurologische Klinik, Klinikum Großhadern, LMU München
  • J. C. Tonn - Neurochirurgische Klinik, Klinikum Großhadern, LMU München
  • R. Goldbrunner - Neurochirurgische Klinik, Klinikum Großhadern, LMU München

Deutsche Gesellschaft für Neurochirurgie. Società Italiana di Neurochirurgia. 59. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 3. Joint Meeting mit der Italienischen Gesellschaft für Neurochirurgie (SINch). Würzburg, 01.-04.06.2008. Düsseldorf: German Medical Science GMS Publishing House; 2008. DocDI.03.02

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgnc2008/08dgnc159.shtml

Veröffentlicht: 30. Mai 2008

© 2008 Grau 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 vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

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Objective: Neoangiogenesis is a critical feature in malignant solid tumors. Thus, anti-angiogenic therapies targeting the VEGF-A/VEGFR-2 system are promising adjuvant treatment modalities. First clinical and pre-clinical studies demonstrate that therapies using anti-VEGF-A antibodies (e.g. Bevacizumab, Avastin®) are capable to improve progression free survival in some solid tumors. However, increasing data show that during long-term anti-VEGF-A therapy, resistance phenomena resulting in secondary re-angiogenesis occur after a transient reduction and normalisation of tumor vascularisation. Thus, alternative signalling molecules are discussed to be involved in escaping anti-VEGF therapies.

Methods: Human brain derived endothelial cell lines and CD31 positive endothelial cells freshly isolated from glioblastoma as well as glioma cell lines U87, U373 and U251, were treated with bevacizumab (Avastin®) for different time periods. Cell growth, expression of vascular endothelial growth factors VEGF-A, VEGF-C, VEGF-D and VEGFR-3 were assessed. Additionally, intracellular and functional response of the cells to these factors were investigated.

Results: Bevacizumab decreased proliferation by 10% after 12 days of treatment in all cell types. No growth reduction was observed during short time treatment (four days). After long-term treatment all cell lines showed a significant up-regulation of VEGF-D protein expression. Even more, cells developed reactivity to VEGF-C and -D by means of increased proliferation while being unreactive to these substances before Bevacizumab treatment. VEGFR3 protein expression was not increased significantly, however, phosphorylation of VEGFR3 by VEGF-A, VEGF-C and -D was enhanced in cells treated with Bevacizumab. Intracellular response to VEGF, VEGF-C and -D changed in a cell type specific manner with a shift from Erk1/2 to p38 and SAP/JNK phosphorylation.

Conclusions: Treatment with anti-VEGF antibodies in glioma leads to a phenotypic change with upregulation of VEGF-D and increased reactivity to VEGF-C and -D accompanied by intracellular changes in signal transduction. This may represent an escape mechanism of the tumor to therapies targeting the VEGF-A/VEGFR-2 system with a secondary activation of the VEGF-C/D-VEGFR3 system.