gms | German Medical Science

55. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e. V. (DGNC)
1. Joint Meeting mit der Ungarischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

25. bis 28.04.2004, Köln

Combined inhibition of VEGF- and PDGF-signaling enforces tumour vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms

Kombinierte Blockade der VEGF- und PDGF-abhängigen Signaltransduktion verstärkt die Regression von Tumorgefäßen durch die Störung perizyten-vermittelter endothelialer Überlebensmechanismen

Meeting Abstract

  • corresponding author Ralf Erber - Neurochirurgische Klinik, Universitätsklinikum Mannheim, Mannheim
  • A. Thurnher - Neurochirurgische Klinik, Universitätsklinikum Mannheim, Mannheim
  • M. D. Menger - Institut für klinische und experimentelle Chirurgie, Homburg/Saar
  • A. Ullrich - Max-Planck-Institut für Biochemie, Martinsried
  • P. Vajkoczy - Neurochirurgische Klinik, Universitätsklinikum Mannheim, Mannheim

Deutsche Gesellschaft für Neurochirurgie. Ungarische Gesellschaft für Neurochirurgie. 55. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 1. Joint Meeting mit der Ungarischen Gesellschaft für Neurochirurgie. Köln, 25.-28.04.2004. Düsseldorf, Köln: German Medical Science; 2004. DocMO.04.07

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgnc2004/04dgnc0050.shtml

Veröffentlicht: 23. April 2004

© 2004 Erber 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

Text

Objective

As all highly vascularized tumours, glioma fit into the concept of treating tumours by interfering with their angiogenesis. However, successful treatment of established human tumours might require not only prevention of angiogenesis but also destruction of existing tumour blood vessels. Recent studies have suggested that this may be achieved by targeting vascular-endothelial growth factor (VEGF) signaling. Paracrine signaling via platelet-derived growth factor B (PDGFB), expressed by endothelial cells, and its receptor PDGFR-β, expressed by pericytes, which plays a central role in blood vessel maturation. We therefore hypothesized that simultaneous targeting of endothelial cells and pericytes in tumours may enhance enforced tumour vessel regression. To test this we compared the effects of selective VEGFR inhibition versus VEGFR plus PDGFR-β inhbition on the established microvasculature of C6 tumour xenografts.

Methods

C6 glioma xenografts were implanted into dorsal skinfold chamber preparations. Tumour vascularization and growth were assessed by intravital multi-fluorescence video microscopy. Immunohistochemistry and electron microscopy were used to study pericyte-endothelial interactions. RT-PCR and in-situ hybridization were performed to analyse the expression of related angiogenic factors.

Results

Specific targeting of VEGF receptors (VEGFRs) failed to induce regression of tumour blood vessels in established C6 tumour xenografts. This resistance of tumour blood vessels to selective VEGFR inhibition is conferred by pericytes that (i) stabilize mature vessels, (ii) are secondarily recruited to immature vessels, and (iii) compensatorily provide endothelial cell survival signals upon VEGFR targeting. A strong upregulation of Ang-1 by pericytes and Tie2 by endothelial cells suggests that the Ang-1/Tie2 pathway plays a central role in tumour blood vessel protection following endothelial cell targeting. In contrast, simultaneous targeting of endothelial cells and pericytes by interfering with VEGFR and PDGFR-β signalling forced 40% of tumour blood vessels into regression.

Conclusions

A successful intervention in advanced tumours and long-term disease control with anti-angiogenic compounds may be achieved by targeting not only endothelial cells but also vascular stabilization and maturation. Furthermore, novel insight is provided of how pericytes differentially promote blood vessel stabilization and maturation via the Ang-1/Tie2 and PDGF-B/PDGFR-β pathways.