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64th Annual Meeting of the German Society of Neurosurgery (DGNC)

German Society of Neurosurgery (DGNC)

26 - 29 May 2013, Düsseldorf

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Endothelial EphB4 mediates vascular resistance to antiangiogenic therapy

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  • Marcus Czabanka - Neurochirurgische Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany
  • Moritz Markel - Neurochirurgische Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany
  • Thomas Broggini - Neurochirurgische Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany
  • Irina Kremetskaia - Neurochirurgische Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany
  • Melina Nieminen - Neurochirurgische Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany
  • Peter Vajkoczy - Neurochirurgische Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany

Deutsche Gesellschaft für Neurochirurgie. 64. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC). Düsseldorf, 26.-29.05.2013. Düsseldorf: German Medical Science GMS Publishing House; 2013. DocMI.07.02

doi: 10.3205/13dgnc332, urn:nbn:de:0183-13dgnc3329

Published: May 21, 2013

© 2013 Czabanka et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

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Objective: Antitumor effects of Anti-VEGF treatment are limited by vascular resistance mechanisms. Pericyte-endothelial cell interactions are important mediators of vascular survival mechanisms. EphrinB2-EphB4 interactions induce pericyte-endothelial interactions. It was the aim of our study to analyze the influence of the EphrinB2-EphB4 system on vascular resistance and pericyte-endothelial cell interactions during Anti-VEGF therapy.

Method: An ecotropic retroviral vector (pLXSN) encoding full length EphB4 (EphB4 wt) was established and Phoenix E virus-producing cells were coimplanted with SF126 glioma cells in dorsal skinfold chambers (N=5) and sc xenografts (N=5). Intravital microscopy was performed focusing on vessel density (TVD). Subcutaneous tumor growth was assessed when tumors reached 50 mm3. Anti-VEGF treatment (Sunitinib 40mg/kg BW) was applied for 6 days. Pericyte-endothelial cell interactions were analysed by immunohistochemistry (Pecam-Desmin).

Results: Anti-VEGF therapy led to reduced vessel density (TVD) in control tumors (NaCl: 100±8 cm/cm2, SU: 40±2 cm/cm2). In EphB4wt tumors, TVD was not reduced by therapy (NaCl: 98±34cm/cm2, SU: 97±19 cm/cm2). Correspondingly, EphB4 wt tumors were resistant to Anti-VEGF therapy in sc xenografts (Control: 81±24,6mm3, EphB4wt: 136±55,8mm3). Tumor vessels in EPHB4 wt tumors were characterized by reduced permeability (Control: 0,86±0,03, EphB4: 0,76±0,07) and increased number of pericyte-endothelial cell interactions (Control: 0,41±0,13, EphB4: 0,82±0,02).

Conclusions: EphB4 mediates resistance to Anti-VEGF treatment by stabilizing vessel density and by altering pericyte-endothelial cell interactions.