gms | German Medical Science

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.