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

• Published in: The FASEB journal Vol. 18; no. 2; pp. 1 - 25
• Main Authors: Erber, Ralf, Thurnher, Andreas, D. Katsen, Alice, Groth, Gesine, Kerger, Heinz, Hammes, Hans‐Peter, D. Menger, Michael, Ullrich, Axel, Vajkoczy, Peter
• Format: Journal Article
• Language: English
• Published: United States 01-02-2004
• Subjects: angiogenesis; Animals; Apoptosis; Cell Survival - drug effects; glioma; Hypoxia; Indoles - pharmacology; Microcirculation - drug effects; Models, Biological; Neoplasms - blood supply; Neovascularization, Pathologic - drug therapy; Pericytes - cytology; Pericytes - drug effects; Platelet-Derived Growth Factor - antagonists & inhibitors; Platelet-Derived Growth Factor - pharmacology; Pyrroles - pharmacology; Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor beta - metabolism; resistance; Signal Transduction - drug effects; tyrosine kinase inhibitors; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; vessel maturation
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.03-0271fje

Destruction of existing tumor blood vessels may be achieved by targeting vascular endothelial growth factor (VEGF) signaling, which mediates not only endothelial cell proliferation but also endothelial cell survival. In this study, however, intravital microscopy failed to demonstrate that targeting of VEGFR‐2 (by the tyrosine kinase inhibitor SU5416) induces significant regression of experimental tumor blood vessels. Immunohistochemistry, electron microscopy, expression analyses, and in situ hybridization provide evidence that this resistance of tumor blood vessels to VEGFR‐2 targeting is conferred by pericytes that stabilize blood vessels and provide endothelial cell survival signals via the Ang‐1/Tie2 pathway. In contrast, targeting VEGFR‐2 plus the plate‐let‐derived growth factor receptor (PDGFR)‐β system (PDGFR‐β signaling (by SU6668) rapidly forced 40% of tumor blood vessels into regression, rendering these tumors hypoxic as shown by phosphorescence quenching. TUNEL staining, electron microscopy, and apoptosis blocking experiments suggest that VEGFR‐2 plus PDGFR‐β targeting enforced tumor blood vessel regression by inducing endothelial cell apoptosis. We further show that this is achieved by an interference with pericyte‐endothelial cell interaction. This study provides novel insights into the mechanisms of how 1) pericytes may provide escape strategies to anti‐angiogenic therapies and 2) novel concepts that target not only endothelial cells but also pericyte‐associated pathways involved in vascular stabilization and maturation exert potent anti‐vascular effects.