The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2008-06, Vol.68 (12), p.4754-4762
• Main Authors: Heckman, Caroline A, Holopainen, Tanja, Wirzenius, Maria, Keskitalo, Salla, Jeltsch, Michael, Ylä-Herttuala, Seppo, Wedge, Stephen R, Jürgensmeier, Juliane M, Alitalo, Kari
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Angiogenesis Inhibitors - pharmacology; Animals; Blotting, Western; Cell Membrane Permeability - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Humans; Immunoprecipitation; Lymphangiogenesis - drug effects; Lymphangiogenesis - physiology; Male; Mice; Mice, Nude; Neovascularization, Pathologic - prevention & control; Phosphorylation - drug effects; Quinazolines - pharmacology; Signal Transduction; Skin - cytology; Skin - drug effects; Skin - metabolism; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor C - genetics; Vascular Endothelial Growth Factor C - metabolism; Vascular Endothelial Growth Factor D - genetics; Vascular Endothelial Growth Factor D - metabolism; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascular Endothelial Growth Factor Receptor-3 - genetics; Vascular Endothelial Growth Factor Receptor-3 - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-5809

Solid tumors express a range of factors required to sustain their growth and promote their dissemination. Among these are vascular endothelial growth factor-A (VEGF-A), the key angiogenic stimulant, and VEGF-C, a primary mediator of lymphangiogenesis. Small molecule tyrosine kinase inhibitors offer the potential to inhibit more than one kinase and impede tumor growth by multiple mechanisms. However, their potency toward individual targets can vary. Cediranib (RECENTIN; AZD2171) is an inhibitor of VEGF signaling that has been shown in experimental models to prevent VEGF-A-induced angiogenesis and primary tumor growth, yet the effects of cediranib on VEGF receptor (VEGFR)-3-mediated endothelial cell function and lymphangiogenesis are unknown. To better understand the activity of cediranib against VEGFR-3 and its associated signaling events compared with its activity against VEGFR-2, we used the receptor-specific ligands VEGF-E and VEGF-C156S. In human endothelial cells, cediranib inhibited VEGF-E-induced phosphorylation of VEGFR-2 and VEGF-C156S-induced phosphorylation of VEGFR-3 at concentrations of