Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation

• Published in: Nature (London) 2008-07, Vol.454 (7204), p.656-660
• Main Authors: Tammela, Tuomas, Zarkada, Georgia, Wallgard, Elisabet, Murtomäki, Aino, Suchting, Steven, Wirzenius, Maria, Waltari, Marika, Hellström, Mats, Schomber, Tibor, Peltonen, Reetta, Freitas, Catarina, Duarte, Antonio, Isoniemi, Helena, Laakkonen, Pirjo, Christofori, Gerhard, Ylä-Herttuala, Seppo, Shibuya, Masabumi, Pytowski, Bronislaw, Eichmann, Anne, Betsholtz, Christer, Alitalo, Kari
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - pharmacology; Animal tumors. Experimental tumors; Animals; Antibodies, Monoclonal - pharmacology; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Dipeptides - pharmacology; Down-Regulation; Endothelial Cells - metabolism; Experimental tumors, general aspects; Female; Gene Expression Regulation, Neoplastic - drug effects; General aspects; Growth factors; Health aspects; Humanities and Social Sciences; Humans; Kinases; letter; Ligands; Macular degeneration; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred BALB C; Mice, Transgenic; Monoclonal antibodies; multidisciplinary; Neoplasms - blood supply; Neoplasms - drug therapy; Neovascularization; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Pharmacology. Drug treatments; Proteins; Receptors, Notch - metabolism; Retina; Rodents; Science; Science (multidisciplinary); Signal Transduction; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-3 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-3 - metabolism
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature07083

Anti-angiogenesis: VEGFR-3 shows its paces The vascular endothelial growth factor (VEGF) receptor subtype VEGFR-3 is expressed only on lymphatic endothelium in adults. A new study, however, finds that VEGFR-3 is upregulated in the vasculature of tumours by Notch signalling. VEGFR-3 inhibition interferes with tumour angiogenesis and tumour growth, in particular in combination with inhibitors of VEGFR-2, suggesting that it represents a novel anti-angiogenic target for cancer therapy. The vascular endothelial growth factor (VEGF) receptor subtype VEGFR-3 is only expressed on lymphatic endothelium in adults. However, VEGFR-3 is upregulated in the vasculature of tumours by Notch signalling. VEGFR-3 inhibition interferes with tumour angiogenesis and tumour growth, in particular in combination with inhibitors of the VEGFR-2, suggesting that it represents a novel anti-angiogenic target for cancer therapy. Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration 1 . Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells 2 . VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium 3 . However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds 4 , 5 . Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are r