A Core Human Primary Tumor Angiogenesis Signature Identifies the Endothelial Orphan Receptor ELTD1 as a Key Regulator of Angiogenesis

• Published in: Cancer cell Vol. 24; no. 2; pp. 229 - 241
• Main Authors: Masiero, Massimo, Simões, Filipa Costa, Han, Hee Dong, Snell, Cameron, Peterkin, Tessa, Bridges, Esther, Mangala, Lingegowda S., Wu, Sherry Yen-Yao, Pradeep, Sunila, Li, Demin, Han, Cheng, Dalton, Heather, Lopez-Berestein, Gabriel, Tuynman, Jurriaan B., Mortensen, Neil, Li, Ji-Liang, Patient, Roger, Sood, Anil K., Banham, Alison H., Harris, Adrian L., Buffa, Francesca M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-08-2013; Cell Press
• Subjects: Animals; Cell Growth Processes - physiology; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Genetic Predisposition to Disease; HCT116 Cells; Humans; Mice; Mice, Nude; Neoplasms - blood supply; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Signal Transduction
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2013.06.004

Limited clinical benefits derived from anti-VEGF therapy have driven the identification of new targets involved in tumor angiogenesis. Here, we report an integrative meta-analysis to define the transcriptional program underlying angiogenesis in human cancer. This approach identified ELTD1, an orphan G-protein-coupled receptor whose expression is induced by VEGF/bFGF and repressed by DLL4 signaling. Extensive analysis of multiple cancer types demonstrates significant upregulation of ELTD1 in tumor-associated endothelial cells, with a higher expression correlating with favorable prognosis. Importantly, ELTD1 silencing impairs endothelial sprouting and vessel formation in vitro and in vivo, drastically reducing tumor growth and greatly improving survival. Collectively, these results provide insight into the regulation of tumor angiogenesis and highlight ELTD1 as key player in blood vessel formation.
•A common core angiogenesis metasignature exists for different types of cancer•ELTD1 is upregulated in tumor endothelial cells and is a good prognostic marker•VEGF/DLL4 regulate ELTD1, which is important for tip cell function and angiogenesis•ELTD1 inhibition blocks tumor angiogenesis and substantially inhibits tumor growth