Glycosylation controls cooperative PECAM-VEGFR2-β3 integrin functions at the endothelial surface for tumor angiogenesis

• Published in: Oncogene 2018-08, Vol.37 (31), p.4287-4299
• Main Authors: Imamaki, Rie, Ogawa, Kazuko, Kizuka, Yasuhiko, Komi, Yusuke, Kojima, Soichi, Kotani, Norihiro, Honke, Koichi, Honda, Takashi, Taniguchi, Naoyuki, Kitazume, Shinobu
• Format: Article
• Language: English
• Subjects: 13/2; 631/45/221; 631/67/2328; 64/110; 82; 82/29; 82/51; 96; 96/63; Angiogenesis; Angiogenesis inhibitors; Animals; Anoikis; Apoptosis; Apoptosis - physiology; Cancer; Cell adhesion & migration; Cell adhesion molecules; Cell Adhesion Molecules - metabolism; Cell Biology; Cell surface; Cell survival; Cells, Cultured; CHO Cells; Cricetulus; Ectopic expression; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Glycoproteins; Glycosylation; Human Genetics; Humans; Integrin beta3 - metabolism; Internal Medicine; Internalization; Medicine; Medicine & Public Health; Mice; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Oncology; Sialyltransferases - metabolism; Signal transduction; Signal Transduction - physiology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascular endothelial growth factor receptors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0271-7

Most of the angiogenesis inhibitors clinically used in cancer treatment target the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway. However, the current strategies for treating angiogenesis have limited efficacy. The issue of how to treat angiogenesis and endothelial dysfunction in cancer remains a matter of substantial debate. Here we demonstrate a glycosylation-dependent regulatory mechanism for tumor angiogenesis. St6gal1 −/− mice, lacking the α2,6-sialylation enzyme, were shown to exhibit impaired tumor angiogenesis through enhanced endothelial apoptosis. In a previous study, St6gal1 −/− endothelial cells exhibited a reduction in the cell surface residency of platelet endothelial cell adhesion molecule (PECAM). In this study, we found that cooperative functionality of PECAM-VEGFR2-integrin β3 was disturbed in St6gal1 −/− mice. First, cell surface PECAM-VEGFR2 complexes were lost, and both VEGFR2 internalization and the VEGFR-dependent signaling pathway were enhanced. Second, enhanced anoikis was observed, suggesting that the absence of α2,6-sialic acid leads to dysregulated integrin signaling. Notably, ectopic expression of PECAM increased cell surface integrin-β3, indicating that the reduction of cell surface integrin-β3 involves loss-of-endothelial PECAM. The results suggest that the cell surface stability of these glycoproteins is significantly reduced by the lack of α2,6-sialic acid, leading to abnormal signal transduction. The present findings highlight that α2,6-sialylation is critically involved in endothelial survival by controlling the cell surface stability and signal transduction of angiogenic molecules, and could be a novel target for anti-angiogenesis therapy.