| First Author | Imamaki R | Year | 2018 |
| Journal | Oncogene | Volume | 37 |
| Issue | 31 | Pages | 4287-4299 |
| PubMed ID | 29717262 | Mgi Jnum | J:264007 |
| Mgi Id | MGI:6193232 | Doi | 10.1038/s41388-018-0271-7 |
| Citation | Imamaki R, et al. (2018) Glycosylation controls cooperative PECAM-VEGFR2-beta3 integrin functions at the endothelial surface for tumor angiogenesis. Oncogene 37(31):4287-4299 |
| abstractText | 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 alpha2,6-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 beta3 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 alpha2,6-sialic acid leads to dysregulated integrin signaling. Notably, ectopic expression of PECAM increased cell surface integrin-beta3, indicating that the reduction of cell surface integrin-beta3 involves loss-of-endothelial PECAM. The results suggest that the cell surface stability of these glycoproteins is significantly reduced by the lack of alpha2,6-sialic acid, leading to abnormal signal transduction. The present findings highlight that alpha2,6-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. |
