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Glycosylation controls cooperative PECAM-VEGFR2-β3 integrin functions at the endothelial surface for tumor angiogenesis.
- Source :
-
Oncogene [Oncogene] 2018 Aug; Vol. 37 (31), pp. 4287-4299. Date of Electronic Publication: 2018 May 02. - Publication Year :
- 2018
-
Abstract
- 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 <superscript>-/-</superscript> mice, lacking the α2,6-sialylation enzyme, were shown to exhibit impaired tumor angiogenesis through enhanced endothelial apoptosis. In a previous study, St6gal1 <superscript>-/-</superscript> 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 <superscript>-/-</superscript> 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.
- Subjects :
- Animals
Apoptosis physiology
CHO Cells
Cells, Cultured
Cricetulus
Glycosylation
Humans
Mice
Sialyltransferases metabolism
Signal Transduction physiology
Cell Adhesion Molecules metabolism
Endothelial Cells metabolism
Endothelial Cells pathology
Integrin beta3 metabolism
Neovascularization, Pathologic metabolism
Neovascularization, Pathologic pathology
Vascular Endothelial Growth Factor Receptor-2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 37
- Issue :
- 31
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 29717262
- Full Text :
- https://doi.org/10.1038/s41388-018-0271-7