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Updated: Feb 11, 2026
Dual Bioluminescence Imaging of Tumor Progression and Angiogenesis
Published on: August 1, 2019
Glycosylation controls cooperative PECAM-VEGFR2-β3 integrin functions at the endothelial surface for tumor
Rie Imamaki1, Kazuko Ogawa1, Yasuhiko Kizuka1
1Disease Glycomics Team, Systems Glycobiology Research Group, RIKEN, Saitama, 351-0198, Japan.
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-/- 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.
Insights
Altered glycosylation, specifically the absence of α2,6-sialic acid, impairs tumor angiogenesis by disrupting endothelial cell survival and signaling. This suggests α2,6-sialylation is a novel target for anti-angiogenesis cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Current anti-angiogenesis cancer therapies targeting VEGF/VEGFR have limited efficacy.
- Endothelial dysfunction in cancer remains a significant therapeutic challenge.
- Glycosylation plays a role in regulating cellular processes, including angiogenesis.
Purpose of the Study:
- To investigate the role of α2,6-sialylation in tumor angiogenesis.
- To elucidate the molecular mechanisms by which altered glycosylation affects endothelial cell function and survival.
- To identify novel therapeutic targets for anti-angiogenesis therapy.
Main Methods:
- Utilized St6gal1-/- mice lacking the α2,6-sialylation enzyme.
- Analyzed endothelial cell apoptosis and anoikis.
- Investigated the cell surface expression and complex formation of PECAM, VEGFR2, and integrin β3.
- Examined VEGFR2 internalization and downstream signaling pathways.
- Assessed the effect of ectopic PECAM expression on integrin β3 levels.
Main Results:
- St6gal1-/- mice exhibited impaired tumor angiogenesis due to enhanced endothelial apoptosis.
- Loss of α2,6-sialic acid disrupted the cooperative function of PECAM-VEGFR2-integrin β3 complexes.
- VEGFR2 internalization and signaling were enhanced, while cell surface PECAM and integrin β3 were reduced.
- Absence of α2,6-sialic acid led to anoikis and dysregulated integrin signaling.
- Ectopic PECAM expression restored cell surface integrin β3 levels.
Conclusions:
- α2,6-sialylation is crucial for maintaining endothelial cell survival and stability of angiogenic molecules at the cell surface.
- Disruption of α2,6-sialylation impairs tumor angiogenesis by affecting PECAM-VEGFR2-integrin β3 signaling.
- α2,6-sialylation represents a potential novel therapeutic target for developing more effective anti-angiogenesis strategies in cancer treatment.
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