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

Oncogene volume 37, pages 4287–4299 (2018)Cite this article

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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.

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Acknowledgements

This work was supported by grants from the Systems Glycobiology Research Project and the Strategic Programs for R&D of RIKEN (to N.T.), MEXT/JSPS KAKENHI grant numbers 16K08601 and 25430122 (to S.K.), and a grant from the Mitsubishi Foundation (to S.K.). The authors would like to acknowledge Dr. Jamey D. Marth for providing the St6gal1−/− mice and the RIKEN BSI-Olympus Collaboration Center for technical support.

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Authors and Affiliations

  1. Disease Glycomics Team, Systems Glycobiology Research Group, RIKEN, Saitama, 351-0198, Japan

    Rie Imamaki, Kazuko Ogawa, Yasuhiko Kizuka, Naoyuki Taniguchi & Shinobu Kitazume

  2. Molecular Ligand Biology Research Team, RIKEN, Saitama, 351-0198, Japan

    Yusuke Komi & Soichi Kojima

  3. Department of Biochemistry, Saitama Medical University, Saitama, 350-0495, Japan

    Norihiro Kotani

  4. Department of Biochemistry, Kochi University Medical School, Kochi, 783-8505, Japan

    Koichi Honke

  5. Department of Human Life Sciences, School of Nursing, Fukushima Medical University, Fukushima, 960-1295, Japan

    Takashi Honda

  6. Preparing section for New Faculty of Medical Science, Fukushima Medical University, Fukushima, 960-1295, Japan

    Shinobu Kitazume

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Imamaki, R., Ogawa, K., Kizuka, Y. et al. Glycosylation controls cooperative PECAM-VEGFR2-β3 integrin functions at the endothelial surface for tumor angiogenesis. Oncogene 37, 4287–4299 (2018). https://doi.org/10.1038/s41388-018-0271-7

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