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Extracellular vesicles released by glioma cells are decorated by Annexin A2 allowing for cellular uptake via heparan sulfate

Abstract

Extracellular vesicles (EVs) play a crucial role in regulating cell behavior by delivering their cargo to target cells. However, the mechanisms underlying EV-cell interactions are not well understood. Previous studies have shown that heparan sulfate (HS) on target cell surfaces can act as receptors for exosomes uptake, but the ligand for HS on EVs has not been identified. In this study, we isolated EVs from glioma cell lines and glioma patients and identified Annexin A2 (AnxA2) on EVs as a key HS-binding ligand and mediator of EV-cell interactions. Our findings suggest that HS plays a dual role in EV-cell interactions, where HS on EVs captures AnxA2, and on target cells, it acts as a receptor for AnxA2. Removal of HS from the EV surface inhibits EV-target cell interaction by releasing AnxA2. Furthermore, we found that AnxA2-mediated binding of EVs to vascular endothelial cells promotes angiogenesis, and that antibody against AnxA2 inhibited the ability of glioma-derived EVs to stimulate angiogenesis by reducing the uptake of EVs. Our study also suggests that the AnxA2-HS interaction may accelerate the glioma-derived EVs-mediated angiogenesis and that combining AnxA2 on glioma cells with HS on endothelial cells may effectively improve the prognosis evaluation of glioma patients.

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Fig. 1: AnxA2 is present on the surface of glioma cells-derived EVs and enhances their uptake to endothelial cells.
Fig. 2: The binding of AnxA2 on EVs to HS chains on endothelial cells mediated the interaction of glioma cells-derived EVs with endothelial cells.
Fig. 3: Interaction of glioma patient-derived EVs with endothelial cells is mediated by AnxA2 binding to HS.
Fig. 4: AnxA2-mediated interaction of EVs with endothelial cells promotes angiogenesis.
Fig. 5: Expression patterns of ANXA2 and HS in glioma samples.
Fig. 6: Kaplan–Meier curves of recurrence and survival among glioma patients.
Fig. 7: Schematic representation of glioma-derived EV-endothelial cell interaction mediated by AnxA2.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 82203235, 81872919, 82070857, and 81573480), the Hunan Provincial Natural Science Foundation of China (Nos. 2019JJ50782 and 2020JJ9001), the “Double-First Class” Application Characteristic Discipline of Hunan Province, Changsha Medical University (Pharmaceutical Science).

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Conceptualization, Project Administration: WS, ST, and LX; Supervision, Methodology, Writing—Review and Editing: LX, NSD, ZD, and LJJ; Writing—Original Draft, Data Curation, Software: WS and LX; Formal Analysis, Data Curation: LX, SDY, and HZX; Visualization, Resources, Validation, Investigation: SYX, WY, ZGY, and DZJ.

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Correspondence to Xin Li, Tao Song or Shan Wang.

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Song, Yx., Li, X., Nie, Sd. et al. Extracellular vesicles released by glioma cells are decorated by Annexin A2 allowing for cellular uptake via heparan sulfate. Cancer Gene Ther 30, 1156–1166 (2023). https://doi.org/10.1038/s41417-023-00627-w

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