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FLT1-enriched extracellular vesicles induce a positive feedback loop between nasopharyngeal carcinoma cells and endothelial cells to promote angiogenesis and tumour metastasis

Oncogene volume 44, pages 2253–2267 (2025)Cite this article

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Abstract

Distant metastasis is one of the main reasons for treatment failure in nasopharyngeal carcinoma (NPC) patients. Tumour angiogenesis is a key basis for the distant metastasis of NPC. However, the molecular mechanisms underlying the mutual interaction between endothelial and NPC cells in tumour angiogenesis and NPC metastasis are still unclear. Here, we found that extracellular vesicles (EVs) mediate intercellular communication between endothelial cells and NPC cells, thereby promoting NPC cell migration, invasion, colony formation, and angiogenesis. Further experiments indicated that EV-mediated information exchange between endothelial cells and NPC cells upregulated the expression of the vascular endothelial growth factor receptor FLT1 in both types of cells. Mechanistically, FLT1-enriched EVs promoted NPC metastasis through the PI3K/AKT pathway and increased tumour angiogenesis, tumour growth, and distant lung and liver metastasis of NPC in xenografted mice. This effect was achieved through the delivery and upregulation of FLT1 in both endothelial and NPC cells. Thus, our findings reveal that FLT1-enriched EVs induce a positive feedback loop between NPC cells and endothelial cells to promote tumour angiogenesis and tumour metastasis. These results increase our understanding of the intricate interplay between tumour angiogenesis and distant metastasis and have major implications for the diagnosis and management of NPC patients with increased levels of FLT1-enriched EVs.

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Fig. 1: EV transfer between endothelial cells and NPC cells mediates cell-cell communication.
Fig. 2: TEC-derived EVs promote EMT, migration, invasion, and colony formation of NPC cells.
Fig. 3: NPC cell-derived EVs increase the angiogenic capacity of endothelial cells.
Fig. 4: EV-mediated intercellular communication increases FLT1 in both endothelial cells and NPC cells.
Fig. 5: FLT1-enriched TEC-EVs promote NPC metastasis by activating the PI3K/AKT pathway.
Fig. 6: FLT1-enriched T-EVs facilitate tumour angiogenesis.
Fig. 7: FLT1-enriched TEC-EVs enhance NPC metastasis in xenograft mice through the PI3K/AKT pathway.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The schematic representation and mechanistic scheme of this study were drawn using Figdraw (https://www.figdraw.com).

Funding

This work was supported by National Natural Science Foundation of China (31771273, 82273467, and 82403550), China Postdoctoral Science Foundation (2024T171077), Guangdong Province Basic and Applied Basic Research Fund (2022A1515140100), Guangdong Province of China Grant (2021A1515011209), Research Funds for the Shenzhen of China (JCYJ20210324120812035), and the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (24qnpy180).

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Authors and Affiliations

  1. State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

    Fei Li, Yue He, Peiling Chen, Jiasheng Wang, Maozhen Zeng, Junru Chen, Haisheng Chen, Qiqi Guo, Jiaxi Fan, Xuan Huang, Qi Wang & Qing Zhang

  2. School of Life Sciences, Huizhou University, Huizhou, China

    Lin Song

  3. The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China

    Chunmou Li

  4. Research Institute of Sun Yat-sen University in Shenzhen, Shenzhen, China

    Qing Zhang

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Contributions

FL planned and carried out experiments, analysed data, and wrote the manuscript. LS, YH, PC, JW, MZ, CL, JC, HC, QG, JF, XH, and QW performed the research and analysed data. QZ supervised the research, planned experiments, analysed data, and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Qing Zhang.

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The authors declare no competing interests.

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All clinical samples were obtained with informed consent from the Sun Yat-sen University Cancer Center and approved by the Hospital’s Ethical Review Committees. The animal studies were authorized by the Institutional Animal Care and Use Committee of the Sun Yat-sen University (approval number: SYSU-LS-IACUC-2023-0087). All animal experiments were strictly implemented in compliance with the ARRIVE guidelines.

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Li, F., Song, L., He, Y. et al. FLT1-enriched extracellular vesicles induce a positive feedback loop between nasopharyngeal carcinoma cells and endothelial cells to promote angiogenesis and tumour metastasis. Oncogene 44, 2253–2267 (2025). https://doi.org/10.1038/s41388-025-03389-x

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