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A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis

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  • Qiyu Feng

    (Cornell University
    Present address: Eastern Hepatobiliary Surgery Institute, National Center for Liver Cancer, Shanghai 201805, P. R. China)

  • Chengliang Zhang

    (Cornell University)

  • David Lum

    (Huntsman Cancer Institute, University of Utah)

  • Joseph E. Druso

    (Cornell University)

  • Bryant Blank

    (Cornell University)

  • Kristin F. Wilson

    (Cornell University)

  • Alana Welm

    (Huntsman Cancer Institute, University of Utah)

  • Marc A. Antonyak

    (Cornell University)

  • Richard A. Cerione

    (Cornell University
    Cornell University)

Abstract

Non-classical secretory vesicles, collectively referred to as extracellular vesicles (EVs), have been implicated in different aspects of cancer cell survival and metastasis. Here, we describe how a specific class of EVs, called microvesicles (MVs), activates VEGF receptors and tumour angiogenesis through a unique 90 kDa form of VEGF (VEGF90K). We show that VEGF90K is generated by the crosslinking of VEGF165, catalysed by the enzyme tissue transglutaminase, and associates with MVs through its interaction with the chaperone Hsp90. We further demonstrate that MV-associated VEGF90K has a weakened affinity for Bevacizumab, causing Bevacizumab to be ineffective in blocking MV-dependent VEGF receptor activation. However, treatment with an Hsp90 inhibitor releases VEGF90K from MVs, restoring the sensitivity of VEGF90K to Bevacizumab. These findings reveal a novel mechanism by which cancer cell-derived MVs influence the tumour microenvironment and highlight the importance of recognizing their unique properties when considering drug treatment strategies.

Suggested Citation

  • Qiyu Feng & Chengliang Zhang & David Lum & Joseph E. Druso & Bryant Blank & Kristin F. Wilson & Alana Welm & Marc A. Antonyak & Richard A. Cerione, 2017. "A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis," Nature Communications, Nature, vol. 8(1), pages 1-17, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14450
    DOI: 10.1038/ncomms14450
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