CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance

Cell Rep. 2021 Aug 17;36(7):109549. doi: 10.1016/j.celrep.2021.109549.


Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid cancers, most individuals become resistant to this therapy, leading to disease progression. Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described here, we demonstrate that cancer-derived small extracellular vesicles package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. The packaging process of VEGF into small extracellular vesicles (EVs) is mediated by the tetraspanin CD63. Furthermore, small EV-VEGF (eVEGF) is not accessible to anti-VEGF antibodies and can trigger intracrine VEGF signaling in endothelial cells. eVEGF promotes angiogenesis and enhances tumor growth despite bevacizumab treatment. These data demonstrate a mechanism where VEGF is partitioned into small EVs and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and therapeutic strategies for ovarian cancer.

Keywords: CD63; VEGF; angiogenesis; bevacizumab; drug resistance; extracellular vesicles.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Bevacizumab / pharmacology
  • Bevacizumab / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Models, Animal
  • Extracellular Vesicles / metabolism*
  • Extracellular Vesicles / ultrastructure
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Ovarian Neoplasms / drug therapy
  • Protein Isoforms / metabolism
  • Signal Transduction
  • Tetraspanin 30 / metabolism*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • Protein Isoforms
  • Tetraspanin 30
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • Vascular Endothelial Growth Factor Receptor-2