EPHB2 carried on small extracellular vesicles induces tumor angiogenesis via activation of ephrin reverse signaling

JCI Insight. 2019 Dec 5;4(23):e132447. doi: 10.1172/jci.insight.132447.


Angiogenesis is a key process that allows nutrient uptake and cellular trafficking and is coopted in cancer to enable tumor growth and metastasis. Recently, extracellular vesicles (EVs) have been shown to promote angiogenesis; however, it is unclear what unique features EVs contribute to the process. Here, we studied the role of EVs derived from head and neck squamous cell carcinoma (HNSCC) in driving tumor angiogenesis. Small EVs (SEVs), in the size range of exosomes (50-150 nm), induced angiogenesis both in vitro and in vivo. Proteomic analysis of HNSCC SEVs revealed the cell-to-cell signaling receptor ephrin type B receptor 2 (EPHB2) as a promising candidate cargo to promote angiogenesis. Analysis of patient data further identified EPHB2 overexpression in HNSCC tumors to be associated with poor patient prognosis and tumor angiogenesis, especially in the context of overexpression of the exosome secretion regulator cortactin. Functional experiments revealed that EPHB2 expression in SEVs regulated angiogenesis both in vitro and in vivo and that EPHB2 carried by SEVs stimulates ephrin-B reverse signaling, inducing STAT3 phosphorylation. A STAT3 inhibitor greatly reduced SEV-induced angiogenesis. These data suggest a model in which EVs uniquely promote angiogenesis by transporting Eph transmembrane receptors to nonadjacent endothelial cells to induce ephrin reverse signaling.

Keywords: Angiogenesis; Head and neck cancer; Oncology; Proteomics; endothelial cells.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Ephrins / metabolism*
  • Exosomes / metabolism
  • Extracellular Vesicles / metabolism*
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • MicroRNAs
  • Neovascularization, Pathologic / metabolism*
  • Proteomics
  • Receptor, EphB2 / metabolism*
  • STAT3 Transcription Factor / drug effects
  • Signal Transduction / physiology*
  • Squamous Cell Carcinoma of Head and Neck
  • Transcriptome


  • Ephrins
  • MicroRNAs
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • EPHB2 protein, human
  • Receptor, EphB2