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

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

Author information

1
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
3
Department of Pathology, Microbiology and Immunology, and.
4
Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Abstract

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

PMID:
31661464
DOI:
10.1172/jci.insight.132447
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