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

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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. Ephrin type-B receptor 2 (EPHB2) in extracellular vesicles drives tumor angiogenesis by activating ephrin reverse signaling.

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Stattic: a small-molecule inhibitor of STAT3 activation and dimerization.

Jochen Schust, Bianca Sperl, Angela Hollis … (2006)

Signal transducers and activators of transcription (STATs) are a family of latent cytoplasmic transcription factors that transmit signals from the cell membrane to the nucleus. One family member, STAT3, is constitutively activated by aberrant upstream tyrosine kinase activities in a broad spectrum of cancer cell lines and human tumors. Screening of chemical libraries led to the identification of Stattic, a nonpeptidic small molecule shown to selectively inhibit the function of the STAT3 SH2 domain regardless of the STAT3 activation state in vitro. Stattic selectively inhibits activation, dimerization, and nuclear translocation of STAT3 and increases the apoptotic rate of STAT3-dependent breast cancer cell lines. We propose Stattic as a tool for the inhibition of STAT3 in cell lines or animal tumor models displaying constitutive STAT3 activation.

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RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer.

Nicholas Robert, Véronique Diéras, John Glaspy … (2011)

This phase III study compared the efficacy and safety of bevacizumab (BV) when combined with several standard chemotherapy regimens versus those regimens alone for first-line treatment of patients with human epidermal growth factor receptor 2-negative metastatic breast cancer. Patients were randomly assigned in 2:1 ratio to chemotherapy plus BV or chemotherapy plus placebo. Before random assignment, investigators chose capecitabine (Cape; 2,000 mg/m(2) for 14 days), taxane (Tax) -based (nab-paclitaxel 260 mg/m(2), docetaxel 75 or 100 mg/m(2)), or anthracycline (Anthra) -based (doxorubicin or epirubicin combinations [doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide, or fluorouracil/doxorubicin/cyclophosphamide]) chemotherapy administered every 3 weeks. BV or placebo was administered at 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), 1-year survival rate, objective response rate, duration of objective response, and safety. Two independently powered cohorts defined by the choice of chemotherapy (Cape patients or pooled Tax/Anthra patients) were analyzed in parallel. RIBBON-1 (Regimens in Bevacizumab for Breast Oncology) enrolled 1,237 patients (Cape cohort, n = 615; Tax/Anthra cohort, n = 622). Median PFS was longer for each BV combination (Cape cohort: increased from 5.7 months to 8.6 months; hazard ratio [HR], 0.69; 95% CI, 0.56 to 0.84; log-rank P < .001; and Tax/Anthra cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52 to 0.80; log-rank P < .001). No statistically significant differences in OS between the placebo- and BV-containing arms were observed. Safety was consistent with results of prior BV trials. The combination of BV with Cape, Tax, or Anthra improves clinical benefit in terms of increased PFS in first-line treatment of metastatic breast cancer, with a safety profile comparable to prior phase III studies.

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Leukemia cell to endothelial cell communication via exosomal miRNAs.

T Umezu, K Ohyashiki, M Kuroda … (2013)

Recent findings indicate that specific microRNAs (miRNAs), such as those of the miR-17-92 cluster, may be responsible for regulating endothelial gene expression during tumor angiogenesis. Secreted miRNAs enclosed in exosomes also have an important role in cell-cell communication. To elucidate whether miRNAs secreted from neoplastic cells transfer into endothelial cells and are functionally active in the recipient cells, we investigated the effect of exosomal miRNAs derived from leukemia cells (K562) on human umbilical vein endothelial cells (HUVECs). As K562 cells released the miR-17-92 cluster, especially miR-92a, into the extracellular environment, K562 cells, transfected with Cy3-labeled pre-miR-92a, were co-cultured with HUVECs. Cy3-miR-92a derived from K562 cells was detected in the cytoplasm of HUVECs, and the Cy3-miR-92a co-localized with the signals of an exosomal marker, CD63. The expression of integrin α5, a target gene for miR-92a, was significantly reduced in HUVECs by exosomal miR-92a, indicating that exogenous miRNA via exosomal transport can function like endogenous miRNA in HUVECs. The most salient feature of this study is the exosome, derived from K562 cells with enforced miR-92a expression, did not affect the growth of HUVECs but did enhance endothelial cell migration and tube formation. Our results support the idea that exosomal miRNAs have an important role in neoplasia-to-endothelial cell communication.