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IL-3R-alpha blockade inhibits tumor endothelial cell-derived extracellular vesicle (EV)-mediated vessel formation by targeting the β-catenin pathway.

Abstract：

:The proangiogenic cytokine Interleukin-3 (IL-3) is released by inflammatory cells in breast and ovarian cancer tissue microenvironments and also acts as an autocrine factor for human breast and kidney tumor-derived endothelial cells (TECs). We have previously shown that IL-3-treated endothelial cells (ECs) release extracellular vesicles (EVs), which serve as a paracrine mechanism for neighboring ECs, by transferring active molecules. The impact of an anti-IL-3R-alpha blocking antibody on the proangiogenic effect of EVs released from TECs (anti-IL-3R-EVs) has therefore been investigated in this study. We have found that anti-IL-3R-EV treatment prevented neovessel formation and, more importantly, also induced the regression of in vivo TEC-derived neovessels. Two miRs that target the canonical wingless (Wnt)/β-catenin pathway, at different levels, were found to be differentially regulated when comparing the miR-cargo of naive TEC-derived EVs (EVs) and anti-IL-3R-EVs. miR-214-3p, which directly targets β-catenin, was found to be upregulated, whereas miR-24-3p, which targets adenomatous polyposis coli (APC) and glycogen synthase kinase-3β (GSK3β), was found to be downregulated. In fact, upon their transfer into the cell, low β-catenin content and high levels of the two members of the "β-catenin destruction complex" were detected. Moreover, c-myc downregulation was found in TECs treated with anti-IL-3R-EVs, pre-miR-214-3p-EVs and antago-miR-24-3p-EVs, which is consistent with network analyses of miR-214-3p and miR-24-3p gene targeting. Finally, in vivo studies have demonstrated the impaired growth of vessels in pre-miR-214-3p-EV- and antago-miR-24-3p-EV-treated animals. These effects became much more evident when combo treatment was applied. The results of the present study identify the canonical Wnt/β-catenin pathway as a relevant mechanism of TEC-derived EV proangiogenic action. Furthermore, we herein provide evidence that IL-3R blockade may yield some significant advantages, than miR targeting, in inhibiting the proangiogenic effects of naive TEC-derived EVs by changing TEC-EV-miR cargo.

journal_name

Oncogene

journal_title

Oncogene

authors

Lombardo G,Gili M,Grange C,Cavallari C,Dentelli P,Togliatto G,Taverna D,Camussi G,Brizzi MF

doi

10.1038/s41388-017-0034-x

subject

Has Abstract

pub_date

2018-03-01 00:00:00

pages

1175-1191

issue

eissn

0950-9232

issn

1476-5594

pii

10.1038/s41388-017-0034-x

journal_volume

pub_type

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IL-3R-alpha blockade inhibits tumor endothelial cell-derived extracellular vesicle (EV)-mediated vessel formation by targeting the β-catenin pathway.