Inhibition of ?v?3 integrin impairs adhesion and uptake of tumor-derived small extracellular vesicles.

ABSTRACT: BACKGROUND:Extracellular vesicles (EVs) are lipid-bound particles that are naturally released from cells and mediate cell-cell communication. Integrin adhesion receptors are enriched in small EVs (SEVs) and SEV-carried integrins have been shown to promote cancer cell migration and to mediate organ-specific metastasis; however, how integrins mediate these effects is not entirely clear and could represent a combination of EV binding to extracellular matrix and cells. METHODS:To probe integrin role in EVs binding and uptake, we employed a disintegrin inhibitor (DisBa-01) of integrin binding with specificity for ?v?3 integrin. EVs were purified from MDA-MB-231 cells conditioned media by serial centrifugation method. Isolated EVs were characterized by different techniques and further employed in adhesion, uptake and co-culture experiments. RESULTS:We find that SEVs secreted from MDA-MB-231 breast cancer cells carry ?v?3 integrin and bind directly to fibronectin-coated plates, which is inhibited by DisBa-01. SEV coating on tissue culture plates also induces adhesion of MDA-MB-231 cells, which is inhibited by DisBa-01 treatment. Analysis of EV uptake and interchange between cells reveals that the amount of CD63-positive EVs delivered from malignant MDA-MB-231 breast cells to non-malignant MCF10A breast epithelial cells is reduced by DisBa-01 treatment. Inhibition of ?v?3 integrin decreases CD63 expression in cancer cells suggesting an effect on SEV content. CONCLUSION:In summary, our findings demonstrate for the first time a key role of ?v?3 integrin in cell-cell communication through SEVs. Video Abstract.

SUBMITTER: Altei WF 

PROVIDER: S-EPMC7520983 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature