Journal
JOURNAL OF EXTRACELLULAR VESICLES
Volume 6, Issue -, Pages -Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/20013078.2017.1265291
Keywords
EV; cancer; MSC; TRAIL
Categories
Funding
- Wellcome Trust [WT107963AIA]
- Rosetrees Trust
- Welton Foundation
- Roy Castle Lung Cancer Foundation
- UCLH Charitable foundation
- MRC DPFS scheme [MR/M015831/1]
- Department of Health's NIHR Biomedical Research Centre
- UCL ECMC
- CRUK Lung Cancer Centre of Excellence
- MRC [MR/M015831/1] Funding Source: UKRI
- Medical Research Council [MR/M015831/1] Funding Source: researchfish
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Extracellular vesicles (EVs) are lipid membrane-enclosed nanoparticles released by cells. They mediate intercellular communication by transferring biological molecules and therefore have potential as innovative drug delivery vehicles. TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of cancer cells. Unfortunately, the clinical application of recombinant rTRAIL has been hampered by its low bioavailability and resistance of cancer cells. EV-mediated TRAIL delivery may circumvent these problems. Mesenchymal stromal cells (MSCs) produce EVs and could be a good source for therapeutic EV production. We investigated if TRAIL could be expressed in MSC-derived EVs and examined their cancer cell-killing efficacy. EVs were isolated by ultracentrifugation and were membranous particles of 50-70 nm in diameter. Both MSC-and TRAIL-expressing MSC (MSCT)-derived EVs express CD63, CD9 and CD81, but only MSCT-EVs express surface TRAIL. MSCT-EVs induced apoptosis in 11 cancer cell lines in a dose-dependent manner but showed no cytotoxicity in primary human bronchial epithelial cells. Caspase activity inhibition or TRAIL neutralisation blocked the cytotoxicity of TRAIL-positive EVs. MSCT-EVs induced pronounced apoptosis in TRAIL-resistant cancer cells and this effect could be further enhanced using a CDK9 inhibitor. These data indicate that TRAIL delivery by MSC-derived EVs is an effective anticancer therapy.
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