TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy

• Published in: Journal of extracellular vesicles Vol. 6; no. 1; pp. 1265291 - n/a
• Main Authors: Yuan, ZhengQiang, Kolluri, Krishna K., Gowers, Kate H. C., Janes, Sam M.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.12.2017; John Wiley & Sons, Inc; Wiley
• Subjects: Antibodies; Apoptosis; Bioavailability; Cancer; Cancer therapies; Caspase; CD63 antigen; CD81 antigen; CD9 antigen; Cell culture; Cell interactions; Cell signaling; Cell surface; Cytotoxicity; Data processing; Drug delivery; Drug dosages; Epithelial cells; Extracellular vesicles; Flow cytometry; Kinases; Ligands; Membrane vesicles; Mesenchymal stem cells; Mesenchyme; MicroRNAs; Microscopy; MSC; Nanoparticles; Original; Plasma; Proteins; Stem cells; Stromal cells; TRAIL; TRAIL protein; Tumor cell lines; Tumor necrosis factor-TNF; Ultracentrifugation; United Kingdom > UK; EV; cancer; TRAIL; MSC
• ISSN: 2001-3078; 2001-3078
• DOI: 10.1080/20013078.2017.1265291

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.