S60 Mesenchymal stem cells expressing TRAIL induce apoptosis in malignant pleural mesothelioma

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Abstract

Background

Malignant pleural mesothelioma (MPM) is an aggressive fatal cancer caused by asbestos exposure. Current treatments are ineffective with an average survival of 4–18 months. Mesenchymal stem cells (MSCs) migrate to tumours and incorporate into tumour stroma making them good vehicles for the delivery of anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) is a transmembrane protein that selectively induces apoptosis in malignant cells without affecting healthy tissues. In this study I tested the hypothesis that MSCs modified to express TRAIL (MSCTRAIL) would cause MPM cell death.

Methods

Human MSCs were transduced with a lentiviral vector containing TRAIL IRES-GFP under the control of a tetracycline dependent promoter. Successful transduction was measured using flow cytometry and immunoblotting. The biological activity of MSCTRAIL was determined using co-culture experiments. 5×105 MPM cells were stained withDiI and plated with 5×105 MSCTRAIL cells. After 24 h doxycycline (10 μg/ml) was added to induce TRAIL production and left for 48 h. Both cells and supernatant were collected and stained with Annexin V and DAPI to detect apoptosis and death respectively onflow cytometry.

Results

MSCs were successfully transduced with TRAIL with 96% showing GFP positivity on flow cytometry. Seven human MPM cell lines were tested with 6/7 (86%) being sensitive to MSCTRAIL. JU77 was highly sensitive with an increase in apoptosis from 10.32±2.34 to 48.73±4.3 (percentage ± SEM, p≤0.0001), while MSTO-211H and ONE 58 showed increases from 3.46±0.81to 27.68±1.1 and 8.92±0.05 to 32.93±1.08 respectively (p≤0.001).

Conclusions

MSCs can be successfully transduced to produce TRAIL and can induce significant levels of apoptosis in the majority of MPM cell lines tested.

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