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Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma

Cancer Gene Therapy volume 22, pages 44–54 (2015)Cite this article

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Abstract

Malignant mesothelioma (MM) remains a highly deadly malignancy with poor treatment option. The MM cells further promote a highly inflammatory microenvironment, which contributes to tumor initiation, development, severity and propagation. We reasoned that the anti-inflammatory actions of mesenchymal stromal cells (MSCs) and further antitumor effects of MSCs engineered to overexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein (MSC-TRAIL) would effectively inhibit mesothelioma growth. Using a mouse xenograft model of intraperitoneal human mesothelioma, native mouse (mMSCs) or human (hMSC) MSCs were administered either systemically (intravenously or intraperitoneally) at various times following tumor inoculation. Both mMSCs and hMSCs localized at the sites of MM tumor growth in vivo and decreased local inflammation. Further, a trend towards decrease in tumor burden was observed. Parallel studies of in vitro exposure of nine primary human mesothelioma cell lines to mMSCs or hMSCs demonstrated reduced tumor cell migration. MSC-TRAIL exposure induced apoptosis of TRAIL-sensitive MM cells in vitro, and both mouse and human MSC-TRAIL significantly reduced the inflammatory tumor environment in vivo. Moreover, human MSC-TRAIL administration significantly reduced peritoneal tumor burden in vivo and increased tumor cell apoptosis. These proof-of-concept studies suggest that TRAIL-expressing MSCs may be useful against malignant mesothelioma.

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Acknowledgements

We thank John Wallis, Zach Borg and Darcy Wagner, PhD, for technical assistance and comments. This research was supported by the Environmental Pathology Training grant T32 ES007122, from the NIEHS (MJL and SLM), and the Vermont Lung Center CoBRE grant P20 RR15557 (DJW). SMJ is a Wellcome Trust Senior Fellow in Clinical Science. EKS is an MRC Clinical Training Fellow. Studies were also supported by NIH ARRA RC4HL106625 (DJW), NHLBI R21HL094611 (DJW), R21HL108689 (DJW) and the UVM Lung Biology Training grant T32 HL076122 from the NHLBI. Some of the materials used in this work were provided by the Texas A&M Health Science Center College of Medicine Institute for Regenerative Medicine at Scott & White through a grant from NCRR of the NIH, Grant No. P40RR017447.

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  1. M J Lathrop and E K Sage: Co-first authors.

Authors and Affiliations

  1. Department of Medicine/Pulmonary, University of Vermont, Burlington, VT, USA

    M J Lathrop, E M Brooks, F Cruz, N R Bonenfant, D Sokocevic & D J Weiss

  2. Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK

    E K Sage & S M Janes

  3. Department of Pathology, University of Vermont, Burlington, VT, USA

    S L Macura, M B MacPherson, S L Beuschel, A Shukla & B T Mossman

  4. Institute of Biophysics Carlos Chagas Filho, Federal, University of Rio de Janeiro, Rio de Janeiro, Brazil

    F Cruz

  5. Department of Medicine, School of Medicine University of Alabama at Birmingham, Birmingham, AL, USA

    C W Dunaway & C Steele

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Correspondence to D J Weiss.

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Lathrop, M., Sage, E., Macura, S. et al. Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma. Cancer Gene Ther 22, 44–54 (2015). https://doi.org/10.1038/cgt.2014.68

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