title: Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma.
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.
authors.affiliation: Department of Medicine/Pulmonary, University of Vermont, Burlington, VT, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Lathrop
authors.affiliation: Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
authors.forename: E K
authors.initials: EK
authors.lastname: Sage
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Macura
authors.affiliation: Department of Medicine/Pulmonary, University of Vermont, Burlington, VT, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Brooks
authors.affiliation: 1] Department of Medicine/Pulmonary, University of Vermont, Burlington, VT, USA [2] Institute of Biophysics Carlos Chagas Filho, Federal, University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: F
authors.initials: F
authors.lastname: Cruz
authors.affiliation: Department of Medicine/Pulmonary, University of Vermont, Burlington, VT, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Bonenfant
authors.affiliation: Department of Medicine/Pulmonary, University of Vermont, Burlington, VT, USA.
authors.forename: D
authors.initials: D
authors.lastname: Sokocevic
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: MacPherson
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Beuschel
authors.affiliation: Department of Medicine, School of Medicine University of Alabama at Birmingham, Birmingham, AL , USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Dunaway
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shukla
authors.affiliation: Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Janes
authors.affiliation: Department of Medicine, School of Medicine University of Alabama at Birmingham, Birmingham, AL , USA.
authors.forename: C
authors.initials: C
authors.lastname: Steele
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Mossman
authors.affiliation: Department of Medicine/Pulmonary, University of Vermont, Burlington, VT, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000086002:Mesothelioma, Malignant; D051379:Mice; D016513:Mice, SCID; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D047368:Tumor Burden; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D053221:TNF-Related Apoptosis-Inducing Ligand