title: Systemic but not topical TRAIL-expressing mesenchymal stem cells reduce tumour growth in malignant mesothelioma.
abstract: Malignant pleural mesothelioma is a rare but devastating cancer of the pleural lining with no effective treatment. The tumour is often diffusely spread throughout the chest cavity, making surgical resection difficult, while systemic chemotherapy offers limited benefit. Bone marrow-derived mesenchymal stem cells (MSCs) home to and incorporate into tumour stroma, making them good candidates to deliver anticancer therapies. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic molecule that selectively induces apoptosis in cancer cells, leaving healthy cells unaffected. We hypothesised that human MSCs expressing TRAIL (MSCTRAIL) would home to an in vivo model of malignant pleural mesothelioma and reduce tumour growth. Human MSCs transduced with a lentiviral vector encoding TRAIL were shown in vitro to kill multiple malignant mesothelioma cell lines as predicted by sensitivity to recombinant TRAIL (rTRAIL). In vivo MSC homing was delineated using dual fluorescence and bioluminescent imaging, and we observed that higher levels of MSC engraftment occur after intravenous delivery compared with intrapleural delivery of MSCs. Finally, we show that intravenous delivery of MSCTRAIL results in a reduction in malignant pleural mesothelioma tumour growth in vivo via an increase in tumour cell apoptosis.
authors.affiliation: Division of Medicine, Lungs for Living Research Centre, University College London, London, UK.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Sage
authors.affiliation: Division of Medicine, Lungs for Living Research Centre, University College London, London, UK.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Kolluri
authors.affiliation: Division of Medicine, Lungs for Living Research Centre, University College London, London, UK.
authors.forename: Katrina
authors.initials: K
authors.lastname: McNulty
authors.affiliation: Division of Medicine, Lungs for Living Research Centre, University College London, London, UK.
authors.forename: Sofia Da Silva
authors.initials: Sda S
authors.lastname: Lourenco
authors.affiliation: Division of Medicine, Lungs for Living Research Centre, University College London, London, UK Division of Medicine and Institute of Child Health, UCL Centre of Advanced Biomedical Imaging, University College London, London, UK.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Kalber
authors.affiliation: Division of Medicine, Lungs for Living Research Centre, University College London, London, UK Division of Medicine and Institute of Child Health, UCL Centre of Advanced Biomedical Imaging, University College London, London, UK.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Ordidge
authors.affiliation: Flow Cytometry Laboratory, Cancer Research UK, London Research Institute, London, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Davies
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Sir Charles Gairdner Hospital, Perth, Australia.
authors.forename: Y C
authors.initials: YC
authors.lastname: Gary Lee
authors.affiliation: Division of Medicine, Lungs for Living Research Centre, University College London, London, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Giangreco
authors.affiliation: Division of Medicine, Lungs for Living Research Centre, University College London, London, UK.
authors.forename: Sam M
authors.initials: SM
authors.lastname: Janes
mesh_terms: D000287:Administration, Topical; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010997:Pleural Neoplasms / Q000378:metabolism* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand
keywords: Asbestos Induced Lung Disease; Lung Cancer; Mesothelioma; Occupational Lung Disease