Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer.
Cancer is a leading cause of mortality throughout the world and new treatments are urgently needed. Recent studies suggest that bone marrow-derived mesenchymal stem cells (MSC) home to and incorporate within tumor tissue. We hypothesized that MSCs engineered to produce and deliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a transmembrane protein that causes selective apoptosis of tumor cells, would home to and kill cancer cells in a lung metastatic cancer model. Human MSCs were transduced with TRAIL and the IRES-eGFP reporter gene under the control of a tetracycline promoter using a lentiviral vector. Transduced and activated MSCs caused lung (A549), breast (MDAMB231), squamous (H357), and cervical (Hela) cancer cell apoptosis and death in coculture experiments. Subcutaneous xenograft experiments confirmed that directly delivered TRAIL-expressing MSCs were able to significantly reduce tumor growth [0.12 cm(3) (0.04-0.21) versus 0.66 cm(3) (0.21-1.11); P < 0.001]. We then found, using a pulmonary metastasis model, systemically delivered MSCs localized to lung metastases and the controlled local delivery of TRAIL completely cleared the metastatic disease in 38% of mice compared with 0% of controls (P < 0.05). This is the first study to show a significant reduction in metastatic tumor burden with frequent eradication of metastases using inducible TRAIL-expressing MSCs. This has a wide potential therapeutic role, which includes the treatment of both primary tumors and their metastases, possibly as an adjuvant therapy in clearing micrometastatic disease following primary tumor resection.
Centre for Respiratory Research, Rayne Institute, and Flow Cytometry Facility, Institute of Child Health, University College London, London, UK.
Michael R
MR
Loebinger
Ayad
A
Eddaoudi
Derek
D
Davies
Sam M
SM
Janes
D017667:Adipocytes / Q000166:cytology / Q000502:physiology; D000328:Adult; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D016923:Cell Death; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009369:Neoplasms / Q000473:pathology; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010957:Plasmids; D015183:Restriction Mapping; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D014162:Transfection
D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D049452:Green Fluorescent Proteins