Mesenchymal Stem Cell Delivery of TRAIL Can Eliminate Metastatic Cancer

Cancer Research - Tập 69 Số 10 - Trang 4134-4142 - 2009
Michael R. Loebinger1, Ayad Eddaoudi2, Derek Davies3, Sam M. Janes1
11Centre for Respiratory Research, Rayne Institute, and
22Flow Cytometry Facility, Institute of Child Health, University College London;
33Flow Cytometry Laboratory, Cancer Research UK, London Research Institute, London, England

Tóm tắt

Abstract 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 cm3 (0.04-0.21) versus 0.66 cm3 (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. [Cancer Res 2009;69(10):4134–42]

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Cancer Research

Tập 69 Số 10

4134-4142

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