Mesenchymal stem cells as a gene therapy carrier for treatment of fibrosarcoma |
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| Authors: | Juanjuan Xiang Jingqun Tang Chao Song Ziquan Yang David Graham Hirst Qiu-Jian Zheng Gang Li |
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| Institution: | 1. Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen''s University Belfast, Belfast, UK;2. The Li Ka Shing Institute of Health Sciences, Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Clinical Sciences Building, Prince of Wales Hospital, Shatin, Hong Kong, PR China;3. School of Pharmacy, Queen''s University Belfast, Belfast, UK;4. Department of Orthopaedics and Traumatology, The People''s Hospital of Guangdong Province, Guangzhou, Guangdong Province, PR China;5. Cancer Research Institute, Xiangya School of Medicine, Central South University, 90 Xiangya Road, Changsha, Hunan, 410078, PR China;6. Department of Cardiothoracic Surgery, Xiangya Second Hospital, Central South University, 139 Renmin Zhong Road, Changsha, Hunan, 410011, PR China;7. Department of Orthopaedics, The 2nd Hospital of Shangxi Medical University, Shanxi, 030001, Taiyuan, PR China;1. Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China;2. Fujian Provincial Hospital, Provincial Clinical Medical College, Fujian Medical University, Fuzhou, Fujian 350001, China;3. Department of Pathology, School of Basic Medical Sciences of Fujian Medical University, Fuzhou, Fujian 350004, China;1. Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany;2. Division of Nutrition, Metabolism & Genomics, Wageningen University, Wageningen, The Netherlands;3. Department of Experimental Molecular Imaging, University Hospital, RWTH Aachen, Aachen, Germany;4. Department of Diagnostic and Interventional Neuroradiology, University Hospital, RWTH Aachen, Aachen, Germany;5. Institute of Pathology, University Hospital, RWTH Aachen, Aachen, Germany;6. Howard Hughes Medical Institute and University of Massachusetts Medical School, Worcester, MA, USA |
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| Abstract: | Background aimsCell-based gene therapy is an alternative to viral and non-viral gene therapy. Emerging evidence suggests that mesenchymal stem cells (MSC) are able to migrate to sites of tissue injury and have immunosuppressive properties that may be useful in targeted gene therapy for sustained specific tissue engraftment.MethodsIn this study, we injected intravenously (i.v.) 1 × 106 MSC, isolated from green fluorescent protein (GFP) transgenic rats, into Rif-1 fibrosarcoma-bearing C3H/HeN mice. The MSC had been infected using a lentiviral vector to express stably the luciferase reporter gene (MSC-GFP-luci). An in vivo imaging system (IVIS 200) and Western blotting techniques were used to detect the distribution of MSC-GFP-luci in tumor-bearing animals.ResultsWe observed that xenogenic MSC selectively migrated to the tumor site, proliferated and expressed the exogenous gene in subcutaneous fibrosarcoma transplants. No MSC distribution was detected in other organs, such as the liver, spleen, colon and kidney. We further showed that the FGF2/FGFR pathways may play a role in the directional movement of MSC to the Rif-1 fibrosarcoma. We performed in vitro co-culture and in vivo tumor growth analysis, showing that MSC did not affect the proliferation of Rif-1 cells and fibrosarcoma growth compared with an untreated control group. Finally, we demonstrated that the xenogenic MSC stably expressing inducible nitric oxide synthase (iNOS) protein transferred by a lentivirus-based system had a significant inhibitory effect on the growth of Rif-1 tumors compared with MSC alone and the non-treatment control group.ConclusionsiNOS delivered by genetically modified iNOS-MSC showed a significant anti-tumor effect both in vitro and in vivo. MSC may be used as a target gene delivery vehicle for the treatment of fibrosarcoma and other tumors. |
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