Mesenchymal stromal cells alone or expressing interferon-β suppress pancreatic tumors in vivo,an effect countered by anti-inflammatory treatment |
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| Authors: | Shannon Kidd Lisa Caldwell Martin Dietrich Ismael Samudio Erika L Spaeth Keri Watson Yuexi Shi James Abbruzzese Marina Konopleva Michael Andreeff Frank C Marini |
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| Institution: | 1. Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, UT-MD Anderson Cancer Center, Houston, Texas, USA;2. Section of Physiology of Reproduction, Department of Animal Science, Texas A&M University, College Station, Texas, USA;3. Department of Gastrointestinal Medical Oncology, UT-MD Anderson Cancer Center, Houston, Texas, USA;4. Department of Leukemia, UT-MD Anderson Cancer Center, Houston, Texas, USA;1. Department of Oral Pathology and Microbiology, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune, India;2. Department of Oral Pathology and Microbiology Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune, India;3. Dr. D. Y. Patil Vidyapeeth, Pune, India;4. Department of Maxillofacial Surgery and Diagnostic Science, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia;1. FirstString Research, Inc., Mount Pleasant, SC, USA;2. Virginia Tech Carilion Research Institute, Roanoke, VA, USA;3. Faculty of Health Science, Virginia Tech, Blacksburg, VA, USA;4. Department of Biological Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA;5. Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA;6. Department of Cellular and Physiological Science, Life Sciences Institute, University of British Columbia, Vancouver, Canada;7. Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Blacksburg, VA, USA;8. Department of Emergency Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA;1. Office of Biotechnology Activities, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA;2. Biotechnology and Pharmacology Laboratory, Ecole Normale Supérieure de Cachan, Cachan, France and Department of Clinical Oncology, Hôpital Saint-Louis, Université Paris-Diderot, Paris, France;3. Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA;4. Cancer Research Institute, University of California–Irvine, Irvine, California, USA;5. Department of Pathology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA;6. Department of Genetics, Cell Biology, and Development, Molecular Genetics Institute, University of Minnesota–Twin Cities, Minneapolis, Minnesota, USA;7. Department of Social Sciences and Health Policy, Wake Forest University Center for Bioethics, Health and Society, Wake Forest University, Winston-Salem, North Carolina, USA;8. Department of Pediatrics, Center for Molecular Genetics, University of California–San Diego, School of Medicine, La Jolla, California, USA;9. Molecular Hematopoiesis Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA;10. San Raffaele TeleThon Institute for Gene Therapy HSR-TIGET, Milan, Italy;11. University Department of Pediatrics, (DPUO), Bambino Gesù Children''s Hospital and Università di Tor Vergata School of Medicine, Rome, Italy;12. Università Vita-Salute San Raffaele, Milan, Italy;13. Department of Experimental Hematology, Hannover Medical School, Hannover, Germany;14. Department of Translational Oncology, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany;15. Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA;16. Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA;17. Experimental Hematology Division, St. Jude Children''s Research Hospital, Memphis, Tennessee, USA;18. IBET, Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Estação Agronómica Nacional, Oeiras, Portugal;19. Laboratory of Host Defenses, Genetic Immunotherapy Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA;20. Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;21. Drinker, Biddle and Reath LLP, Milwaukee, Wisconsin, USA;22. Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;23. Department of Virology, Clinical Research Comprehensive Cancer Center, Beckman Research Institute of the City of Hope, Duarte, California, USA;24. Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA |
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| Abstract: | Background aimsBecause of the inflammatory nature and extensive stromal compartment in pancreatic tumors, we investigated the role of mesenchymal stromal cells (MSC) to engraft selectively in pancreatic carcinomas and serve as anti-tumor drug delivery vehicles to control pancreatic cancer progression.MethodsHuman pancreatic carcinoma cells, PANC-1, expressing renilla luciferase were orthotopically implanted into SCID mice and allowed to develop for 10 days. Firefly luciferase-transduced MSC or MSC expressing interferon (IFN)-β were then injected intraperitoneally weekly for 3 weeks. Mice were monitored by bioluminescent imaging for expression of renilla (PANC-1) and firefly (MSC) luciferase.ResultsMSC selectively homed to sites of primary and metastatic pancreatic tumors and inhibited tumor growth (P = 0.032). The production of IFN-β within the tumor site by MSC–IFN-β further suppressed tumor growth (P = 0.0000083). Prior studies indicated that MSC home to sites of inflammation; therefore, we sought to alter the tumor microenvironment through treatment with a potent anti-inflammatory agent. After treatment, inflammation-associated mediators were effectively down-regulated, including NFκB, vascular endothelial growth factor (VEGF) and interleukin (IL)-6 as well as chemokines involved in MSC migration (CCL3 and CCL25). Treatment with the anti-inflammatory agent CDDO-Me before and after MSC–IFN-β injections resulted in reduction of MSC in the tumors and reversed the positive effect of tumor inhibition by MSC–IFN-β alone (P = 0.041).ConclusionsThese results suggest that MSC exhibit innate anti-tumor effects against PANC-1 cells and can serve as delivery vehicles for IFN-β for the treatment of pancreatic cancer. However, these beneficial effects may be lost in therapies combining MSC with anti-inflammatory agents. |
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