Evaluating the Effect of Therapeutic Stem Cells on TRAIL Resistant and Sensitive Medulloblastomas 英文参考文献.docVIP

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Evaluating the Effect of Therapeutic Stem Cells on TRAIL Resistant and Sensitive Medulloblastomas 英文参考文献.doc

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Evaluating the Effect of Therapeutic Stem Cells on TRAIL Resistant and Sensitive Medulloblastomas 英文参考文献

EvaluatingtheEffectofTherapeuticStemCellsonTRAIL ResistantandSensitiveMedulloblastomas IrinaNesterenko1,2.,SimoneWanningen1,2.,TugbaBagci-Onder1,2,MaartenAnderegg1,2 KhalidShah1,2,3,4 , * 1Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 2Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 3Department of Neurology, MassachusettsGeneralHospital,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,4HarvardStemCellInstitute,HarvardUniversity,Cambridge, Massachusetts,UnitedStatesofAmerica Abstract Mesenchymal stem cells (MSC) are emerging as novel cell-based delivery agents; however, a thorough investigation addressing their therapeutic potential in medulloblastomas (MB) has not been explored to date. In this study, we engineered human MSC to express a potent and secretable variant of a tumor specific agent, tumor necrosis factor- apoptosis-inducingligand(S-TRAIL)andassessedtheabilityofMSC-S-TRAILmediatedMBkillingaloneorincombination withasmallmoleculeinhibitorofhistone-deacetylase,MS-275,inTRAIL-sensitiveand-resistantMBinvitroandinvivo .We showthatTRAILsensitivity/resistancecorrelateswiththeexpressionofitscognatedeathreceptor(DR)5andMSC-S-TRAIL inducescaspase-3mediatedapoptosisinTRAIL-sensitiveMBlines.InTRAIL-resistantMB,weshowupregulationofDR4/5 levels when pre-treated with MS-275 and a subsequent sensitization to MSC-S-TRAIL mediated apoptosis. Using intracranially implanted MB and MSC lines engineered with different combinations of fluorescent and bioluminescent proteins, we show that MSC-S-TRAIL has significant anti-tumor effects in mice bearing TRAIL-sensitive and MS-275 pre- treatedTRAIL-resistantMBs.Toourknowledge,thisisthefirststudythatexplorestheuseofhumanMSCasMB-targeting therapeutic-vehiclesinvivoinTRAIL-sensitiveandresistanttumors,andhasimplicationsfordevelopingeffe