title: Evaluating the effect of therapeutic stem cells on TRAIL resistant and sensitive medulloblastomas.
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-inducing ligand (S-TRAIL) and assessed the ability of MSC-S-TRAIL mediated MB killing alone or in combination with a small molecule inhibitor of histone-deacetylase, MS-275, in TRAIL-sensitive and -resistant MB in vitro and in vivo. We show that TRAIL sensitivity/resistance correlates with the expression of its cognate death receptor (DR)5 and MSC-S-TRAIL induces caspase-3 mediated apoptosis in TRAIL-sensitive MB lines. In TRAIL-resistant MB, we show upregulation of DR4/5 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-treated TRAIL-resistant MBs. To our knowledge, this is the first study that explores the use of human MSC as MB-targeting therapeutic-vehicles in vivo in TRAIL-sensitive and resistant tumors, and has implications for developing effective therapies for patients with medulloblastomas.
authors.affiliation: Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Irina
authors.initials: I
authors.lastname: Nesterenko
authors.forename: Simone
authors.initials: S
authors.lastname: Wanningen
authors.forename: Tugba
authors.initials: T
authors.lastname: Bagci-Onder
authors.forename: Maarten
authors.initials: M
authors.lastname: Anderegg
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
mesh_terms: D000818:Animals; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology; D002528:Cerebellar Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005818:Genetic Engineering; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008164:Luminescent Proteins / Q000032:analysis; D008527:Medulloblastoma / Q000532:radiotherapy / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D011725:Pyridines / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D001549:Benzamides; D004337:Drug Carriers; D056572:Histone Deacetylase Inhibitors; D008164:Luminescent Proteins; D011725:Pyridines; D053221:TNF-Related Apoptosis-Inducing Ligand; C118739:entinostat