title: Antiangiogenic variant of TSP-1 targets tumor cells in glioblastomas.
abstract: Three type-1 repeat (3TSR) domain of thrombospondin-1 is known to have anti-angiogenic effects by targeting tumor-associated endothelial cells, but its effect on tumor cells is unknown. This study explored the potential of 3TSR to target glioblastoma (GBM) cells in vitro and in vivo. We show that 3TSR upregulates death receptor (DR) 4/5 expression in a CD36-dependent manner and primes resistant GBMs to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced caspase-8/3/7 mediated apoptosis. We engineered human mesenchymal stem cells (MSC) for on-site delivery of 3TSR and a potent and secretable variant of TRAIL (S-TRAIL) in an effort to simultaneously target tumor cells and associated endothelial cells and circumvent issues of systemic delivery of drugs across the blood-brain barrier. We show that MSC-3TSR/S-TRAIL inhibits tumor growth in an expanded spectrum of GBMs. In vivo, a single administration of MSC-3TSR/S-TRAIL significantly targets both tumor cells and vascular component of GBMs, inhibits tumor progression, and extends survival of mice bearing highly vascularized GBM. The ability of 3TSR/S-TRAIL to simultaneously act on tumor cells and tumor-associated endothelial cells offers a great potential to target a broad spectrum of cancers and translate 3TSR/TRAIL therapies into clinics.
authors.affiliation: Molecular Neurotherapy and Imaging Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sung Hugh
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Molecular Neurotherapy and Imaging Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Molecular Neurotherapy and Imaging Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rajiv Kumar
authors.initials: RK
authors.lastname: Khajuria
authors.affiliation: Molecular Neurotherapy and Imaging Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhere
authors.affiliation: Molecular Neurotherapy and Imaging Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Nesterenko
authors.affiliation: Division of Experimental Pathology, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Lawler
authors.affiliation: 1] Molecular Neurotherapy and Imaging Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [3] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
mesh_terms: D000818:Animals; D017209:Apoptosis; D018955:CD36 Antigens / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000737:chemistry / Q000235:genetics*; D014161:Transduction, Genetic
chemical_list: D018955:CD36 Antigens; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D019700:Thrombospondin 1; D020169:Caspases