Antiangiogenic Variant of TSP-1 Targets Tumor Cells in Glioblastomas
CD36 Antigens
0301 basic medicine
Genetic Vectors
Apoptosis
Angiogenesis Inhibitors
TNF-Related Apoptosis-Inducing Ligand
Thrombospondin 1
Mice
03 medical and health sciences
Transduction, Genetic
Cell Line, Tumor
Drug Discovery
Genetics
Humans
Animals
Protein Interaction Domains and Motifs
Molecular Biology
Pharmacology
0303 health sciences
Neovascularization, Pathologic
Brain Neoplasms
Lentivirus
Endothelial Cells
Mesenchymal Stem Cells
3. Good health
Gene Expression Regulation, Neoplastic
Disease Models, Animal
Receptors, TNF-Related Apoptosis-Inducing Ligand
Caspases
Molecular Medicine
Glioblastoma
DOI:
10.1038/mt.2014.214
Publication Date:
2014-10-31T12:18:14Z
AUTHORS (7)
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.
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CITATIONS (47)
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