Antiangiogenic Variant of TSP-1 Targets Tumor Cells in Glioblastomas

• DOI: 10.1038/mt.2014.214
• Publication Date: 2014-10-31T12:18:14Z
• Authors: Sung Hugh Choi; Kaoru Tamura; Rajiv Kumar Khajuria; Deepak Bhere; Irina Nesterenko; Jack Lawler; Khalid Shah
• Keywords: 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

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.