Abstract
Despite many refinements in current therapeutic strategies, the overall prognosis for a patient with glioblastoma is dismal. Neural precursor cells (NPCs) are capable of tracking glioma tumors and thus could be used to deliver therapeutic molecules. We have engineered mouse NPCs to deliver a secreted form of tumor necrosis factor-related apoptosis-inducing ligand (S-TRAIL); S-TRAIL is optimized to selectively kill neoplastic cells. Furthermore, we have developed means to simultaneously monitor both the migration of NSCs toward gliomas and the changes in glioma burden in real time. Using a highly malignant human glioma model expressing Renilla luciferase (Rluc), intracranially implanted NPC-FL-sTRAIL expressing both firefly luciferase (Fluc) and S-TRAIL was shown to migrate into the tumors and have profound antitumor effects. These studies demonstrate the potential of NPCs as therapeutically effective delivery vehicles for the treatment of gliomas and also provide important tools to evaluate the migration of NPCs and changes in glioma burden in vivo.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Apoptosis Regulatory Proteins
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Blotting, Western / methods
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Brain Neoplasms / pathology
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Brain Neoplasms / physiopathology
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Brain Neoplasms / therapy*
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Cell Count / methods
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Cell Line, Tumor
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Cell Movement / physiology*
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Cell Survival
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Cell Transplantation / methods
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Cloning, Molecular / methods
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Diagnostic Imaging / methods
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Dose-Response Relationship, Drug
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Enzyme-Linked Immunosorbent Assay / methods
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Galactosides / metabolism
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Glioblastoma / pathology
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Glioblastoma / physiopathology
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Glioblastoma / therapy*
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Green Fluorescent Proteins / metabolism
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Humans
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Immunohistochemistry / methods
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Indoles / metabolism
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Intracellular Signaling Peptides and Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / therapeutic use
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / therapeutic use*
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Mice
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Mice, Nude
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Mutagenesis / physiology
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Neurons / cytology*
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Neurons / physiology
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Recombinant Proteins / metabolism
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Recombinant Proteins / therapeutic use
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Stem Cells / cytology*
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Stem Cells / physiology
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TNF-Related Apoptosis-Inducing Ligand
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Time Factors
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / therapeutic use*
Substances
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Apoptosis Regulatory Proteins
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Galactosides
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Indoles
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Recombinant Proteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha
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Green Fluorescent Proteins
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5-bromo-4-chloro-3-indolyl beta-galactoside