Abstract
Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient-derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monocytoid cells and found that AmpB enhanced the microglial reduction of BTIC spheres. In mice harboring intracranial mouse or patient-derived BTICs, daily systemic treatment with non-toxic doses of AmpB substantially prolonged life. Notably, microglia and monocytes cultured from glioma patients were inefficient at reducing the sphere-forming capacity of autologous BTICs, but this was rectified by AmpB. These results provide new insights into the treatment of gliomas.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AC133 Antigen
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Amphotericin B / pharmacology*
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Analysis of Variance
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Animals
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Annexin A5 / metabolism
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Antigens, CD / metabolism
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Antineoplastic Agents / pharmacology*
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Brain Neoplasms / drug therapy
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Brain Neoplasms / mortality
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Brain Neoplasms / pathology*
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Bromodeoxyuridine / metabolism
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Calcium-Binding Proteins / metabolism
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Chemokine CCL2 / pharmacology
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Coculture Techniques
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Culture Media, Conditioned / pharmacology
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Flow Cytometry
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Gene Expression Profiling
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Glioma / drug therapy
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Glioma / mortality
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Glioma / pathology*
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Glycoproteins / metabolism
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Humans
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Interleukin-1 / pharmacology
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Kaplan-Meier Estimate
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Macrophages / drug effects
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Macrophages / physiology*
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Magnetic Resonance Imaging
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Mice
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Microfilament Proteins / metabolism
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Microglia / drug effects
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Microglia / physiology*
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Neoplasm Transplantation
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Nerve Tissue Proteins / metabolism
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Nitric Oxide Synthase Type II / metabolism
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Oligonucleotide Array Sequence Analysis
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Peptides / metabolism
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Receptors, CCR2 / genetics
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Time Factors
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Transfection
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Tumor Cells, Cultured / drug effects*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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AC133 Antigen
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Aif1 protein, mouse
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Annexin A5
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Antigens, CD
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Antineoplastic Agents
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Calcium-Binding Proteins
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Ccl2 protein, mouse
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Ccr2 protein, mouse
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Chemokine CCL2
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Culture Media, Conditioned
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Glycoproteins
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Interleukin-1
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Microfilament Proteins
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Nerve Tissue Proteins
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Peptides
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RNA, Messenger
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RNA, Small Interfering
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Receptors, CCR2
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Tumor Necrosis Factor-alpha
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Amphotericin B
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Nitric Oxide Synthase Type II
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Bromodeoxyuridine