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PMID: 24316889 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells.

Nature neuroscience ·Vol. 17 ·No. 1 ·2014-01-00 ·Pages 46-55

Sarkar S, Döring A, Zemp FJ, Silva C, Lun X, Wang X, Kelly J, Hader W, Hamilton M, Mercier P, Dunn JF, Kinniburgh D, van Rooijen N, Robbins S, Forsyth P, Cairncross G, Weiss S, Yong VW

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.

MeSH Terms
AC133 Antigen Amphotericin B/pharmacology Analysis of Variance Animals Annexin A5/metabolism Antigens, CD/metabolism Antineoplastic Agents/pharmacology Brain Neoplasms/drug therapy,mortality,pathology Bromodeoxyuridine/metabolism Calcium-Binding Proteins/metabolism Cell Cycle/drug effects,genetics Cell Differentiation/drug effects,genetics Chemokine CCL2/pharmacology Coculture Techniques Culture Media, Conditioned/pharmacology Dose-Response Relationship, Drug Drug Evaluation, Preclinical Flow Cytometry Gene Expression Profiling Glioma/drug therapy,mortality,pathology Glycoproteins/metabolism Humans Interleukin-1/pharmacology Kaplan-Meier Estimate Macrophages/drug effects,physiology Magnetic Resonance Imaging Mice Microfilament Proteins/metabolism Microglia/drug effects,physiology Neoplasm Transplantation Nerve Tissue Proteins/metabolism Nitric Oxide Synthase Type II/metabolism Oligonucleotide Array Sequence Analysis Peptides/metabolism RNA, Messenger/metabolism RNA, Small Interfering/pharmacology Receptors, CCR2/genetics Time Factors Transfection Tumor Cells, Cultured/drug effects Tumor Necrosis Factor-alpha/metabolism
Chemicals
AC133 Antigen Aif1 protein, mouse Annexin A5 Antigens, CD Antineoplastic Agents Calcium-Binding Proteins Ccl2 protein, mouse Ccr2 protein, mouse Chemokine CCL2 Culture Media, Conditioned Glycoproteins Interleukin-1 Microfilament Proteins Nerve Tissue Proteins Peptides RNA, Messenger RNA, Small Interfering Receptors, CCR2 Tumor Necrosis Factor-alpha Amphotericin B Nitric Oxide Synthase Type II Bromodeoxyuridine
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Sarkar Susobhan
1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Döring Axinia
1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. [3].
Zemp Franz J
1] The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada. [2].
Silva Claudia
1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Lun Xueqing
The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
Wang Xiuling
The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
Kelly John
1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Hader Walter
1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Hamilton Mark
1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Mercier Philippe
1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Dunn Jeff F
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Kinniburgh Dave
Centre for Toxicology, University of Calgary, Calgary, Alberta, Canada.
van Rooijen Nico
Department of Molecular Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands.
Robbins Stephen
The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
Forsyth Peter
The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
Cairncross Gregory
1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
Weiss Samuel
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Yong V Wee
1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
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Article Info
Journal
Nature neuroscience
Abbr.
Nat Neurosci
ISSN
1546-1726
DOI
10.1038/nn.3597
Published
2014-01-00
Epub
2013-00-08
Pages
46-55
Language
English
Region
United States
NLM ID
9809671
Subset
IM
Grants
Canadian Institutes of Health Research · Canada
Databases
GEO
GSE52127
Corrections
CommentIn
PMID: 24366097
CommentIn
PMID: 24468879
External Links
PubMed source DOI: 10.1038/nn.3597 View journal details
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