title: Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells.
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.
authors: 1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Susobhan
authors: S
authors: Sarkar
authors: 1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. [3].
authors: Axinia
authors: A
authors: Döring
authors: 1] The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada. [2].
authors: Franz J
authors: FJ
authors: Zemp
authors: 1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Claudia
authors: C
authors: Silva
authors: The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Xueqing
authors: X
authors: Lun
authors: The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Xiuling
authors: X
authors: Wang
authors: 1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: John
authors: J
authors: Kelly
authors: 1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Walter
authors: W
authors: Hader
authors: 1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Mark
authors: M
authors: Hamilton
authors: 1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Philippe
authors: P
authors: Mercier
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Jeff F
authors: JF
authors: Dunn
authors: Centre for Toxicology, University of Calgary, Calgary, Alberta, Canada.
authors: Dave
authors: D
authors: Kinniburgh
authors: Department of Molecular Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands.
authors: Nico
authors: N
authors: van Rooijen
authors: The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Stephen
authors: S
authors: Robbins
authors: The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Peter
authors: P
authors: Forsyth
authors: 1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Gregory
authors: G
authors: Cairncross
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Samuel
authors: S
authors: Weiss
authors: 1] Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. [2] Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: V Wee
authors: VW
authors: Yong
mesh_terms: D000071916:AC133 Antigen; D000666:Amphotericin B / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D018932:Chemokine CCL2 / Q000494:pharmacology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005910:Glioma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D054390:Receptors, CCR2 / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; C491049:Aif1 protein, mouse; D017304:Annexin A5; D015703:Antigens, CD; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D006023:Glycoproteins; D007375:Interleukin-1; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054390:Receptors, CCR2; D014409:Tumor Necrosis Factor-alpha; D000666:Amphotericin B; D052247:Nitric Oxide Synthase Type II; D001973:Bromodeoxyuridine