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

• Published in: Nature neuroscience Vol. 17; no. 1; pp. 46 - 55
• Main Authors: Sarkar, Susobhan, Döring, Axinia, Zemp, Franz J, Silva, Claudia, Lun, Xueqing, Wang, Xiuling, Kelly, John, Hader, Walter, Hamilton, Mark, Mercier, Philippe, Dunn, Jeff F, Kinniburgh, Dave, van Rooijen, Nico, Robbins, Stephen, Forsyth, Peter, Cairncross, Gregory, Weiss, Samuel, Yong, V Wee
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-01-2014; Nature Publishing Group
• Subjects: 13/105; 13/21; 13/31; 631/378/1689/1690; 631/378/2596/1953; 631/67; 692/699/375/1922; AC133 Antigen; Amphotericin B - pharmacology; Analysis of Variance; Animal experimentation; Animal Genetics and Genomics; Animals; Annexin A5 - metabolism; Antigens, CD - metabolism; Antineoplastic Agents - pharmacology; Behavioral Sciences; Biological Techniques; Biomedicine; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Brain research; Brain tumors; Bromodeoxyuridine - metabolism; Calcium-Binding Proteins - metabolism; Care and treatment; Cell cycle; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Differentiation - drug effects; Cell Differentiation - 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; Glioma - mortality; Glioma - pathology; Glycoproteins - metabolism; Health aspects; Humans; Interleukin-1 - pharmacology; Kaplan-Meier Estimate; Macrophages; Macrophages - drug effects; Macrophages - physiology; Magnetic Resonance Imaging; Medical research; Mice; Microfilament Proteins - metabolism; Microglia - drug effects; Microglia - physiology; Neoplasm Transplantation; Nerve Tissue Proteins - metabolism; Neurobiology; Neurosciences; Nitric Oxide Synthase Type II - metabolism; Oligonucleotide Array Sequence Analysis; Peptides - metabolism; Physiological aspects; Receptors, CCR2 - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; Spheres; Time Factors; Transfection; Tumor Cells, Cultured - drug effects; Tumor Necrosis Factor-alpha - metabolism; Alberta Canada; Canada; Calgary Alberta Canada
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.3597

Growth of malignant glioma involves a rare population of stem-like cells in the brain called brain tumor-initiating cells (BTICs). This study shows that immune cells in the brain can attenuate tumorigenic capacity of cancer patient-derived BTICs. The authors also identify a drug amphotericin B as an activator of microglia and macrophages that can enhance the microglial activation and mitigate BTIC proliferation in culture. This drug also improved the lifespan of a mouse model of malignant glioma
in vivo
.
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.