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

Nature Neuroscience volume 17, pages 4655 (2014) | Download Citation

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.

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Acknowledgements

We acknowledge the technical assistance of Y. Fan, X. Zhang, F. Yong, J. Wang, H. Mowbray, B. Verhaeghe, M. Keough, R. Hassam, B. Mckenzie and A. Luchman. Clodronate was a gift from Roche Diagnostics GmbH. We thank Alberta Innovates – Health Solutions/Alberta Cancer Foundation and the Canadian Institutes of Health Research for operating grant support. V.W.Y. is a Canada Research Chair (Tier 1) in Neuroimmunology, for which salary support is gratefully acknowledged.

Author information

Author notes

    • Axinia Döring
    •  & Franz J Zemp

    These authors contributed equally to this work.

Affiliations

  1. Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.

    • Susobhan Sarkar
    • , Axinia Döring
    • , Claudia Silva
    • , John Kelly
    • , Walter Hader
    • , Mark Hamilton
    • , Philippe Mercier
    • , Gregory Cairncross
    •  & V Wee Yong
  2. Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

    • Susobhan Sarkar
    • , Axinia Döring
    • , Claudia Silva
    • , John Kelly
    • , Walter Hader
    • , Mark Hamilton
    • , Philippe Mercier
    • , Jeff F Dunn
    • , Samuel Weiss
    •  & V Wee Yong
  3. The Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.

    • Franz J Zemp
    • , Xueqing Lun
    • , Xiuling Wang
    • , Stephen Robbins
    • , Peter Forsyth
    •  & Gregory Cairncross
  4. Centre for Toxicology, University of Calgary, Calgary, Alberta, Canada.

    • Dave Kinniburgh
  5. Department of Molecular Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands.

    • Nico van Rooijen

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Contributions

S.S. designed all of the experiments, conducted and analyzed the data from the majority of the experiments, supervised the acquisition of all datasets, and wrote and edited the manuscript. A.D. performed the PCR analyses, conducted the liposome treatment of mice and edited the manuscript. F.J.Z. transfected GL261 with luciferase reporter, performed bioluminescence imaging and analyses, and guided aspects of the study. C.S. helped process the cells from tumor specimens and conducted some of the experiments. X.L. implanted mice with intracranial human BTICs, cross-checked the in vivo datasets and edited the manuscript. X.W. performed the microarray experiments and analyses. J.K. was instrumental in the derivation of BTIC lines from resected human specimens and in the analyses of the genetic alterations of the cells, and edited the manuscript. W.H. provided the surgically resected brain materials from epilepsy cases from which non-transformed adult human microglia were derived and edited the manuscript. M.H. provided the resected glioblastoma and blood specimens from which BTICs, tumor-derived microglia and monocytes were obtained and edited the manuscript. P.M. provided the resected glioblastoma and blood specimens from which BTICs, tumor-derived microglia and monocytes were obtained and edited the manuscript. J.F.D. performed the MRI studies, adapted human imaging to evaluation in mice and edited the manuscript. D.K. supervised the measurements of levels of AmpB in mice. N.V.R. supplied the clodronate liposomes and advised on its use. S.R. supervised the microarray analyses and edited the manuscript. P.F. provided expertise with regards to the implantation of BTICs in mice and the treatment procedures of mice with intracranial tumors and edited the manuscript. G.C. supervised the BTIC bank that houses the patient-derived lines used in this study, provided general expertise on brain tumors and edited the manuscript. S.W. co-supervised the BTIC bank, provided expertise on stem cells and edited the manuscript. V.W.Y. supervised all aspects of this work, designed the majority of experiments, obtained the funding for this study and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to V Wee Yong.

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DOI

https://doi.org/10.1038/nn.3597

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