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Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth

Nature Cell Biology volume 17, pages 170182 (2015) | Download Citation

Abstract

Tumour-associated macrophages (TAMs) are enriched in glioblastoma multiformes (GBMs) that contain glioma stem cells (GSCs) at the apex of their cellular hierarchy. The correlation between TAM density and glioma grade suggests a supportive role for TAMs in tumour progression. Here we interrogated the molecular link between GSCs and TAM recruitment in GBMs and demonstrated that GSCs secrete periostin (POSTN) to recruit TAMs. TAM density correlates with POSTN levels in human GBMs. Silencing POSTN in GSCs markedly reduced TAM density, inhibited tumour growth, and increased survival of mice bearing GSC-derived xenografts. We found that TAMs in GBMs are not brain-resident microglia, but mainly monocyte-derived macrophages from peripheral blood. Disrupting POSTN specifically attenuated the tumour-supportive M2 type of TAMs in xenografts. POSTN recruits TAMs through the integrin αvβ3 as blocking this signalling by an RGD peptide inhibited TAM recruitment. Our findings highlight the possibility of improving GBM treatment by targeting POSTN-mediated TAM recruitment.

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Acknowledgements

We thank the Brain Tumor and Neuro-Oncology Centers at Cleveland Clinic and University Hospitals Case Medical Center for providing GBM surgical specimens for this study. We are grateful to members in J.N.R.’s laboratory for their assistance and scientific discussion. We also thank C. Shemo and S. O’Bryant of the Flow Cytometry Core, J. Drazba and L. Vargo of the Imaging Core at Cleveland Clinic Lerner Research Institute, and D. Schumick of the Center for Medical Art and Photography for their assistance. This work was supported by the Cleveland Clinic Foundation and an NIH R01 grant (NS070315) to S.B.

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Affiliations

  1. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA

    • Wenchao Zhou
    • , Susan Q. Ke
    • , Zhi Huang
    • , William Flavahan
    • , Xiaoguang Fang
    • , Jeremy Paul
    • , Jeremy N. Rich
    •  & Shideng Bao
  2. Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA

    • Ling Wu
    •  & Xiaoxia Li
  3. Departments of Neurological Surgery & Pathology, University Hospitals, Case Medical Center & Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA

    • Andrew E. Sloan
  4. Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA

    • Roger E. McLendon

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Contributions

W.Z. and S.B. designed the experiments, analysed data and prepared the manuscript. W.Z., S.Q.K., Z.H., X.F., J.P. and L.W. performed the experiments. W.F. performed database analysis. A.E.S. and R.E.M. provided GBM surgical specimens. R.E.M. performed pathological analyses. J.N.R. and X.L. provided scientific input and helped to edit the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shideng Bao.

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DOI

https://doi.org/10.1038/ncb3090

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