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Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors

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Abstract

Myeloid cells are an essential part of the glioblastoma microenvironment. However, in brain tumors the function of these immune cells is not sufficiently clarified. In our study, we investigated differential pro-angiogenic activities of resident microglia and peripheral macrophages and their impact on glioma vascularization and progression. Our data demonstrate stable accumulation of microglia/macrophages during tumor growth. These cells often interact with tumor blood vessels correlating with vascular remodeling. Here, we identified resident microglia as well as peripheral macrophages as part of the perivascular niche, primarily contacting endothelial cells. We found overexpression of a variety of pro-angiogenic molecules within freshly isolated microglia/macrophages from glioma. CXCL2, until now a poorly described chemokine, was strongly up-regulated and showed better angiogenic activity than VEGF in vitro. Blocking the CXCL2-CXCR2 signaling pathway resulted in considerably diminished glioma sizes. Additionally, the importance of microglia/macrophages in tumor angiogenesis was confirmed by depletion of these cells in vivo. Vessel density decreased by 50 % leading to significantly smaller tumor volumes. Remarkably, selective reduction of resident microglia affected tumoral vessel count comparable to ablation of the whole myeloid cell fraction. These results provide evidence that resident microglia are the crucial modulatory cell population playing a central role in regulation of vascular homeostasis and angiogenesis in brain tumors. Thus, resident microglia represent an alternative source of pro-angiogenic growth factors and cytokines.

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Acknowledgments

The authors thank Dr. Jana Glumm and Martin Pohland for the kind supply of the C57BL6/J-TgN(beta-act-EGFP) mice. We especially thank Thomas Broggini for providing the bEnd.4 cell line. Additionally, we thank Susanne Müller for her assistance in MRI measurement and analyses. This work was supported by the German Research Foundation (DFG, SPP1190) and SFB TRR43. A. Müller was funded by a doctoral scholarship from Sonnenfeld foundation.

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Authors and Affiliations

  1. Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany

    Susan Brandenburg, Annett Müller, Kati Turkowski, Yordan T. Radev, Sergej Rot, Christin Schmidt, Alexander D. Bungert, Güliz Acker & Peter Vajkoczy

  2. Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Güliz Acker & Peter Vajkoczy

  3. Department of Dermatology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany

    Anne Schorr, Andreas Hippe & Bernhard Homey

  4. Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany

    Kelly Miller & Frank L. Heppner

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  1. Susan Brandenburg
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Correspondence to Peter Vajkoczy.

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This work was supported by the German Research Foundation (DFG, SPP1190) and SFB TRR43. A. Müller was funded by a doctoral scholarship from Sonnenfeld foundation.

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Brandenburg, S., Müller, A., Turkowski, K. et al. Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors. Acta Neuropathol 131, 365–378 (2016). https://doi.org/10.1007/s00401-015-1529-6

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