Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors
- 1.5k Downloads
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.
KeywordsGlioblastoma multiforme Tumor angiogenesis Microglia/macrophages Angiogenic molecules CXCL2
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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.
- 5.Batchelor TT, Sorensen AG, di TE, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95Google Scholar
- 18.Cloughesy TF, Wen PY, Robins HI, Chang SM, Groves MD, Fink KL, Junck L, Schiff D, Abrey L, Gilbert MR, Lieberman F, Kuhn J, DeAngelis LM, Mehta M, Raizer JJ, Yung WK, Aldape K, Wright J, Lamborn KR, Prados MD (2006) Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol 24:3651–3656CrossRefPubMedGoogle Scholar
- 27.Hiratsuka S, Duda DG, Huang Y, Goel S, Sugiyama T, Nagasawa T, Fukumura D, Jain RK (2011) C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase in myeloid differentiation antigen (Gr-1)-positive cells. Proc Natl Acad Sci USA 108:302–307PubMedCentralCrossRefPubMedGoogle Scholar
- 33.Markovic DS, Vinnakota K, Chirasani S, Synowitz M, Raguet H, Stock K, Sliwa M, Lehmann S, Kalin R, van Rooijen N, Holmbeck K, Heppner FL, Kiwit J, Matyash V, Lehnardt S, Kaminska B, Glass R, Kettenmann H (2009) Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci USA 106:12530–12535PubMedCentralCrossRefPubMedGoogle Scholar