title: Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors.
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.
authors.affiliation: Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Brandenburg
authors.affiliation: Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Müller
authors.affiliation: Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kati
authors.initials: K
authors.lastname: Turkowski
authors.affiliation: Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Yordan T
authors.initials: YT
authors.lastname: Radev
authors.affiliation: Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sergej
authors.initials: S
authors.lastname: Rot
authors.affiliation: Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Bungert
authors.affiliation: Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Güliz
authors.initials: G
authors.lastname: Acker
authors.affiliation: Department of Dermatology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schorr
authors.affiliation: Department of Dermatology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hippe
authors.affiliation: Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kelly
authors.initials: K
authors.lastname: Miller
authors.affiliation: Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
authors.affiliation: Department of Dermatology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Homey
authors.affiliation: Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany. peter.vajkoczy@charite.de.|Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. peter.vajkoczy@charite.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Vajkoczy
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D054426:Chemokine CXCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: Angiogenic molecules; CXCL2; Glioblastoma multiforme; Microglia/macrophages; Tumor angiogenesis