title: Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1.
abstract: Malignant glioma belong to the most aggressive neoplasms in humans with no successful treatment available. Patients suffering from glioblastoma multiforme (GBM), the highest-grade glioma, have an average survival time of only around one year after diagnosis. Both microglia and peripheral macrophages/monocytes accumulate within and around glioma, but fail to exert effective anti-tumor activity and even support tumor growth. Here we use microarray analysis to compare the expression profiles of glioma-associated microglia/macrophages and naive control cells. Samples were generated from CD11b+ MACS-isolated cells from naïve and GL261-implanted C57BL/6 mouse brains. Around 1000 genes were more than 2-fold up- or downregulated in glioma-associated microglia/macrophages when compared to control cells. A comparison with published data sets of M1, M2a,b,c-polarized macrophages revealed a gene expression pattern that has only partial overlap with any of the M1 or M2 gene expression patterns. Samples for the qRT-PCR validation of selected M1 and M2a,b,c-specific genes were generated from two different glioma mouse models and isolated by flow cytometry to distinguish between resident microglia and invading macrophages. We confirmed in both models the unique glioma-associated microglia/macrophage phenotype including a mixture of M1 and M2a,b,c-specific genes. To validate the expression of these genes in human we MACS-isolated CD11b+ microglia/macrophages from GBM, lower grade brain tumors and control specimens. Apart from the M1/M2 gene analysis, we demonstrate that the expression of Gpnmb and Spp1 is highly upregulated in both murine and human glioma-associated microglia/macrophages. High expression of these genes has been associated with poor prognosis in human GBM, as indicated by patient survival data linked to gene expression data. We also show that microglia/macrophages are the predominant source of these transcripts in murine and human GBM. Our findings provide new potential targets for future anti-glioma therapy.
authors: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
authors: Frank
authors: F
authors: Szulzewsky
authors: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany; Department of Experimental Neurology, Charité-University Medicine Berlin, Berlin, Germany.
authors: Andreas
authors: A
authors: Pelz
authors: Department of Neurosciences, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors: Xi
authors: X
authors: Feng
authors: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany; Department of Neurosurgery, Charité -Universitätsmedizin Berlin, Berlin, Germany.
authors: Michael
authors: M
authors: Synowitz
authors: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany; Department of Neurosurgery, Helios Clinics, Berlin, Germany.
authors: Darko
authors: D
authors: Markovic
authors: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors: Thomas
authors: T
authors: Langmann
authors: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Inge R
authors: IR
authors: Holtman
authors: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
authors: Xi
authors: X
authors: Wang
authors: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Bart J L
authors: BJ
authors: Eggen
authors: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Hendrikus W G M
authors: HW
authors: Boddeke
authors: Department of Neurosciences, Cleveland Clinic, Cleveland, Ohio, United States of America; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors: Dolores
authors: D
authors: Hambardzumyan
authors: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
authors: Susanne A
authors: SA
authors: Wolf
authors: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
authors: Helmut
authors: H
authors: Kettenmann
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000502:physiology*; D009368:Neoplasm Transplantation; D053495:Osteopontin / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis
chemical_list: C503042:GPNMB protein, human; D008562:Membrane Glycoproteins; C506895:SPP1 protein, human; D053495:Osteopontin