gms | German Medical Science

73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

29.05. - 01.06.2022, Köln

Artikel

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Activation of the CCR8-ACP5 axis by human, microglia/macrophage derived CCL18 promotes glioma growth

Aktivierung der CCR8-ACP5-Achse in humanen gliomassoziierten Mikroglia und Macrophagen durch das Chemokin CCL18 befördert das humane Gliomwachstum

Meeting Abstract

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  • Yimin Huang - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland; Charité – Universitätsmedizin Berlin, Berlin, Deutschland; Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Department of Neurosurgery, Wuhan, China, Volksrepublik
  • Edyta Motta - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Cynthia Nanvuma - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Leonard Kuhrt - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland; Charité – Universitätsmedizin Berlin, Berlin, Deutschland
  • Yang Yuan - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Pengfei Xia - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Malgorzata Lubas - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Shuai Zhu - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Niyeti Quazi - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Feng Hu - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Huaqiu Zhang - Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Department of Neurosurgery, Wuhan, China, Volksrepublik
  • Lei Ting - Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Department of Neurosurgery, Wuhan, China, Volksrepublik
  • Michael Synowitz - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Neurochirurgie, Kiel, Deutschland
  • Helmut Kettenmann - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China, Volksrepublik
  • presenting/speaker Charlotte Flüh - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Neurochirurgie, Kiel, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie. Köln, 29.05.-01.06.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. DocP049

doi: 10.3205/22dgnc362, urn:nbn:de:0183-22dgnc3629

Veröffentlicht: 25. Mai 2022

© 2022 Huang et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.

Gliederung

Text

Objective: Glioblastoma multiforme is a highly malignant primary brain tumor with an average survival of 14 months and very limited therapeutic options. Glioma associated microglia and macrophages (GAMs) foster tumor growth by releasing several cytokines, which have only partly been identified. Here, we studied the chemokine (C-C motif) ligand 18 (CCL18), a chemokine which is only expressed in human, but not rodent GAMs, in a novel ex-vivo brain slice model including transplantation of human induced pluripotent stem cells (iPSC) derived human microglia (iMGL) and human glioma cells in to murine brain slices, which had been depleted of intrinsic murine microglia before.

Methods: After establishing the humanized ex-vivo brain slice model, we performed immunohistochemical analysis (IHC) of growth and invasiveness, qrtPCR on glioma cells isolated by magnetic-activated cell sorting (MACS), functional assays measuring invasiveness, proliferation, migration and colony formation of glioma cells in vitro and in slice experiments. Corresponding studies on tumor growth and invasiveness were performed after treatment with a CCL18 neutralizing antibody, a CCR8 neutralizing antibodies and knockdown of CCR8, ACP5 (Acid Phosphatase 5) and PITPNM3 with small interfering RNA (siRNA) and short hairpin RNA (shRNA). QrtPCR, IHC and Westernblot analysis were performed on primary glioma specimens. We also conducted bioinformatic analyses, based on the TCGA GBM, GLIOVIS and GEPIA databases.

Results: We observed, that CCL18 was highly expressed in GAMs, whereas CCR8 was only expressed in glioma cells. We identified the chemokine (C-C motif) receptor 8 (CCR8) as a functional receptor for CCL18 and ACP5 as an important down-stream signaling component in glioma cells. Activation of the CCL18/CCR8/ACP5 signaling pathway in human glioblastoma was associated with enhanced tumor growth and invasiveness.

Conclusion: GAMs derived CCL18 promoted glioma growth by activation of the CCR8/ACP5 axis in human glioma cells and therefore is a potential therapeutic target.