Artikel
The CCL18/CCR8 signalling cascade promotes the growth ofhuman glioblastoma in dependence on glioma associated monocytes
Die CCL18/CCR8 Signalkaskade fördert das humane Glioblastomwachstum in Abhängigkeit von gliom-assoziierten Monozyten
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Autoren
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Yimin Huang
- Max-Delbrück-Centrum für molekulare Medizin, Zelluläre Neurowissenschaften, Berlin, Deutschland
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Yang Yuan
- Max-Delbrück-Centrum für molekulare Medizin, Zelluläre Neurowissenschaften, Berlin, Deutschland
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Leo Kuhrt
- Max-Delbrück-Centrum für molekulare Medizin, Zelluläre Neurowissenschaften, Berlin, Deutschland
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Xia Pengfei
- Max-Delbrück-Centrum für molekulare Medizin, Zelluläre Neurowissenschaften, Berlin, Deutschland
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Marina Schnauss
- Max-Delbrück-Centrum für molekulare Medizin, Zelluläre Neurowissenschaften, Berlin, Deutschland
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Michael Synowitz
- Universitätsklinikum Schleswig-Holstein, Klinik für Neurochirurgie, Kiel, Deutschland
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Helmut Kettenmann
- Max-Delbrück-Centrum für molekulare Medizin, Zelluläre Neurowissenschaften, Berlin, Deutschland
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Charlotte Flüh
- Universitätsklinikum Schleswig-Holstein, Klinik für Neurochirurgie, Kiel, Deutschland; Max-Delbrück-Centrum für molekulare Medizin, Zelluläre Neurowissenschaften, Berlin, Deutschland
| Veröffentlicht: | 26. Juni 2020 |
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Gliederung
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Objective: With an average survival of 14 months and an incidence of 3.2 cases per 100.000 persons per year, glioblastoma multiforme is the most frequent and most malignant primary human brain tumor. Up to 40% of the tumor mass consists of tumor-associated microglia/macrophages (GAMs). GAMs are known to have a profound effect on tumorigenesis in glioma. There are various known interaction pathways between GAMs and glioma cells, which have been studied mostly in mice. Chemokine C-C motif ligand 18 (CCL18) is a chemokine, which predominantly is expressed by microglia and activated monocytes. Chemokine (C-C motif) receptor 8 (CCR8) is a receptor for CCL18, which is expressed on glioma cells. Both, ligand and receptor are expressed in human, but not in mice.
Methods: We performed an expression analysis using The Cancer Genome Atlas (TCGA) database and identified a direct association between high CCL18 expression level and survival time in GBM (12,7 vs. 14.7 months). We confirmed that CCL18 expression was higher in GAMs isolated by magnetic-activated cell sorting (MACS) for CD11b from human glioma resections, while CCR8 expression was higher in the CD11b-negative fraction (predominantly the glioma cells) as assessed by qrtPCR and Western blot. To test the impact of CCL18 signaling on glioma growth, we developed a humanized brain slice model by replacing the intrinsic microglia in a cultured mouse brain slice by human THP-1 derived monocytes. After an incubation time of 5 days, we inoculated the human glioma cell lines U251MG, U87 and LN229 into the murine slice.
Results: Comparing slices with and without THP-1 derived monocytes showed that the human THP-1 cells promoted the growth of the human glioma cell lines, confirming our previous observation from the murine system that microglia promote glioma growth. The promotion of U87 and LN229 glioma growth by THP-1 could be attenuated by either a specific CCR8 neutralizing antibody or a CCL18 neutralizing antibody, indicating that THP-1 glioma interaction is mediated by the CCL18-CCR8 axis.
Conclusion: The CCL18/CCR8 signaling pathway between GAMs and tumor cells could be an interesting target for future therapeutic regimens in glioblastoma multiforme.
