CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology
Glioblastoma multiforme (GBM) shows a high influx of tumor-associated macrophages (TAMs). The CCR2/CCL2 pathway is considered a relevant signal for the recruitment of TAMs and has been suggested as a therapeutic target in malignant gliomas. We found that TAMs of human GBM specimens and of a syngenei...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/7/1882 |
| _version_ | 1797562510360969216 |
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| author | Matthäus Felsenstein Anne Blank Alexander D. Bungert Annett Mueller Adnan Ghori Irina Kremenetskaia Olga Rung Thomas Broggini Kati Turkowski Lea Scherschinski Jonas Raggatz Peter Vajkoczy Susan Brandenburg |
| author_facet | Matthäus Felsenstein Anne Blank Alexander D. Bungert Annett Mueller Adnan Ghori Irina Kremenetskaia Olga Rung Thomas Broggini Kati Turkowski Lea Scherschinski Jonas Raggatz Peter Vajkoczy Susan Brandenburg |
| author_sort | Matthäus Felsenstein |
| collection | DOAJ |
| description | Glioblastoma multiforme (GBM) shows a high influx of tumor-associated macrophages (TAMs). The CCR2/CCL2 pathway is considered a relevant signal for the recruitment of TAMs and has been suggested as a therapeutic target in malignant gliomas. We found that TAMs of human GBM specimens and of a syngeneic glioma model express CCR2 to varying extents. Using a <i>Ccr2</i>-deficient strain for glioma inoculation revealed a 30% reduction of TAMs intratumorally. This diminished immune cell infiltration occurred with augmented tumor volumes likely based on increased cell proliferation. Remaining TAMs in <i>Ccr2<sup>-/-</sup></i> mice showed comparable surface marker expression patterns in comparison to wildtype mice, but expression levels of inflammatory transcription factors (<i>Stat3</i>, <i>Irf7</i>, <i>Cox2</i>) and cytokines (<i>Ifnβ</i>, <i>Il1β</i>, <i>Il12α</i>) were considerably affected. Furthermore, we demonstrated an impact on blood vessel integrity, while vascularization of tumors appeared similar between mouse strains. The higher stability and attenuated leakiness of the tumor vasculature imply improved sustenance of glioma tissue in <i>Ccr2<sup>-/-</sup></i> mice. Additionally, despite TAMs residing in the perivascular niche in <i>Ccr2<sup>-/-</sup></i> mice, their pro-angiogenic activity was reduced by the downregulation of <i>Vegf</i>. In conclusion, lacking CCR2 solely on tumor microenvironmental cells leads to enhanced tumor progression, whereby high numbers of TAMs infiltrate gliomas independently of the CCR2/CCL2 signal. |
| first_indexed | 2024-03-10T18:30:14Z |
| format | Article |
| id | doaj.art-0a3cad3fd598435cb8bf2d63373d5729 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T18:30:14Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-0a3cad3fd598435cb8bf2d63373d57292023-11-20T06:38:50ZengMDPI AGCancers2072-66942020-07-01127188210.3390/cancers12071882CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma BiologyMatthäus Felsenstein0Anne Blank1Alexander D. Bungert2Annett Mueller3Adnan Ghori4Irina Kremenetskaia5Olga Rung6Thomas Broggini7Kati Turkowski8Lea Scherschinski9Jonas Raggatz10Peter Vajkoczy11Susan Brandenburg12Department of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyDepartment of Experimental Neurosurgery Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, GermanyGlioblastoma multiforme (GBM) shows a high influx of tumor-associated macrophages (TAMs). The CCR2/CCL2 pathway is considered a relevant signal for the recruitment of TAMs and has been suggested as a therapeutic target in malignant gliomas. We found that TAMs of human GBM specimens and of a syngeneic glioma model express CCR2 to varying extents. Using a <i>Ccr2</i>-deficient strain for glioma inoculation revealed a 30% reduction of TAMs intratumorally. This diminished immune cell infiltration occurred with augmented tumor volumes likely based on increased cell proliferation. Remaining TAMs in <i>Ccr2<sup>-/-</sup></i> mice showed comparable surface marker expression patterns in comparison to wildtype mice, but expression levels of inflammatory transcription factors (<i>Stat3</i>, <i>Irf7</i>, <i>Cox2</i>) and cytokines (<i>Ifnβ</i>, <i>Il1β</i>, <i>Il12α</i>) were considerably affected. Furthermore, we demonstrated an impact on blood vessel integrity, while vascularization of tumors appeared similar between mouse strains. The higher stability and attenuated leakiness of the tumor vasculature imply improved sustenance of glioma tissue in <i>Ccr2<sup>-/-</sup></i> mice. Additionally, despite TAMs residing in the perivascular niche in <i>Ccr2<sup>-/-</sup></i> mice, their pro-angiogenic activity was reduced by the downregulation of <i>Vegf</i>. In conclusion, lacking CCR2 solely on tumor microenvironmental cells leads to enhanced tumor progression, whereby high numbers of TAMs infiltrate gliomas independently of the CCR2/CCL2 signal.https://www.mdpi.com/2072-6694/12/7/1882tumor-associated macrophages (TAMs), blood vessel integritytumor angiogenesisCCR2/CCL2 signalingGBM |
| spellingShingle | Matthäus Felsenstein Anne Blank Alexander D. Bungert Annett Mueller Adnan Ghori Irina Kremenetskaia Olga Rung Thomas Broggini Kati Turkowski Lea Scherschinski Jonas Raggatz Peter Vajkoczy Susan Brandenburg CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology Cancers tumor-associated macrophages (TAMs), blood vessel integrity tumor angiogenesis CCR2/CCL2 signaling GBM |
| title | CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology |
| title_full | CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology |
| title_fullStr | CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology |
| title_full_unstemmed | CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology |
| title_short | CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology |
| title_sort | ccr2 of tumor microenvironmental cells is a relevant modulator of glioma biology |
| topic | tumor-associated macrophages (TAMs), blood vessel integrity tumor angiogenesis CCR2/CCL2 signaling GBM |
| url | https://www.mdpi.com/2072-6694/12/7/1882 |
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