CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology

被引：25

作者：

Felsenstein, Matthaeus ^{[1
,2
,3
,4
,6
]}

Blank, Anne ^{[1
,2
,3
,4
]}

Bungert, Alexander D. ^{[1
,2
,3
,4
]}

Mueller, Annett ^{[1
,2
,3
,4
]}

Ghori, Adnan ^{[1
,2
,3
,4
]}

Kremenetskaia, Irina ^{[1
,2
,3
,4
]}

Rung, Olga ^{[1
,2
,3
,4
]}

Broggini, Thomas ^{[1
,2
,3
,4
,7
]}

Turkowski, Kati ^{[1
,2
,3
,4
]}

Scherschinski, Lea ^{[1
,2
,3
,4
]}

Raggatz, Jonas ^{[1
,2
,3
,4
]}

Vajkoczy, Peter ^{[1
,2
,3
,4
,5
]}

Brandenburg, Susan ^{[1
,2
,3
,4
]}

机构：

[1] Univ Med Berlin, Charite, Dept Expt Neurosurg, D-10117 Berlin, Germany

[2] Free Univ Berlin, D-10117 Berlin, Germany

[3] Humboldt Univ, D-10117 Berlin, Germany

[4] Berlin Inst Hlth, D-10117 Berlin, Germany

[5] Univ Med Berlin, Dept Neurosurg, Charite, D-10117 Berlin, Germany

[6] Charite Univ Med Berlin, Dept Surg, D-10117 Berlin, Germany

[7] Univ Calif San Diego, Dept Phys, La Jolla, CA 92093 USA

来源：

CANCERS | 2020年 / 12卷 / 07期

关键词：

tumor-associated macrophages (TAMs); blood vessel integrity; tumor angiogenesis; CCR2; CCL2; signaling; GBM; PERIPHERAL MACROPHAGES; RESIDENT MICROGLIA; MYELOID CELLS; CANCER; ANGIOGENESIS; PROGRESSION; EXPRESSION; MICROGLIA/MACROPHAGES; INFILTRATION; MIGRATION;

D O I：

10.3390/cancers12071882

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 aCcr2-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 inCcr2(-/-)mice showed comparable surface marker expression patterns in comparison to wildtype mice, but expression levels of inflammatory transcription factors (Stat3,Irf7,Cox2) and cytokines (Ifn beta,Il1 beta,Il12 alpha) 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 inCcr2(-/-)mice. Additionally, despite TAMs residing in the perivascular niche inCcr2(-/-)mice, their pro-angiogenic activity was reduced by the downregulation ofVegf. 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.

引用

页码：1 / 19

页数：19

共 55 条

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