Abstract
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 Ccr2-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 Ccr2-/- mice showed comparable surface marker expression patterns in comparison to wildtype mice, but expression levels of inflammatory transcription factors (Stat3, Irf7, Cox2) and cytokines (Ifnβ, Il1β, Il12α) 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 Ccr2-/- mice. Additionally, despite TAMs residing in the perivascular niche in Ccr2-/- mice, their pro-angiogenic activity was reduced by the downregulation of Vegf. 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.
Highlights
Glioblastoma multiforme (GBM) is a poorly differentiated human brain tumor entity (WHO IV◦ )and displays markedly aggressive and invasive features
We demonstrate an impaired influx of myeloid cells in Ccr2-deficient animals, whereby remaining tumor-associated macrophages (TAMs) displayed a varied expression of pro-inflammatory molecules
It has been demonstrated that CCR2/CCL2 signaling plays a pivotal role in chemo-attraction during neuro-inflammatory processes [15,24]
Summary
Glioblastoma multiforme (GBM) is a poorly differentiated human brain tumor entity (WHO IV◦ )and displays markedly aggressive and invasive features. Glioblastoma multiforme (GBM) is a poorly differentiated human brain tumor entity (WHO IV◦ ). GBM tumors account for 60–70% of all malignant gliomas and have high recurrence rates with a dismal prognosis [1,2]. Its chemokine (C–C motif) receptor 2 (CCR2) is mainly located on the surface of TAMs [9,10]. The impact of this interaction has been demonstrated in several brain pathologies such as in atherosclerosis, autoimmune encephalitis, or even post-stroke inflammatory condition [11,12,13,14]
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