gms | German Medical Science

Objective: Glioblastoma multiforme belongs to malignant glial tumors, and is extremely aggressive, invasive and highly vascularized. In addition, these tumors consist of large amounts of microglia/macrophages. In previous experiments, we detected an upregulation of CCR2 in microglia/macrophages of glioma-bearing brains while tumor cells express the corresponding ligand CCL2. Thus, we focused on the precise function of CCR2-signaling for migration of myeloid cells to glioma tissue and its role for tumor progression.

Method: We stereotactically implanted glioma cells (GL261) into the brain parenchyma of transgenic CCR2ko as well as wildtype BL6/J mice. Here, we determined the amount and phenotype of infiltrated microglia/macrophages and the vascularization status by immunofluorescence stainings. For further characterization of the microglia/macrophage cell population fluorescence activated cell sorting (FACS) was performed. Moreover, we used magnetic resonance imaging (MRI) for measurement of tumor volumes at different time points of glioma growth.

Results: Infiltration of microglia/macrophages was significantly reduced in CCR2ko mice compared to control animals due to the disrupted CCR2-CCL2 signaling. However, remaining microglia/macrophages expressed characteristic markers (e.g. Iba-1, CD11b, CD68) and molecules for antigen-presentation (MHCI and MHCII). Remarkably, the CCR2-deficient mice showed strongly enhanced tumor growth. Here, a doubling in glioma volumes was observed. Surprisingly, the vessel density of the tumor tissue was nearly unchanged despite the enlarged tumors. Solely, the detailed analyses of the vasculature revealed an angiogenic phenotype. Here, in the transgenic mice rather microvessels than macrovessels were contributed to the overall tumor vessel covered area, contrasting the wildtype animals with the opposite distribution.

Conclusions: Our data clearly demonstrate the importance of the CCR2-CCL2 signaling in the context of microglia/macrophage accumulation and glioma progression. Migration of microglia/macrophages into the tumor tissue of CCR2ko mice is significantly decreased suggesting the CCR2-CCL2 pathway as a crucial signal in recruitment of myeloid cells by glioma cells. Here, reduced numbers of microglia/macrophages within the tumor are accompanied by accelerated glioma growth implying that myeloid cells have potential anti-tumoral functions. Thus, microglia/macrophages are promising targets for future glioma therapy.