Possible involvement of the M2 anti‐inflammatory macrophage phenotype in growth of human gliomas

Abstract

Within tumours, many non-neoplastic cells such as fibroblasts, endothelial cells, and macrophages assist tumour growth by producing various growth factors and pro-angiogenic cytokines. Various tumour-derived molecules drive tumour-associated macrophages towards an anti-inflammatory phenotype (M2) and thus promoting tumour growth. Here we investigated microglia/macrophage differentiation in glioma tissues by means of immunostaining of paraffin-embedded glioma samples. The number of microglia/macrophages with positive staining for CD163 and CD204, which are believed to be markers for M2 macrophages, was correlated with the histological grade of the gliomas. The ratio of M2 macrophages in the tumour-associated microglia/macrophages was also associated with the histological grade. Culture supernatant from the glioma cell line can stimulate macrophages to develop into the M2 phenotype in vitro. Macrophage colony-stimulating factor (M-CSF), which strongly induces M2 polarization of macrophages, was significantly correlated with histological malignancy and with the proportion of M2 microglia/macrophages in vivo. In addition, the proportion of M2 microglia/macrophages and M-CSF expression in tumour cells correlated well with proliferation of glioblastoma cells. These results suggest that tumour-derived M-CSF induces a shift of microglia/macrophages towards the M2 phenotype, which influences tumour growth. Evaluation of the proportion of M2 microglia/macrophages and M-CSF expression in tumour tissue would be useful for assessment of microglia/macrophage proliferative activity and the prognosis of patients with gliomas.

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

“…CD11c and MRC1 are commonly used to identify M1-and M2-like TAMs, respectively (52). In many malignant tumor settings, including GBM, TAMs are skewed toward a protumoral M2-like phenotype and promote tumor angiogenesis and progression through the secretion of molecules such as VEGF and MMP-9 (32,(53)(54)(55)(56)(57)(58)(59)(60). Both MEDI3617-treated tumors (P = 0.054) and dual therapy-treated tumors (P = 0.096) exhibited a trend toward increased TAMs compared with cediranib-treated tumors (Fig.…”

The brain tumor microenvironment

“…The proportion of glioma associated microglia which resemble the M2 phenotype of (CD163 and CD204-positive) macrophages positively correlates with the histological malignancy of the tumor. This population shift is thought to be regulated by M-CSF (Komohara et al, 2008). The M2 macrophage phenotype most likely represents the default setting under homeostatic conditions while the M1 phenotype is associated with inflammation.…”

Glioblastoma cells induce differential glutamatergic gene expressions in human tumor-associated microglia/macrophages and monocyte-derived macrophages

“…7,8 These analyses moreover show that the number of TAMs in the tumor region correlated with the histological grade of gliomas. 9,10 TAMs in the presence of glioma cells become immunosuppressive and elicit an anti-inflammatory response by increasing the expression and release of cytokines such as IL-10 and VEGF, thereby contributing to a milieu that promotes the survival and growth of the glioblastoma cells. 8,11,12 Microglia express functional glutamate receptors, 13,14 and microglia as well as macrophages are capable of inducing expression of glutamate transporters and glutamine synthetase in neuropathological conditions, 15 suggesting a functional role of microglia and macrophages in glutamate signaling.…”