We previously showed tumor-associated macrophages/microglia (TAMs) polarized to the M2 phenotype were significantly involved in
tumor cell proliferation and poor clinical prognosis in patients with high grade
gliomas. However, the detailed molecular mechanisms involved in the interaction between TAMs and
tumor cells have been unclear. Current results reveal that, in coculture with human macrophages,
BrdU incorporation was significantly elevated in
glioma cells, and signal transducer and activator of transcription-3 (Stat3) activation was found in both cell types. Direct mixed coculture led to stronger Stat3 activation in
tumor cells than did indirect separate coculture in Transwell chamber dishes. Screening with an array kit for phospho-
receptor tyrosine kinases revealed that phosphorylation of
macrophage-colony stimulating factor receptor (M-CSFR, CD115, or c-fms) is possibly involved in this cell-cell interaction; M-CSFR activation was detected in both cell types. Coculture-induced
tumor cell activation was suppressed by
siRNA-mediated downregulation of the M-CSFR in macrophages and by an inhibitor of M-CSFR (
GW2580). Immunohistochemical analysis of phosphorylated (p)M-CSFR, pStat3,
M-CSF, M2 ratio, and MIB-1(%) in high grade
gliomas revealed that higher staining of pM-CSFR in
tumor cells was significantly associated with higher
M-CSF expression and higher MIB-1(%). Higher staining of pStat3 was associated with higher MIB-1(%). High M2 ratios were closely correlated with high MIB-1(%) and poor clinical prognosis. Targeting these molecules or deactivating M2 macrophages might be useful therapeutic strategies for high grade
glioma patients.