title: Importance of direct macrophage-tumor cell interaction on progression of human glioma.
abstract: 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.
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.forename: Hasita
authors.initials: H
authors.lastname: Horlad
authors.forename: Koji
authors.initials: K
authors.lastname: Ohnishi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Bing
authors.initials: B
authors.lastname: Bai
authors.forename: Takenobu
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Suzu
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kuratsu
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D015536:Down-Regulation; D005260:Female; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D016186:Receptor, Macrophage Colony-Stimulating Factor