Open AccessImportance of direct macrophage ‐ Tumor cell interaction on progression of human glioma
Author(s) -
Komohara Yoshihiro,
Horlad Hasita,
Ohnishi Koji,
Fujiwara Yukio,
Bai Bing,
Nakagawa Takenobu,
Suzu Shinya,
Nakamura Hideo,
Kuratsu Junichi,
Takeya Motohiro
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12015
Subject(s) - microglia , glioma , stat3 , stat protein , tumor associated macrophage , cancer research , cell , immunohistochemistry , tumor progression , downregulation and upregulation , cell growth , tumor microenvironment , biology , chemistry , phosphorylation , medicine , immunology , microbiology and biotechnology , cancer , inflammation , tumor cells , biochemistry , gene , genetics
We previously showed tumor‐associated macrophages/microglia ( TAM s) polarized to the M 2 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 TAM s and tumor cells have been unclear. Current results reveal that, in coculture with human macrophages, B rd U incorporation was significantly elevated in glioma cells, and signal transducer and activator of transcription‐3 ( S tat3) activation was found in both cell types. Direct mixed coculture led to stronger S tat3 activation in tumor cells than did indirect separate coculture in T ranswell chamber dishes. Screening with an array kit for phospho‐receptor tyrosine kinases revealed that phosphorylation of macrophage‐colony stimulating factor receptor ( M‐CSFR , CD 115, 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 si RNA ‐mediated downregulation of the M‐CSFR in macrophages and by an inhibitor of M‐CSFR ( GW 2580). Immunohistochemical analysis of phosphorylated (p) M‐CSFR , p S tat3, M‐CSF , M 2 ratio, and MIB ‐1(%) in high grade gliomas revealed that higher staining of p M‐CSFR in tumor cells was significantly associated with higher M‐CSF expression and higher MIB ‐1(%). Higher staining of p S tat3 was associated with higher MIB ‐1(%). High M 2 ratios were closely correlated with high MIB ‐1(%) and poor clinical prognosis. Targeting these molecules or deactivating M 2 macrophages might be useful therapeutic strategies for high grade glioma patients.