These authors contributed equally to this work.
Importance of direct macrophage - Tumor cell interaction on progression of human glioma
Article first published online: 26 OCT 2012
© 2012 Japanese Cancer Association
Volume 103, Issue 12, pages 2165–2172, December 2012
How to Cite
(Cancer Sci 2012; 103: 2165–2172)
- Issue published online: 5 DEC 2012
- Article first published online: 26 OCT 2012
- Accepted manuscript online: 7 SEP 2012 06:16AM EST
- Manuscript Accepted: 2 SEP 2012
- Manuscript Revised: 31 AUG 2012
- Manuscript Received: 10 JUL 2012
- Grants-in-Aid for Scientific Research. Grant Numbers: B20390113, 21790388
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.