gms | German Medical Science

Objective: Tumor associated macrophages (TAM) arising from both activated microglia and systemic macrophages are supposed to enhance glioma growth and invasion. However, our previous finding that a depletion of systemic macrophages by clodronate distinctly promotes glioma progression rather suggests a pivotal role of blood-derived macrophages in tumor defense. The aim of our current study was to analyze tumor progression pattern after systemic stimulation of macrophages using recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF).

Method: 20 Sprague-Dawley rats carrying orthotopically implanted C6 glioma spheroids were treated with repetitive s.c. rhGM-CSF, 10 animals served as controls. Tumor volumes were determined by serial MRI scans (T1, T2 and 3D CISS-sequences) performed on days 7, 14, 21, 28, 32 and 42 post-implantation. Histological work-up of animals sacrificed at different time points included HE, ED-1 macrophage, CD8 T-cell and Ki-67 proliferation staining of brains with implanted tumors and spleen.

Results: In the GM-CSF group, tumors developed in only 13 of 20 animals, reached their peak volume earlier and remained smaller with a median size of 134 (mu)m³ compared to controls with 150 (mu)m³. Whereas in controls macrophages were merely scattered and confined to the peritumoral region and necrotic areas, their numbers increased after systemic administration of GM-CSF. Furthermore, stimulated macrophages were infiltrating the solid portions of the tumors. Their arrangement in perivascular cuffs indicated their rather hematogenous provenience instead of an origin from activated microglia. An effect of GM-CSF on macrophage stimulation was checked by counting ED-1+ cells in the corresponding spleens.

Conclusions: Stimulation of macrophages by GM-CSF leads to a significantly reduced and delayed tumor growth in the rodent C6 glioma model. The presented data suggest a significant role of blood derived macrophages in host control of experimental gliomas. Our results question the concept of a predominant reprogramming and differentiation of blood-derived macrophages invading high-grade glioma from an inflammatory-type macrophage into the pro-invasive phenotype of TAM.