GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis.
High-grade gliomas are the most common primary brain tumors. Their malignancy is promoted by the complex crosstalk between different cell types in the central nervous system. Microglia/brain macrophages infiltrate high-grade gliomas and contribute to their progression. To identify factors that mediate the attraction of microglia/macrophages to malignant brain tumors, we established a glioma cell encapsulation model that was applied in vivo. Mouse GL261 glioma cell line and human high-grade glioma cells were seeded into hollow fibers (HF) that allow the passage of soluble molecules but not cells. The glioma cell containing HF were implanted into one brain hemisphere and simultaneously HF with non-transformed fibroblasts (controls) were introduced into the contralateral hemisphere. Implanted mouse and human glioma- but not fibroblast-containing HF attracted microglia and up-regulated immunoreactivity for GFAP, which is a marker of astrogliosis. In this study, we identified GDNF as an important factor for microglial attraction: (1) GL261 and human glioma cells secret GDNF, (2) reduced GDNF production by siRNA in GL261 in mouse glioma cells diminished attraction of microglia, (3) over-expression of GDNF in fibroblasts promoted microglia attraction in our HF assay. In vitro migration assays also showed that GDNF is a strong chemoattractant for microglia. While GDNF release from human or mouse glioma had a profound effect on microglial attraction, the glioma-induced astrogliosis was not affected. Finally, we could show that injection of GL261 mouse glioma cells with GDNF knockdown by shRNA into mouse brains resulted in reduced tumor expansion and improved survival as compared to injection of control cells.
Department of Cellular Neuroscience, Max Delbrück Center for Molecular Medicine (MDC), Robert Rössle Str. 10, 13125 Berlin, Germany.
Min-Chi
MC
Ku
Susanne A
SA
Wolf
Dorota
D
Respondek
Vitali
V
Matyash
Andreas
A
Pohlmann
Sonia
S
Waiczies
Helmar
H
Waiczies
Thoralf
T
Niendorf
Michael
M
Synowitz
Rainer
R
Glass
Helmut
H
Kettenmann
D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002633:Chemotaxis; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005911:Gliosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009368:Neoplasm Transplantation
D051100:Glial Cell Line-Derived Neurotrophic Factor