GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis

Abstract

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.

MiRNAs Mediate GDNF-Induced Proliferation and Migration of Glioma Cells

“…Subsequent research revealed that GDNF strongly induces glioma cell proliferation and migration [11-13]. Knocking down expression of GDNF or its receptor GDNF family receptor α1 (GFRα1) effectively inhibits the pathological progression of glioma [14, 15]. GDNF mainly exerts its functions via the GFRα1/Ret receptor complex [16].…”

Probing the Bi-directional Interaction Between Microglia and Gliomas in a Tumor Microenvironment on a Microdevice

“…2a). In some in vivo studies, microglia were polarized and recruited by tumor-released chemokines such as colony-stimulating factor, monocyte chemotactic protein-1, hepatocyte growth factor, and glial cell line-derived neurotrophic factor [32,33] and migrated to the tumor cells. The activated microglia released active substances such as granulocyte macrophage colony-stimulating factor that further increased glioma migration [10].…”

Effects of Gas1 on gliomas: a review on current preclinical studies

“…[82] On the other hand, the expression and activity of GDNF and its receptor GFRα1 are increased by their soluble forms in gliomas. [130][131][132][133] Based on the above, we developed a lentiviral vector in which the expression of tGAS1 is inducible. [87,88] This soluble form of GAS1 acts both in autocrine and paracrine manners in GBM cells and inhibits glioma tumor growth in vivo.…”