The ability of glioma tumor cells to infiltrate the surrounding brain parenchyma makes complete removal of these tumors nearly impossible. We investigated how microglia, the resident macrophages of the brain, stimulate glioma cell invasion. Coculture with microglia stimulates the invasion of GL261 glioma cells in-vitro. Pharmacological inhibition of EGFR using Iressa strongly inhibits microglia-stimulated invasion. Furthermore, we demonstrate using novel CSF-1R (c-fms) inhibitors that CSF-1R signaling is also required for microglial enhancement of glioma invasion. GL261 cells were found to constitutively secrete CSF-1, the levels of which are unaffected by EGF stimulation, EGFR inhibition or coculture with microglia. GL261 tumors orthotopically injected into the brains of C57 mice fed with the CSF-1R inhibitor PLX3397 showed a dramatic reduction in microglia/macrophages infiltration compared with tumors from animals fed control chow. Tumors from the PLX3397-fed animals also showed a 50% reduction in invasion into the parenchyma. We discovered that GL261 cell secretion of CSF-1 is involved in upregulating EGFR ligands in microglia including AREG, EREG and TGFA. Microglia isolated from GL261 tumors express AREG mRNA whereas naïve microglia from control animals do not. Depletion of AREG from microglia using siRNA interfered with their ability to promote GL261 invasion in vitro. These data indicate that during invasion, glioma and microglia cells signal to each other using EGFR Ligands and CSF-1 similar to what has been observed in breast cancer models. The results of this study indicate the possibility of inhibiting glioblastoma invasion by targeting functions of tumor-associated microglia in addition to glioma cells.

Citation Format: Salvatore J. Coniglio, Jeffrey E. Segall. Mechanisms of microglia-stimulated glioma invasion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4928. doi:10.1158/1538-7445.AM2013-4928

©2013 American Association for Cancer Research
2013