ME-03 * BONE MARROW DERIVED MICROGLIA AND THEIR FUNCTION WITHIN TUMOR MICROENVIRONMENT

Abstract

We have previously demonstrated that BMDC are recruited to Glioblastoma Multiforme (GBM), in a highly tumor-growth and region-dependent pattern, demonstrating that the majority of BMDCs differentiate into inflammatory cells, MAC3 + , and CD11b+ IBA1+ microglia-like cells. The majority of microglia seen in GBM microenvironment are derived from the BMDC rather than being resident brain microglia. The role of microglial cells in GBMs remains unknown, with evidence supporting both an anti- and pro- tumorgenic function. In this study we aimed to understand the contribution of microglia to GBM growth and tumor vascularity. Chimeric mice with reconstituted green-fluorescent bone marrow were used to create intracranial GBM xenografts, by implanting red fluorescent glioma stem cells or U87 into the frontal lobe. Using a known inhibitor of microglial activation, minocycline, we show that treatment with this agent increased tumor cell growth and invasiveness and reduced animal survival compared to controls. We show that Minocycline decreases activation of microglia, inhibits the phagocytic activity of microglia in GBMs and decreases the perivascular localization of microglia. The mRNA expression profile of microglia isolated from the GBM microenvironment showed, through Ingenuity Pathway Analysis (IPA), a loss of engulfment and migration of cells and phaocytotic pathways in BM-derived microglia, additionally we see a reorganization of cytoskeletal pathways leading to an increase in the migration and invasiveness of GBM cells following treatment with Minocycline. We also have preliminary data to suggest that this property of Minocycline is dependent on VEGF levels, where in the context of low VEGF Minocycline does not provide a significant anti-angiogenic role. We demonstrate that microglia in GBM microenvironment, are primarily recruited and differentiated from the BM and not resident, and that these cells have an anti-tumorgenic functions, and inhibition of the activated microglia by Minocycline, results in a more invasive phenotype of GBM cells.