The role of microglia and macrophages in glioma maintenance and progression

Abstract

There is a growing recognition that gliomas are complex tumors composed of neoplastic and non-neoplastic cells, which each individually contribute to cancer formation, progression and response to treatment. The majority of the non-neoplastic cells are tumor-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, that create a supportive stroma for neoplastic cell expansion and invasion. TAMs are recruited to the glioma environment, have immune functions, and can release a wide array of growth factors and cytokines in response to those factors produced by cancer cells. In this manner, TAMs facilitate tumor proliferation, survival and migration. Through such iterative interactions, a unique tumor ecosystem is established, which offers new opportunities for therapeutic targeting.

Figure 1

Microglia and monocytes have distinct cellular origins. Under steady-state conditions, these different mononuclear cell populations reside in separate locations. In adult life, monocytes are generated from HSCs that differentiate into granulocyte-macrophage progenitors (GMPs) and then into monocyte-dendritic cell progenitors (MDPs). Mature Ly6C^hi CCR2⁺ CX3CR1^low/int inflammatory monocytes are released into circulation, where they can migrate to tissues in response to specific pathological conditions. These cells can also give a rise to circulating monocytes. Microglia originate from yolk sac progenitors in the neuroepithelium beginning around E8.5 in the mouse. In the adult brain, they express high levels of CX3CR1, CD11b and F4/80, but low levels of CD45 and no CCR2. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2015. All rights reserved.

Figure 2

Microglia and monocytes converge in high-grade glioma (HGG). HGG cells induce local inflammation that compromises the integrity of the blood-brain barrier (BBB) and results in Ly6C^hi CCR2⁺ CX3CR1^low/int monocytes infiltrating into the tumor. Once in the CNS, these cells can differentiate into tumor-associated macrophages and become nearly indistinguishable from activated resident microglia. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2015. All rights reserved.

Figure 3

M1/M2 profile of TMAs. Comparison of TAMs with M1- and M2a-, M2b- and M2c-stimulated macrophage data sets (http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-32690/) containing macrophages stimulated for 24 h in vitro into different polarization states (M0 (unstimulated), M1 (IFNγ + LPS), M2a (IL4), M2b (IFNγ + complexed Ig) and M2c (dexamethasone)), which were compared with TAMs. (a) A graphical representation of the overlap of upregulated genes in TAMs and the four macrophage data sets. The TAMs gene expression profile shows the greatest overlap with M1- and M2b-polarized macrophages. The number of overlapping genes is indicated. (b) Using Gene Set Enrichment Analysis reveals that only a minority of genes that were upregulated in TAMs were also induced in the M1 to M2c phenotype; 59.5% of the genes upregulated in TAMs were not regulated in any of the four macrophage phenotypes.

Figure 4

Glioma cells release several factors, which attract TAMs to the tumor tissue. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2015. All rights reserved.

Figure 5

TAM glioma crosstalk. (a) TAMs release several factors that promote glioma cell invasion. (b) Microglia release TGF-β, which triggers the release of pro-MMP2 from glioma cells. Pro-MMP2 is then cleaved into active MMP2 by microglia-expressed MT1-MMP. Microglial MT1-MMP expression is stimulated by versican, which is released from glioma cells. Versican activates TLR2 and p38- MAP-kinase signaling in microglial cells, which leads to MT1-MMP upregulation. TLR2 signaling in microglia also triggers MMP9 release. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2015. All rights reserved.

Figure 6

Illustration of the complexity and cellular composition of glioma. Gliomas consist of neoplastic tumor cells and non-neoplastic cells from microenvironment, including endothelial cells, pericytes, infiltrating monocytes, activated astrocytes and TAMs. TAMs are recruited to the tumor by tumor bulk and GSCs. These recruited and reprogrammed TAMs secrete soluble factors that both expand the tumor bulk and GSCs as well. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2015. All rights reserved.