Macrophages and microglia: the cerberus of glioblastoma

Abstract

Glioblastoma (GBM) is the most aggressive and deadliest of the primary brain tumors, characterized by malignant growth, invasion into the brain parenchyma, and resistance to therapy. GBM is a heterogeneous disease characterized by high degrees of both inter- and intra-tumor heterogeneity. Another layer of complexity arises from the unique brain microenvironment in which GBM develops and grows. The GBM microenvironment consists of neoplastic and non-neoplastic cells. The most abundant non-neoplastic cells are those of the innate immune system, called tumor-associated macrophages (TAMs). TAMs constitute up to 40% of the tumor mass and consist of both brain-resident microglia and bone marrow-derived myeloid cells from the periphery. Although genetically stable, TAMs can change their expression profiles based upon the signals that they receive from tumor cells; therefore, heterogeneity in GBM creates heterogeneity in TAMs. By interacting with tumor cells and with the other non-neoplastic cells in the tumor microenvironment, TAMs promote tumor progression. Here, we review the origin, heterogeneity, and functional roles of TAMs. In addition, we discuss the prospects of therapeutically targeting TAMs alone or in combination with standard or newly-emerging GBM targeting therapies.

Keywords: Glioblastoma; Heterogeneity; Macrophages; Microenvironment; Microglia.

Fig. 1

Myeloid cell lineage and morphology in healthy brain and glioblastoma. Microglia arise from yolk sac progenitors in the embryonic stage and reside permanently in the brain parenchyma. They appear as highly-ramified cells, but they rapidly change their morphology into an amoeboid-like shape in glioblastoma. Monocytes originate from the bone marrow and circulate in the blood, until they invade the brain when a glioblastoma emerges and differentiate into macrophages. They are round shaped while in circulation and upon infiltration into glioblastoma, making them morphologically indistinguishable from microglia. Images are taken from the murine glioblastoma model generated by using RCAS/tv-a, a somatic cell type-specific technology [41]. Reciprocal bone-marrow chimeras generated by using Cx3cr1-GFP mice allowed generation of only GFP-labeled bone marrow-derived macrophages or GFP-labeled microglia for imaging. Blood vessels are visualized with TRICT-dextran. Scale bars, 30 and 50 µm [41]

Fig. 2

Tumor-associated macrophage (TAM)-glioma cell crosstalk creates a strong interdependence that leads to increased TAM recruitment, which supports tumor growth. Glioma cells—including both glioma non-stem cells and glioma stem cells—release chemoattractant molecules (Periostin, SSP1, GM-CSF, SDF-1, ATP, GDNF, CX3CL1, LOX, HGF/SF, MCP-1, MCP-3, CSF-1, Versican, and IL-33) that recruit and reprogram TAMs. In turn, TAMs release factors (IL-6, IL-1β, EGF, TGF-β, STI1 and PTN) that promote tumor progression

Fig. 3

Vasogenic cerebral edema in glioblastoma. Schematic illustration of the cell populations and soluble factors that regulate glioblastoma-associated vasogenic cerebral edema in the perivascular area. Magenta color indicates the tumor, while yellow color shows edema surrounding the tumor. Edema causes additional mass effects, often exceeding the mass induced by the tumor itself. When secreted in the perivascular areas, IL-1β [3] and MMPs [79] produced by TAMs, and VEGFA [166] produced by TAMs and tumor cells, increase vascular permeability and edema formation

Fig. 4

The glioblastoma microenvironment. Schematic illustration of TAM interactions with glioma cells and the non-neoplastic cells of the tumor microenvironment, including endothelial cells, pericytes, activated astrocytes, and T cells. In addition, interactions between tumor cells and neutrophils, neurons, and astrocytes are illustrated. TAMs communicate with the other non-neoplastic cells to regulate tumor progression, either by direct contact or via secreted factors

Fig. 5

Tumor-associated macrophages (TAMs): The Cerberus of glioblastoma (GBM). Representation of the main functions of TAMs in promoting GBM, including contributions to tumor progression, immunosuppression, and development of vasogenic cerebral edema. TAMs can be metaphorically compared to the three-headed dog Cerberus from Greek mythology, who guards the Underworld gates, preventing the dead from living. In GBM, TAMs protect the tumor cells from dying and support their living