The Role of Microglia in Glioblastoma

Abstract

Glioblastoma (GB), the most aggressive malignant glioma, is made up of a large percentage of glioma-associated microglia/macrophages (GAM), suggesting that immune cells play an important role in the pathophysiology of GB. Under physiological conditions, microglia, the phagocytes of the central nervous system (CNS), are involved in various processes such as neurogenesis or axonal growth, and the progression of different conditions such as Alzheimer's disease. Through immunohistochemical studies, markers that enhance GB invasiveness have been shown to be expressed in the peritumoral area of ​​the brain, such as Transforming Growth Factor α (TGF-α), Stromal Sell-Derived Factor 1 (SDF1/CXCL12), Sphingosine-1-Phosphate (S1P) and Neurotrophic Factor Derived from the Glial cell line (GDNF), contributing to the increase in tumor mass. Similarly, it has also been described 17 biomarkers that are present in hypoxic periarteriolar HSC niches in bone marrow and in hypoxic periarteriolar GSC niches in glioblastoma. Interestingly, microglia plays an important role in the microenvironment that supports GB progression, being one of the most important focal points in the study of therapeutic targets for the development of new drugs. In this review, we describe the altered signaling pathways in microglia in the context of GB. We also show how microglia interact with glioblastoma cells and the epigenetic mechanisms involved. Regarding the interactions between microglia and neurogenic niches, some authors indicate that glioblastoma stem cells (GSC) are similar to neural stem cells (NSC), common stem cells in the subventricular zone (SVZ), suggesting that this could be the origin of GB. Understanding the similarities between SVZ and the tumor microenvironment could be important to clarify some mechanisms involved in GB malignancy and to support the discovering of new therapeutic targets for the development of more effective glioblastoma treatments.

Keywords: epigenetic; glioblastoma; microglia; signaling pathways; therapeutic target.

Figure 1

Glioblastoma and the subventricular zone. Details of the subventricular zone (SVZ), microglia cells and its relationship with glioblastoma (GB). Type B cells, knowing as the resident neural stem cells (NSC) within the SVZ are postulated as an origin of glioblastoma stem cells (GSC) because of the accumulation of some mutations. Signaling pathways are modified in response of the changing cancer niche soluble factors that promote M2 microglial cells phenotype. (A) SVZ niche in physiological conditions. (B) SVZ niche in the GB context.

Figure 2

Alterations in microglia in the context of glioblastoma. The gene expression patterns in microglia in homeostatic conditions vs glioblastoma differ significantly, presenting in the latter an inflammatory pattern characterized by an increase in the expression of SPP1, HLA-DR, TREM2, APOE, CD163, GPR56, and interferons.