Microglia/Astrocytes-Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors

Abstract

In recent years, the functions of glial cells, namely, astrocytes and microglia, have gained prominence in several diseases of the central nervous system, especially in glioblastoma (GB), the most malignant primary brain tumor that leads to poor clinical outcomes. Studies showed that microglial cells or astrocytes play a critical role in promoting GB growth. Based on the recent findings, the complex network of the interaction between microglial/astrocytes cells and GB may constitute a potential therapeutic target to overcome tumor malignancy. In the present review, we summarize the most important mechanisms and functions of the molecular factors involved in the microglia or astrocytes-GB interactions, which is particularly the alterations that occur in the cell's extracellular matrix and the cytoskeleton. We overview the cytokines, chemokines, neurotrophic, morphogenic, metabolic factors, and non-coding RNAs actions crucial to these interactions. We have also discussed the most recent studies regarding the mechanisms of transportation and communication between microglial/astrocytes - GB cells, namely through the ABC transporters or by extracellular vesicles. Lastly, we highlight the therapeutic challenges and improvements regarding the crosstalk between these glial cells and GB.

Keywords: astrocytes; communication mechanisms; crosstalk; cytokines; glioblastoma; microenvironmental factors; microglia; molecular mechanisms.

FIGURE 1

Factors involved in microglial/astrocytic– GB cells crosstalk. (A) Astrocytic cells release IL-6 that contributes for tumor migration and invasion through the release of MMP14s by tumors cells. The astrocytic cells released CCL20, which increases HIF-1α in GB cells via CCR6/NF-êB activation. GDNF released, by glioma cells, also promotes astrogliosis. GB cells transfer miR-5096 to astrocytes. (B) The GB cells release interleukins (IL10, IL4, and IL13) that induce the microglial cells to acquire M2-like phenotype. In turn, microglial cells secrete TGF-β that stimulate the glioma growth. The invasion and migration of tumor cells are stimulated by the MMPs production by microglial cells. The tumor cells release the CCL2, which stimulates the release of IL-6 by microglia, and consequently induce the invasion of tumor cells. Also CCL5, produced by the GB cells, increases gene expression and function of the M2 markers ARG-1 and IL-10 on microglial cells. In addition, the GB cells express chemokine CX3CL1, which promotes the recruitment of microglial cells, through its receptor CX3CR1, and increases the expression of MMPs 2, 9, and 14, in the tumor cells, promoting tumor invasion. GDNF secreted from gliomas acts as chemoattractant for microglia. The IL-6 produced by microglia stimulates the expression of VEGF in tumor cells. Also, microglial cells release VEGF-A in tumor hypoxia areas. Immune brain cells express EGF in the tumor border, and thus stimulate invasion. Wnt5a released by glioma cells induces the M2-like phenotype in microglial cells through the increase of CX3CR1, CX43, CD163, and IBA-1. Glioma-released glucose induces the expression of GLUT5 in microglia and contributes to tumor growth. The downregulated levels of miR-142-3p are associated with M2-like phenotype in GAMs. IL-1 induces upregulation of miRNAs in gliomas involved in inflammation, such as miR-21 and miR-146. MiR-146 is downregulated in microglial cells and is associated with glioma growth. miRNA-21 and miRNA-451 are overexpressed in GB and are transferred to microglial cells.

FIGURE 2

Transportation mechanism involved in glial cells and GB crosstalk. (A) GB cells express several ABC transporters, such as ABCB1, ABCC1, ABCG2 and ABCC13, and ABCA13. GB cells express prostaglandins (PG), leukotrienes (LTs), and sphingosine-1-phosphate (S1P), which can be ABS transporters subtracts in microglial/astrocytic cells. The astrocytes and microglial cells express ABCG1 and ABCG2. Other mechanism of cell–cell communication is through the EVs, such as exosomes. GB miRNAs, namely the miR451, miR21, and miR-221, can be transferred through EVs to microglial cells. However, how can they be transferred to astrocytes is still unclear. Also, EVs are a mechanism for GB to induce MT1–MMP expression in GB-associated microglia. Moreover, extracellular ATP promotes microglia activation and induces the release of EVs in order to enable the communication between microenvironment cells. In fact, miR-9 released from Tat-stimulated astrocytes can be taken up by microglial cells, which result in their migratory phenotype. (B) ABCG2 is only expressed in GB-stem-like cells. Also, GB-released EVs can transport miRNAs, such as miR2. However, their role in astrocytic and microglial cells is not exploited. (C) Lactadherin (Lyd), syntenin-1(Syn-1), myristoylated alanine-rich C-kinase substrate (MARCKS), integrin alpha-V and alpha-3 (αV and α3), and EGFR can be detected in the membrane of GB-released EVs.