Tumor Microenvironment in Glioma Invasion

Abstract

A major malignant trait of gliomas is their remarkable infiltration capacity. When glioma develops, the tumor cells have already reached the distant part. Therefore, complete removal of the glioma is impossible. Recently, research on the involvement of the tumor microenvironment in glioma invasion has advanced. Local hypoxia triggers cell migration as an environmental factor. The transcription factor hypoxia-inducible factor (HIF) -1α, produced in tumor cells under hypoxia, promotes the transcription of various invasion related molecules. The extracellular matrix surrounding tumors is degraded by proteases secreted by tumor cells and simultaneously replaced by an extracellular matrix that promotes infiltration. Astrocytes and microglia become tumor-associated astrocytes and glioma-associated macrophages/microglia, respectively, in relation to tumor cells. These cells also promote glioma invasion. Interactions between glioma cells actively promote infiltration of each other. Surgery, chemotherapy, and radiation therapy transform the microenvironment, allowing glioma cells to invade. These findings indicate that the tumor microenvironment may be a target for glioma invasion. On the other hand, because the living body actively promotes tumor infiltration in response to the tumor, it is necessary to reconsider whether the invasion itself is friend or foe to the brain.

Keywords: glioma; invasion; microenvironment.

Figure 1

Schematic presentation of hypoxia-inducible factor-1 (HIF-1) function. In normoxia, prolyl hydroxylase (PHD) induced the degradation of HIF-1. In hypoxic conditions, HIF-1 contributes to several steps of glioma invasion. At first, HIF-1 detaches glioma cells from the original tumor mass by activating zinc finger E-box binding homeobox 1 (ZEB1) and roundabout guidance receptor 1 (ROBO1). In the next step, HIF-1 contributes to attachment to the surrounding extracellular matrix (ECM) by focal adhesion kinase (FAK), Ras homolog family member B (RhoB), and glycogen synthase kinase 3β (GSK-3β). Finally, HIF-1 activates matrix metalloproteinases (MMPs) and degrades ECMs.

Figure 2

Schematic of the factors affecting the alteration of the glioma microenvironment by extracellular matrices (ECMs) and enzymes. Basically, there are some types of ECM that are independent of glioma cell invasions. However, the alteration of the microenvironment surrounding gliomas is affected by ECMs and enzymes, which almost promote the invasiveness of glioma cells. There are mainly two signaling pathways subserving glioma cell invasion: the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Red arrows indicate the activation of signaling, while blue arrows indicate the inhibition of signaling. Abbreviation: ADAM; a disintegrin and metalloproteinase, ADAMTS; ADAM with thrombospondin domain, FNMA; fibronectin matrix assembly, HA; hyaluronic acid, MMP; matrix metalloproteinase, MT-MMP; membrane-type MMP, TIMP; tissue inhibitor of metalloproteinase, uPA; urokinase-type plasminogen activator, uPAR; uPA receptor.

Figure 3

Signaling pathways of glioma–astrocyte crosstalk associated with invasion. The major signaling pathways involved in glioma–astrocyte crosstalk that promote tumor invasion (Black arrows). The activation of nuclear factor kappa-B (NF-κB) and sonic hedgehog (SHH)-Gli signaling pathway induced normal astrocytes into reactive astrocytes (tumor-associated astrocytes (TAAs)). TAAs promote glioma cell invasion by activating some pathways, such as Janus kinase (JAK)/signal transducer and activator of transcription (STAT), phosphatidylinositol-3 kinase (PI3K)/Akt, and NF-κB pathways. The squared arrows show indirect pathways. Abbreviation: cGAMP; 2′3′-cyclic GMP-AMP, Cx43; connexin 43, EVs; extracellular vesicles, GBM; glioblastoma, GDNF; glial cell line-derived neurotrophic factor, IFN-α; interferon-α, IL; interleukin, RANKL; receptor activator of nuclear factor kappa-B ligand, STING; stimulator of interferon genes, TNF; tumor necrosis factor.

Figure 4

Scheme of the mechanisms of glioma-associated macrophages/microglia (GAM). GAM plays a major role in glioma invasion, angiogenesis, and immunosuppression. The main enzyme contributing to glioma cell invasion is the matrix metalloproteinases (MMP) family. The activation of vascular endothelial growth factor (VEGF) associates with angiogenesis, and programmed cell death-1 (PD-1) is the one of the key molecules for immunosuppression. Glioma cells are involved in the recruitment and activation of GAMs. GAM–glioma cell crosstalk is caused by various chemoattractant molecules and extracellular vesicles (EVs). Abbreviation: CD; clusters of differentiation, CFS-1; colony stimulating factor-1, EGF; epidermal growth factor, GM-CSF; granulocyte-macrophage colony stimulating factor, HGF; hepatocyte growth factor, IL; interleukin, MCP; monocyte chemoattractant protein, MMP; matrix metalloproteinase, SDF-1; stroma-derived factor-1, TGF; transforming growth factor.

Figure 5

Cell-to-cell systems schema related to the glioma microenvironment. Glioma cells form the tumor environment, developing microtube networks, erythropoietin-producing human hepatocellular receptor (Ephs)–ephrin pathways, and Notch signals. Cell-to-cell systems are mainly associated with invasion (red line), proliferation (green dotted line), stemness maintenance (black dotted line), and phenotypic regulation (blue dotted line) in glioma cells. Invasion ability is acquired from the microtube network, EphB–ephrin-B pathway, and Notch signaling. Cell proliferation and stemness maintenance are involved in the ephrinA–ephrinA pathway and Notch signaling. The glioma phenotype is regulated by the microtube network, EphA–ephrinA pathway, and Notch signaling. P in a grey circle indicate the phosphorylation. Abbreviation: NICD; notch intracellular domain.

Figure 6

Schema of the mechanisms that underlie the alteration of the glioma microenvironment affected by therapy. Three main therapeutic strategies, namely surgical resection, radiotherapy, and chemotherapy, induce some mechanisms and contribute to glioma invasion in a complementary manner. Some of these mechanisms can divided into two categories: the alteration of the tumor surrounding microenvironment (black arrows), and phenotype change of glioma cells (blue arrows). Proneural mesenchymal transition (PMT) is a main program of phenotype change of glioma cells (green arrows). According to these mechanisms, glioma cells activate invasiveness (red arrows). Abbreviation: ECM, extracellular matrix.