Tumor microenvironment in glioblastoma: Current and emerging concepts

Abstract

Glioblastoma (GBM) tumor microenvironment (TME) is a highly heterogeneous and complex system, which in addition to cancer cells, consists of various resident brain and immune cells as well as cells in transit through the tumor such as marrow-derived immune cells. The TME is a dynamic environment which is heavily influenced by alterations in cellular composition, cell-to-cell contact and cellular metabolic products as well as other chemical factors, such as pH and oxygen levels. Emerging evidence suggests that GBM cells appear to reprogram their the TME, and hijack microenvironmental elements to facilitate rapid proliferation, invasion, migration, and survival thus generating treatment resistance. GBM cells interact with their microenvironment directly through cell-to-cell by interaction mediated by cell-surface molecules, or indirectly through apocrine or paracrine signaling via cytokines, growth factors, and extracellular vehicles. The recent discovery of neuron-glioma interfaces and neurotransmitter-based interactions has uncovered novel mechanisms that favor tumor cell survival and growth. Here, we review the known and emerging evidence related to the communication between GBM cells and various components of its TME, discuss models for studying the TME and outline current studies targeting components of the TME for therapeutic purposes.

Keywords: cell–cell communication; electrical coupling; exosome; extracellular matrix; glioblastoma; paracrine signaling; tumor microenvironment.

Figure 1.

Schematic representation of the glioma tumor microenvironment components. The glioma tumor microenvironment is a complex, heterogeneous, and interactive system that is consisted of glioma and glioma stem cells, immune cells, nervous system, brain vascular system, and extracellular matrix layers. The factors involved in direct and indirect cell communication and chemical tumor microenvironment such as pH and oxygen also play a significant role in modulating glioma tumor microenvironment.

Figure 2.

Relationship between chemical and biological factors influencing the glioma tumor microenvironment in the nervous system.

Figure 3.

The role of oxygen dependent (HIF1-α mediated) and independent (Warburg effect), chemical tumor microenvironment in glioma angiogenesis, immunosuppression, and therapy resistance. ARNT, aryl hydrocarbon receptor nuclear translocator; EFG, epidermal growth factor; FGF, fibroblast growth factor; HIF1-α, hypoxia-inducible factor 1-α; HIF1-β, hypoxia-inducible factor 1-β; HRE, hypoxia response element; IGF, insulin-like growth factor; VEGF, vascular endothelial growth factor; VHL, Von Hippel–Lindau; TGFB, transforming growth factor β.