Contribution of the Microenvironmental Niche to Glioblastoma Heterogeneity

Abstract

Glioblastoma is the most aggressive cancer of the brain. The dismal prognosis is largely attributed to the heterogeneous nature of the tumor, which in addition to intrinsic molecular and genetic changes is also influenced by the microenvironmental niche in which the glioma cells reside. The cancer stem cells (CSCs) hypothesis suggests that all cancers arise from CSCs that possess the ability to self-renew and initiate tumor formation. CSCs reside in specialized niches where interaction with the microenvironment regulates their stem cell behavior. The reciprocal interaction between glioma stem cells (GSCs) and cells from the microenvironment, such as endothelial cells, immune cells, and other parenchymal cells, may also promote angiogenesis, invasion, proliferation, and stemness of the GSCs and be likely to have an underappreciated role in their responsiveness to therapy. This crosstalk may also promote molecular transition of GSCs. Hence the inherent plasticity of GSCs can be seen as an adaptive response, changing according to the signaling cue from the niche. Given the association of GSCs with tumor recurrence and treatment sensitivity, understanding this bidirectional crosstalk between GSCs and its niche may provide a framework to identify more effective therapeutic targets and improve treatment outcome.

Figure 1

Tumor microenvironment and its effect on GSCs. Dialogues between tumor cells and other cell types in the microenvironment create vascular niches that regulate tumor growth. The perivascular niche contains cells such as ECs, pericytes, astrocytes, macrophages, and microglial. Each component of the perivascular niche interacts with GSCs to promote glioma cells growth and proliferation, maintain GSCs stemness, and control vascular integrity. GBM contains areas of pseudopalisading necrosis that is the core of the hypoxic niche. Hypoxia upregulates HIFs that induce the expression of oncogenes and transcription factors such as c-Myc and STAT3 involved in stem cells maintenance and expansion. Hypoxia also contributes to metabolic programming and recruitment of macrophages and microglial. These cells form the inflammatory niche, where TAMs secrete soluble factors such as TGF-β and IL-6 that expand GSCs population and promote glioma invasion. Interaction between GSCs and the various players in the microenvironment orchestrate tumor cells responds to therapeutic interventions, thus contributing to the heterogeneity of the tumor.