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.

Apoptotic Signaling Pathways in Glioblastoma and Therapeutic Implications

“…The most frequent and aggressive human brain tumor is glioblastoma multiforme (GBM), which is a glial cell-derived tumor (glioma) with high malignant potential that has a tendency to invade the surrounding tissue [ 1 ]. These tumors arise either from glioma altered cells that facilitate tumor initiation and progression or from glioblastoma stem cells (GSCs) that possess the ability to self-renew and initiate tumor formation [ 2 ].…”

The Invasive Region of Glioblastoma Defined by 5ALA Guided Surgery Has an Altered Cancer Stem Cell Marker Profile Compared to Central Tumour

“…It is hypothesized that CSCs may be concentrated in close proximity to neo-angiogenic vessels in the growing and invading tumour, and, which may provide a supportive microenvironment [ 13 ]. These niches may protect the CSCs from apoptotic stimuli, where endothelial cells secrete paracrine factors that promote cell survival and self-renewal [ 14 ]. Microvascular proliferation is a hallmark characteristic of GBM, which suggests that the CSCs could benefit from these highly vascularized tumour regions.…”

Perivascular niches as points of the utmost expression of tumor microenvironment

“…GSCs/progenitors activate endothelial cells for angiogenesis by VEGF [16] and endothelial cells keep GSC/progenitor stemness and migration capacity by Notch signaling and NO [2,5,8,17] that condition tumor progression [18]. The perivascular position of GSCs/progenitors is the consequence of the occurrence of angiogenesis in high infiltration and hyper-proliferation areas, composed mainly by GSCs/progenitors [19][20][21] and regulated by tumor microenvironment. From the reciprocal signaling exchange between endothelial cells and GSCs/progenitors tumor progression and angiogenesis are triggered [22] with the latter originating from the switch from an avascular to a vascular state with matrix degradation and basal membrane dissolution.…”