Abstract
Malignant gliomas are aggressive brain tumors with limited therapeutic options, possibly because of highly tumorigenic subpopulations of glioma stem cells. These cells require specific microenvironments to maintain their “stemness,” described as perivascular and hypoxic niches. Each of those niches induces particular signatures in glioma stem cells (e.g., activation of Notch signaling, secretion of VEGF, bFGF, SDF1 for the vascular niche, activation of HIF2α, and metabolic reprogramming for hypoxic niche). Recently, accumulated knowledge on tumor-associated macrophages, possibly delineating a third niche, has underlined the role of immune cells in glioma progression, via specific chemoattractant factors and cytokines, such as macrophage-colony stimulation factor (M-CSF). The local or myeloid origin of this new component of glioma stem cells niche is yet to be determined. Such niches are being increasingly recognized as key regulators involved in multiple stages of disease progression, therapy resistance, immune-escaping, and distant metastasis, thereby substantially impacting the future development of frontline interventions in clinical oncology. This review focuses on the microenvironment impact on the glioma stem cell biology, emphasizing GSCs cross talk with hypoxic, perivascular, and immune niches and their potential use as targeted therapy.
Highlights
Gliomas, representing tumors of astroglial origin, have been classified by World Health Organization (WHO) into four grades of ascending malignancy according to the histological criteria
Malignant gliomas are aggressive brain tumors with limited therapeutic options, possibly because of highly tumorigenic subpopulations of glioma stem cells. These cells require specific microenvironments to maintain their “stemness,” described as perivascular and hypoxic niches. Each of those niches induces particular signatures in glioma stem cells
There is a bidirectional cross talk between Glioma Stem Cells (GSCs) and perivascular niche: on one hand, perivascular niches enhance stem-like proprieties of GSCs, promote invasion and metastasis of these cells, and promote GSCs escape from therapy
Summary
Gliomas, representing tumors of astroglial origin, have been classified by World Health Organization (WHO) into four grades of ascending malignancy according to the histological criteria. A crucial regulatory role for the GSC phenotype is played by the hypoxic microenvironment, by directly inducing the expression of self-renewal genes, suppressing differentiation, and promoting the cross talk between HIFs and other signaling pathways required for GSC maintenance. These discoveries emphasize the key role of the microenvironment in regulating the differentiation status of tumor cells and its possible involvement in controlling the plasticity of the cancer stem cell hierarchy. Accumulated knowledge on TAMs and GSCs roles on immune cell modulation, possibly delineating a third niche, underlined the role of immune system in GBM progression and GSCs escape from therapy
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