Glioma revisited: from neurogenesis and cancer stem cells to the epigenetic regulation of the niche

Abstract

Gliomas are the most incident brain tumor in adults. This malignancy has very low survival rates, even when combining radio- and chemotherapy. Among the gliomas, glioblastoma multiforme (GBM) is the most common and aggressive type, and patients frequently relapse or become refractory to conventional therapies. The fact that such an aggressive tumor can arise in such a carefully orchestrated organ, where cellular proliferation is barely needed to maintain its function, is a question that has intrigued scientists until very recently, when the discovery of the existence of proliferative cells in the brain overcame such challenges. Even so, the precise origin of gliomas still remains elusive. Thanks to new advents in molecular biology, researchers have been able to depict the first steps of glioma formation and to accumulate knowledge about how neural stem cells and its progenitors become gliomas. Indeed, GBM are composed of a very heterogeneous population of cells, which exhibit a plethora of tumorigenic properties, supporting the presence of cancer stem cells (CSCs) in these tumors. This paper provides a comprehensive analysis of how gliomas initiate and progress, taking into account the role of epigenetic modulation in the crosstalk of cancer cells with their environment.

Figure 1

A summary of gliomagenesis. (a) The interactions between the neurogenic niche (subventricular zone, SVZ) and neural stem cells (NSCs) highlighting the most relevant cell types and the secreted factors that affect the neural proliferation. Oligodendrocyte progenitors are more likely to undergo malignant transformation. (b) The role of cancer stem cells (CSCs) in tumor progression. There are different subpopulations of CSCs, which may contribute to tumor heterogeneity. Histone deacetylase inhibitors (HDACis) may be effective against CSCs by promoting their differentiation. The perivascular niches (PVNs) provide growth factors that enhance CSC proliferation and self-renewal. Because of the rapid tumor growth, hypoxic niches (HNs) are formed and, through the action of HIFs, secrete VEGF, which in turn may lead to new vascular niches.

Figure 2

Glioma tumorspheres. (a) U87 glioma cell line in DMEM + 10% of FBS. (b) Tumorspheres of U87 cells after 3 days in NSCs medium. (c) Tumorspheres after two dissociations.

Figure 3

Tumorsphere formation assay upon treatment of U87-MG cells with Trichostatin A (TSA). A seventy-two-hour treatment with the histone deacetylase inhibitor TSA affects tumorsphere formation and cellular proliferation after medium shift to NSC medium. Bar represents control percentage. *represents P < 0.02 for 100 nM and P < 0.001 for 300 and 500 nM for spheres count, and ^#represents P < 0.046 for 100 nM P < 0.011 for 300 nM and P < 0.001 for 500 nM for cell count as measured by trypan blue. One-way ANOVA, followed by Turkey's post hoc test were used for statistical analysis, where P-values <0.05 were considered significant.