Glial progenitors as targets for transformation in glioma

Abstract

Glioma is the most common primary malignant brain tumor and arises throughout the central nervous system. Recent focus on stem-like glioma cells has implicated neural stem cells (NSCs), a minor precursor population restricted to germinal zones, as a potential source of gliomas. In this review, we focus on the relationship between oligodendrocyte progenitor cells (OPCs), the largest population of cycling glial progenitors in the postnatal brain, and gliomagenesis. OPCs can give rise to gliomas, with signaling pathways associated with NSCs also playing key roles during OPC lineage development. Gliomas can also undergo a switch from progenitor- to stem-like phenotype after therapy, consistent with an OPC-origin even for stem-like gliomas. Future in-depth studies of OPC biology may shed light on the etiology of OPC-derived gliomas and reveal new therapeutic avenues.

Keywords: Brain; Cancer; Glioblastoma; Glioma; Neural stem cell; Oligodendrocyte progenitor cell.

Figure 1

OPCs are the most widely distributed population of cycling cells in forebrain and hindbrain regions. In contrast, a discrete population of NSCs is found in the SVZ lining the lateral ventricles.

Figure 2

Activation of NOTCH, SHH, and WNT signaling inhibits OPC differentiation into oligodendrocytes. On the contrary, acetylation of histone H3 promotes differentiation of OPCs. Growth factor-mediated activation of PDGFRA or EGFR increases proliferation in OPCs.

Figure 3

GBMs displaying G34 and K27 in the H3F3A mutations localize to forebrain and hindbrain regions, respectively.

Figure 4

IDH1^R132H mutant gliomas show reduced levels of α-ketoglutarate and overproduction of 2-hydroxyglutarate (2-HG) that leads to a hypermethylated phenotype.

Figure 5

Transcriptomal profiling of human GBMs identified a proneural subgroup of patients with better overall survival compared to proliferative or mesenchymal subgroups. With no stratification based on survival, Verhaak et al. identified four subgroups and found that approximately 35% of proneural GBMs displayed IDH1/2 mutations along with a hypermethylated (CIMP+) phenotype. Sturm et al. extended these observations to also include childhood GBMs and found that hotspot mutations in H3F3A and IDH1 defined distinct epigenetic and biological subgroups. While proneural GBMs are associated with OPC-like gene expression signature, more aggressive GBMs express genes known to drive mesenchymal transcriptional networks.

Figure 6

OPCs, but not NSCs, are highly abundant in regions where IDH1^R132H mutant and H3F3A K27 mutant tumors arise in GBM patients, implicating their role in gliomagenesis.