A glial blueprint for gliomagenesis

Abstract

Gliomas are heterogeneous tumours derived from glial cells and remain the deadliest form of brain cancer. Although the glioma stem cell sits at the apex of the cellular hierarchy, how it produces the vast cellular constituency associated with frank glioma remains poorly defined. We explore glioma tumorigenesis through the lens of glial development, starting with the neurogenic-gliogenic switch and progressing through oligodendrocyte and astrocyte differentiation. Beginning with the factors that influence normal glial linage progression and diversity, a pattern emerges that has useful parallels in the development of glioma and may ultimately provide targetable pathways for much-needed new therapeutics.

Figure 1.. Overview of Glioma Subtypes

Gliomas have been classified by the World Health Organization (WHO) as ranging from low grade astrocytomas and oligodendrogliomas to high grade astrocytomas or glioblastoma using histopathological and genetic parameters. A. Summary of the predominant subtypes of adult glioma based on the 2016 WHO Classification. B. Comparison of 5 year progression–free survival rates for different tumor subtypes, which represents the percentage of people whose glioma has not worsened 5 years after treatment. Data are derived from the following sources: American Cancer Society, National Brain Tumor Society, and ref. AA-Anaplastic Astrocytoma, GBM-Glioblastoma, Oligo-Diffuse and Anaplastic Oligodendroglioma. Note the AA and GBM have significantly worse outcomes than all other forms of brain tumors and oligodendroglioma. C. Common genetic criteria for glioma subtypes are list. Gliomas are diagnosed by histopathological name and genetic features. For example a glioma subtype would be represented as oligodendroglioma, IDH-mutant and 1p/19q codeletion. Genetic criteria used to classify glioma subtypes were derived from 11. Recently, the WHO has reclassified glioma subtypes based on a set of defining genetic mutations. These defining mutations are shown in C. While pediatric high-grade glioma is histologically indistinguishable from adult GBM, it is considered distinct from adult GBM because the spectrum of driver mutations is considerably different^,.

Figure 2.. The Gliogenic Switch and Glioma

A) Illustration of the cellular and transcriptional events that occur during the gliogenic switch in the developing spinal cord. Neural stem cell populations (NSCs) are self-renewing (indicated by curved arrow) and are present during neurogenesis around embryonic day 9.5(E9.5) to E11. The gliogenic switch occurs around E12.5 where NSCs are gradually replaced by glial progenitor populations (GPC), astrocyte precursors (APC) and oligodendrocyte precursors (OPC). Notch functions throughout the gliogenic switch interval to maintain the glial progenitor pool, while Brn2 and Sox9 collaborate to drive NFIA induction. It’s important to note that APCs and OPCs are generated in distinct progenitor domains within the developing brain and accordingly, spatial patterning mechanisms also contribute to specifying their identities. B) There are a number of molecular and functional properties that are conserved between GPC and glioma stem cell (GSC) populations. These parallels suggest that the GSC behaves like glial precursor populations.

Figure 3.. Glial Developmental Factors Influences Tumor “Identity”

A) NFIA functions to promote astrocyte lineage development and suppress the maturation of oligodendrocytes. Consistent with this developmental observation, NFIA is highly expressed in astrocytoma, but demonstrates scant expression in oligodendroglioma. (B) Functional studies in endogenously generated mouse models of oligodendroglioma indicate that overexpression of NFIA can convert an oligodendroglioma to an astrocytoma. These observations are consistent with its developmental role in promoting the astrocyte fate at the expense of the oligodendrocyte fate and suggest that manipulating glial fate determinants may influence the sub-type or identity of the glioma. In the future, it will be important to test this hypothesis with other transcriptional and signaling determinants of glial fate, as this approach may be harnessed for differentiation therapy. A list of candidate transcription factors and signaling pathways that play crucial roles in glial development and are implicated in glioma tumorigenesis is provided.

Figure 4.. Astrocyte and Oligodendrocyte Lineage Trajectories.

A) Phases of oligodendrocyte lineage development and depiction of Olig2, Sox10, and PDGFRa expression. As oligodendrocytes develop NFIA and PDGFRa are downregulated while Olig2 and Sox10 expression are maintained as maturation and myelination occur. During oligodendrocyte maturation, cells lose their proliferative and migratory capacity, coinciding with Wnt and Shh signaling repression. B) NG2 Glia as a resident OPC population in the adult CNS. NG2 glia, although similar to other precursor populations in the CNS in their proliferative and migratory capacity, can potentially give rise to oligodendrocytes and protoplasmic astrocytes in vivo. NG2 glia express NG2 and PDGFRa in conjunction with Olig2. Olig2 expression persists in NG2 cells that differentiate into myelinating oligodendrocytes. However, NG2 glia fated to become protoplasmic astrocytes lose Olig2 expression and begin expressing astrocyte markers such as GFAP and ALDH1L1. Numerous issues regarding the cellular origin of these cells and the full range of downstream cell fates remain to be adequately established. (C) Phases of astrocyte lineage development and depiction of NFIA, Sox9, Aldh1l1, and GFAP expression. The various stages of astrocyte lineage development remain poorly defined; the “pioneering” astrocyte is a feature of the developing cortex, and analogous population in the developing spinal cord has been termed the “Intermediate Astrocyte Precursor” IAP. Over the course of this development, Notch signaling repression and JAK/Stat3 signaling activation initiates astrocyte maturation. A unifying feature of OPCs, NG2-cells, IAP and “pioneering” astrocytes is proliferation and migration outside the germinal centers. These are fundamental properties of glioma tumor cells, suggesting parallel populations may exist in tumors, highlighting the need to further delineate the properties of intermediate astrocyte lineage populations.