The cellular origin for malignant glioma and prospects for clinical advancements

Abstract

Glioma remains incurable despite great advancements in medicine. Targeting the cell of origin for gliomas could bring great hope for patients. However, as a collection of diverse diseases, each subtype of glioma could derive from a distinct cell of origin. To resolve such a complex problem, one must use multiple research approaches to gain deep insights. Here we review current evidence regarding the cell of origin from clinical observations, whole-genome molecular pathology and glioma animal models. We conclude that neural stem cells, glial progenitors (including oligodendrocyte progenitor cells) and astrocytes could all serve as cells of origin for gliomas, and that cells incurring initial mutations (cells of mutation) might not transform, while their progeny cells could instead transform and act as cells of origin. Further studies with multidisciplinary approaches are needed to link each subtype to a particular cell of origin, and to develop effective therapies that target the signaling network within these cells.

Figure 1. The gliomagenic potential of the different neural lineages

Neural stem cells and multipotent progenitors in the subventricular zone can give rise to cells of neuronal and glial lineage. Glial progenitors, which include a heterogeneous population of immature cycling cells, can give rise to astrocytes and oligodendrocytes. Glioma is a heterogeneous disease that can be divided into distinct subtypes. We propose that the different glioma subtypes arise from different cells of origin. APC: Astrocyte progenitor cell; GRP: Glial-restricted progenitor; OPC: Oligodendrocyte progenitor cell.

Figure 2. Transcriptomic and genomic associations of glioblastoma multiforme gene expression subtypes

Proneural, neural, classical and mesenchymal gene expression subtypes were established and associated with genomic abnormalities in a set of 116 glioblastoma multiforme (GBM) samples. The first five rows represent the overall level of expression of a number of developmental neural lineage gene sets in each of the 116 GBMs, with each column representing one GBM sample and each row representing a gene set. Blue indicates a lack of gene set activation, and red denotes a high level of expression. Gene set activation was assessed using single sample gene set enrichment analysis. Sample gene set enrichment analysis scores were calculated for five developmental mouse neural lineages. The next eight rows visualize the relationship between GBM expression subtypes and genomic associations. In rows TP53 mutations, IDH1 mutations, PDGFRA mutations, EGFR mutations and NF1 mutations: red indicates presence of a point mutation; yellow indicates presence of the vIII variant/intragenic deletion; and black indicates wild-type. In rows PDGFRA copy number, EGFR copy number and NF1 copy number: red indicates presence of a DNA copy number gain; green indicates presence of DNA copy number deletion; and black indicates diploid DNA copy number. Adapted with permission from [50, 85].

Figure 3. The distinction between cell of mutation and cell of origin for gliomas

In genetically engineered animal glioma models, tumorigenic mutations could be introduced into a neural stem cell or glial progenitor population. It should be noted that NSCs, the cell type in which the mutations are introduced, might not have the signaling context for malignant transformation, and hence should be called the ‘cell of mutation‘. On the other hand, OPCs, a progeny cell type derived from NSCs, actively respond to the genetic mutations, overexpand and eventually lead to the formation of malignant glioma. In this case, OPCs, as the transforming cell type, should be considered the ‘cell of origin‘, a critical target for effective therapies. NSC: Neural stem cell; OPC: Oligodendrocyte progenitor cell. Adapted with permission from [80].