Cell of origin for malignant gliomas and its implication in therapeutic development

Abstract

Malignant glioma remains incurable despite tremendous advancement in basic research and clinical practice. The identification of the cell(s) of origin should provide deep insights into leverage points for one to halt disease progression. Here we summarize recent studies that support the notion that neural stem cell (NSC), astrocyte, and oligodendrocyte precursor cell (OPC) can all serve as the cell of origin. We also lay out important considerations on technical rigor for further exploring this subject. Finally, we share perspectives on how one could apply the knowledge of cell of origin to develop effective treatment methods. Although it will be a difficult battle, victory should be within reach as along as we continue to assimilate new information and facilitate the collaboration among basic scientists, translational researchers, and clinicians.

Figure 1.

Cell lineage in the brain. Neural stem cells (NSCs) give rise to neurons, astrocytes, and oligodendrocyte precursor cells (OPCs) that can in turn differentiate into oligodendrocytes. It should be noted that there could be transient, intermediate progenitor cell types between NSCs and progeny cell types, and that OPC is a stable cell type in the adult brain. Dotted red lines depict the cell types that could serve as the cell of origin for malignant gliomas.

Figure 2.

Supporting evidence for NSC as the cell of origin for glioma. (A) Oncogenic mutations induced by viral vector injection into the brain parenchyma failed to lead to gliomagenesis. (B) Oncogenic mutations induced by viral vector injection near NSC niche consistently led to gliomagenesis. LV, lateral ventricle.

Figure 3.

Supporting evidence for astrocyte as the cell of origin for glioma. Oncogenic mutations introduced into both astrocytes and NSCs in adult brains with GFAP-CreER led to full penetrance of glioma formation. Because >20% of tumors formed in areas clearly away from NSC niches, it suggested that adult astrocytes could be transformed into malignant gliomas. SVZ, subventricular zone.

Figure 4.

Supporting evidence for OPC as the cell of origin for glioma. (A) Scheme of the mosaic analysis with double markers (MADM) system. From a heterozygous, colorless mouse, Cre-induced somatic recombination generates sparse “twin spots”: a green mutant cell and a red wild-type (WT) cell. The ratio between green and red cells in a given cell lineage reveals its transforming potential. (B) Mutations (p53 and NF1) introduced into NSCs led to massive overexpansion of OPCs but not other cell types, suggesting that OPC is the cell origin for gliomas in this model. RFP, red fluorescent protein; GFP, green fluorescent protein. (From Liu and Zong 2012; adapted, with permission, from the authors in conjunction with Elsevier © 2012.)