Brain stem cells as the cell of origin in glioma

Abstract

Glioma incidence rates in the United States are near 20000 new cases per year, with a median survival time of 14.6 mo for high-grade gliomas due to limited therapeutic options. The origins of these tumors and their many subtypes remain a matter of investigation. Evidence from mouse models of glioma and human clinical data have provided clues about the cell types and initiating oncogenic mutations that drive gliomagenesis, a topic we review here. There has been mixed evidence as to whether or not the cells of origin are neural stem cells, progenitor cells or differentiated progeny. Many of the existing murine models target cell populations defined by lineage-specific promoters or employ lineage-tracing methods to track the potential cells of origin. Our ability to target specific cell populations will likely increase concurrently with the knowledge gleaned from an understanding of neurogenesis in the adult brain. The cell of origin is one variable in tumorigenesis, as oncogenes or tumor suppressor genes may differentially transform the neuroglial cell types. Knowledge of key driver mutations and susceptible cell types will allow us to understand cancer biology from a developmental standpoint and enable early interventional strategies and biomarker discovery.

Keywords: Cancer stem cells; Cell of origin; Genetic models; Glioma; Gliomagenesis; Neurogenesis.

Figure 1

Targeted oncogenesis in the neuroglial cellular hierarchy. (A) Neurogenesis in the adult mammalian brain; (B) Summary of murine models that targeted selected cell types for the purposes of discovering the glioma cell of origin. Horizontal bars in (B) correlate to the representative cell types in (A). ¹Experimental results by authors suggest differentiated progeny acted as the cell of mutation and de-differentiated before forming a tumor; ²Lack of lineage trace, distinguishing cell of mutation from cell of origin is inconclusive despite tumor forming capacity of differentiated progeny. Partially adapted from Ref. [8,48]. SVZ: Subventricular zone; NSCs: Neural stem cells; TAP: Transit amplifying progenitors.