On the origin of glioma

Abstract

Glioma is the most frequent primary brain tumor of adults that has a presumably glial origin. Although our knowledge regarding molecular mechanisms and signaling pathways involved in gliomagenesis has increased immensely during the past decade, high-grade glioma remains a lethal disease with dismal prognosis. The failure of current therapies has to a large extent been ascribed the functional heterogeneity of glioma cells. One reason for this heterogeneity is most certainly the large number of variations in genetic alterations that can be found in high-grade gliomas. Another factor that may influence glioma heterogeneity could be the cell type from which the glioma is initiated. The cell of origin for glioma is still undefined, and additional knowledge about this issue may prove critical for a more complete understanding of glioma biology. Based on information from patients, developmental biology, and experimental glioma models, the most putative target cells include astrocytes, neural stem cells, and oligodendrocyte precursor cells, which are all discussed in more detail in this article. Animal modeling of glioma suggests that these three cell types have the capability to be the origin of glioma, and we have reason to believe that, depending on the initiating cell type, prognosis and response to therapy may be significantly different. Thus, it is essential to explore further the role of cellular origin in glioma.

Figure 1.

Putative glioma cell of origin and its role for glioma development. A: A simplified schematic representation of glial cell development from the multipotent CNS stem cell into astrocytes and oligodendrocytes, where each stage is defined by the expression of markers. Red lightings indicate the occurrence of an oncogenic event that will induce glioma development. B: The role of cellular origin for glioma initiation, progression, recurrence and response to therapy remains largely unknown. The search for biomarkers that could distinguish phenotypically distinct glioma subgroups based on cell of origin could be one path towards elucidating this matter. NSC = neural stem cell; GRPC = glial restricted progenitor cell; APC = astrocyte precursor cell; OPC = oligodendrocyte precursor cell.