Non-Stem Cell Origin for Oligodendroglioma

Abstract

Summary Malignant astrocytic brain tumors are among the most lethal cancers. Quiescent, and therapy-resistant neural stem cell (NSC)-like cells in astrocytomas are likely to contribute to poor outcome. Malignant oligodendroglial brain tumors, in contrast, are therapy-sensitive. Using magnetic resonance imaging (MRI) and detailed developmental analyses, we demonstrated that murine oligodendroglioma cells show characteristics of oligodendrocyte progenitor cells (OPCs), are therapy-sensitive; and that OPC rather than NSC markers enriched for tumor formation. MRI of human oligodendroglioma also suggested a white-matter (WM) origin, with markers for OPCs rather than NSCs similarly enriching for tumor formation. Our results suggest that oligodendroglioma cells show hallmarks of OPCs, and that a progenitor rather than a NSC origin underlies improved prognosis in patients with this tumor.

Progenitor-like Traits Contribute to Patient Survival and Prognosis in Oligodendroglial Tumors

“…Moreover, CMAP þ patients display a progenitor-like transcriptomic program that correlates with lower tumor grade, consistent with the idea previously established in a transgenic mouse model of oligodendroglioma that identified the more lineage-committed oligodendrocyte progenitor cell as the tumor cell-of-origin (48). Furthermore, these cells are more sensitive to standard chemotherapeutic drugs than neural stem cells.…”

“…Proneurals are typically lower grade gliomas with oligodendroglial features, frequently associated with better prognosis; in contrast, the mesenchymal subclass characterizes highly aggressive, recurrent gliomas such as GBM. Interestingly, recent work has suggested that oligodendrogliomas are more chemosensitive because their cells-of-origin are oligodendrocyte precursor cells (OPC), compared with the more resistant neural stem cells and astrocytes in GBM (48). Although this conclusion arose from transgenic mouse models, we find it intriguing that all cultured patientderived GPCs from multiple studies are transcriptomically consistent with this hypothesis; however, we cannot definitively pinpoint the identity of GPCs due to its human origin.…”

Cell of Origin for Malignant Gliomas and Its Implication in Therapeutic Development

“…Importantly, actively proliferating tumor cells in these models expressed OPC markers (PDGFRa and NG2), suggesting that OPCs are the transformed cell type (Assanah et al 2006). In addition to the PDGF overexpression models, it was reported that S100b promoter-directed expression of verbB, an activated variant of EGFR, could induce glioma formation in a p53 null mouse model (Weiss et al 2003;Persson et al 2010). The fact that S100b does not turn on its expression in NSCs strongly suggests that cells other than NSCs can function as the glioma origin.…”

Emerging insights into the molecular and cellular basis of glioblastoma

“…Distributed progenitor cells, such as OPCs, actually represent the largest pool of cycling cells in the brain and are defined by expression of OLIG2 and NG2 (Dawson et al 2003;Geha et al 2010). Targeting of these nonstem cell progenitors through transgenic or viral approaches has been shown to lead to malignant astrocytomas or oligodendrogliomas, depending on the combination of mutations and cell types targeted (Geha et al 2010;Persson et al 2010).…”