Cell of Origin Determines Tumor Phenotype in an Oncogenic Ras/p53 Knockout Transgenic Model of High-Grade Glioma

Abstract

Human high-grade gliomas (HGGs) are known for their histologic diversity. To address the role of cell of origin in glioma phenotype, transgenic mice were generated in which oncogenic Ras and p53 deletion were targeted to neural stem/progenitor cells (NSPCs) as well as mature astrocytes. hGFAP-Cre/KrasG12D/p53fl/fl mice develop multifocal HGG that vary histopathologically and with respect to the expression of markers associated with NSPCs. One HGG pattern strongly expressed markers of NSPCs and arose near the subventricular zone. Additional, non-overlapping patterns that recapitulate human HGG variants were present simultaneously in the same brain. These neoplastic foci were more often cortical- or leptomeningeal-based and the neoplastic cells lacked expression of NSPC markers. To determine whether cell of origin determines tumor phenotype, astrocytes and NSPCs were harvested from neonatal mutant pups. Upon orthotopic transplantation, early-passage astrocytes and NSPCs formed tumors that differed in engraftment rates, latency to clinical signs, histopathology and protein expression. Astrocyte-derived tumors were more aggressive had giant cell histology and glial fibrillary acidic protein expression. NSPC-derived tumors retained NSPC markers and showed evidence of differentiation along astrocytic, oligodendroglial, and neuronal lineages. These results indicate that identical tumorigenic stimuli produce markedly different glioma phenotypes depending on the differentiation status of the transformed cell.

Analysis of Olig2 and YKL-40 expression: a clinicopathological/immunohistochemical study for the distinction between subventricular zone II and III glioblastomas

“…Under the stem cell hypothesis, Olig2 fulfills criteria of a lineagerestricted compe tence factor for gliogenesis [8,15] that is necessary for the development of neural progenitors and prog eny cells in the CNS [12]. Like others, [22] we have suggested that Olig2 expression may be downregu lated in mature astrocyte.…”

“…Subventricular zone may be a source of tumors with higher proliferative and invasive capaci ties [5]. Recent research efforts in neurooncology are focused in targeting the tumorigenesis theory and to find signal transduction pathways that influence the GB development and change its dismal progno sis, given that surgery and adjuvant chemotherapy with radiotherapy are insufficient due to a diffuse infiltration by tumor tissue into the brain [4,12,37]. Therefore, identifying molecular targets that could provide prognostic new data is needed and would be helpful for its therapy.…”

“…Olig2 (a basic helixloophelix transcription factor) is expressed in the postnatal SVZ and plays a critical role in the lineage specification of progenitor cells into neurons and oligodendrocytes [20]. However, the literature on Olig2 and its asso ciation with glioblastoma prognosis is ambivalent [1,11,12,22]. Recent reports have found associations between glioblastoma and neural stem cells express ing Olig2 [8,12,20,35].…”

“…However, the literature on Olig2 and its asso ciation with glioblastoma prognosis is ambivalent [1,11,12,22]. Recent reports have found associations between glioblastoma and neural stem cells express ing Olig2 [8,12,20,35]. Therefore, a significant amount of the ongoing GB research is focused on better under standing how cells expressing Olig2 contribute to the gliomagenesis and therapeutic targets.…”

“…Recent research efforts hypothesize that gliomagenesis occurs in perivascular niches with high ly invasive peripheral proliferating zones [6,12,29]. Several studies report that Olig2 expression is limit ed in GSCs [7,12,22] and is probably being related to the SVZ type II as a proliferation regulator and glioma progenitor cell marker. Olig2 (a basic helixloophelix transcription factor) is expressed in the postnatal SVZ and plays a critical role in the lineage specification of progenitor cells into neurons and oligodendrocytes [20].…”