Neural precursor cell apoptosis and glial tumorigenesis following transplacental ethyl-nitrosourea exposure

Abstract

Neural precursor cells (NPCs) populate the embryonic ventricular zone and persist in the subependymal zone of the adult brain. We hypothesized that hereditary and/or acquired mutations in apoptosis-associated genes, such as p53 and caspases, may protect NPCs from DNA damage-induced death and predispose them to subsequent neoplastic transformation. To test this hypothesis, we exposed NPCs from wild-type and targeted gene-disrupted mouse embryos (p53, caspase-9, caspase-3, and bax mutants) to ethyl-nitrosourea (ENU), a known DNA mutagen and neural carcinogen, and measured NPC viability. We found that ENU produced caspase-3 activation and apoptotic NPC death 6 ± 24 h after administration both in vivo and in vitro. This eect was critically dependent on p53 and caspase-9 expression. The long-term eect of intrauterine ENU exposure was examined in control and p53-de®cient mice. High grade glial tumors were found in 60% of p53 7/7 young adult mice exposed to ENU on gestational day 12.5 but not in p53 +/7 or p53 +/+ littermates or in untreated p53-de®cient mice. All the tumors were located supratentorially and possessed strong immunoreactivity for glial ®brillary acidic protein and the anti-apoptotic molecule Bcl-X L . These results suggest that intrauterine exposure of NPCs to certain DNA damaging agents may synergistically interact with speci®c genetic abnormalities (e.g. p53 de®ciency) to produce glial neoplasms in the adult brain. Oncogene (2001) 20, 8281 ± 8286.

Loss ofp53Induces Changes in the Behavior of Subventricular Zone Cells: Implication for the Genesis of Glial Tumors

“…They also resemble the previously described hyperplastic areas observed after intraventricular grafting of astrocytes-like stem cells (Zheng et al, 2002). The increased number of cells in the SVZ of p53 Ϫ/Ϫ mice is not attributable to decreased apoptosis, as predicted by the well known proapoptotic function of p53 (D'Sa-Eipper et al, 2001;Leonard et al, 2001;Katayama et al, 2005). Our results clearly indicate an increase in compensatory apoptosis in p53 Ϫ/Ϫ mice.…”

“…The concept that glioblastoma formation involves the synergism between distinct pathways is supported by several other studies demonstrating tumor formation in p53 Ϫ/Ϫ mice after increased PDGF signaling (Hesselager et al, 2003), prenatal exposure to ENU (Oda et al, 1997;Leonard et al, 2001), or Ras activation (Reilly et al, 2000).…”

“…It is important to mention, however, that loss of p53 results in a 60% incidence of glioblastoma-like tumors in p53 Ϫ/Ϫ mice, but not in p53 ϩ/ Ϫ or in p53 ϩ/ϩ littermates, after prenatal exposure to the mutagen ENU (Oda et al, 1997;Leonard et al, 2001). These tumors were typically localized in periventricular locations, at the border between the SVZ and the corpus callosum (Fig.…”

“…The importance of SVZ cells in the genesis of glioblastomas (Recht et al, 2003) has been suggested by the isolation of neurosphere-forming cells from human glioblastomas (Ignatova et al, 2002) and by studies on transgenic mice (Holland, 2000) and on animals prenatally exposed to the mutagen N-ethyl-Nnitrosourea (ENU) (Oda et al,1997;Leonard et al, 2001;Slikker et al, 2004;Savarese et al, 2005).…”

Brain tumour stem cells: the undercurrents of human brain cancer and their relationship to neural stem cells

“…Animals are more vulnerable with prenatal exposure to ENU (when there is more neural precursor activity) and the preneoplastic lesions that occur are identified in the SVZ (Schiffer et al 1978;Pilkington & Lantos 1979). In mice, ENU-induced brain tumorigenesis occurs only in the context of p53 homozygous deletion and, in these animals, preneoplastic/early neoplastic lesions are also identified in the SVZ (Oda et al 1997;Leonard et al 2001;Wilhelmsson et al 2003). p53K/K Mice have increased proliferative activity in the SVZ and more neurospheres can be isolated from this region, suggesting an expansion of the NSC pool, which may make it more susceptible to neoplastic transformation (Gil-Perotin et al 2006;Meletis et al 2006).…”