Increased age of transformed mouse neural progenitor/stem cells recapitulates age-dependent clinical features of human glioma malignancy

Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.
Aging cell (Impact Factor: 6.34). 09/2012; 11(6). DOI: 10.1111/acel.12004
Source: PubMed


Increasing age is the most robust predictor of greater malignancy and treatment resistance in human gliomas. However, the adverse association of clinical course with aging is rarely considered in animal glioma models, impeding delineation of the relative importance of organismal versus progenitor cell aging in the genesis of glioma malignancy. To address this limitation, we implanted transformed neural stem/progenitor cells (NSPCs), the presumed cells of glioma origin, from 3- and 18-month-old mice into 3- and 20-month host animals. Transplantation with progenitors from older animals resulted in significantly shorter (P ≤ 0.0001) median survival in both 3-month (37.5 vs. 83 days) and 20-month (38 vs. 67 days) hosts, indicating that age-dependent changes intrinsic to NSPCs rather than host animal age accounted for greater malignancy. Subsequent analyses revealed that increased invasiveness, genomic instability, resistance to therapeutic agents, and tolerance to hypoxic stress accompanied aging in transformed NSPCs. Greater tolerance to hypoxia in older progenitor cells, as evidenced by elevated HIF-1 promoter reporter activity and hypoxia response gene (HRG) expression, mirrors the upregulation of HRGs in cohorts of older vs. younger glioma patients revealed by analysis of gene expression databases, suggesting that differential response to hypoxic stress may underlie age-dependent differences in invasion, genomic instability, and treatment resistance. Our study provides strong evidence that progenitor cell aging is responsible for promoting the hallmarks of age-dependent glioma malignancy and that consideration of progenitor aging will facilitate development of physiologically and clinically relevant animal models of human gliomas.

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Available from: Andrei M Mikheev,
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    • "Loss of heterozygosity (LOH) occurs in NPCs during normal aging (Bailey et al., 2004). Genomic instability may be exacerbated by the loss or mutation of p53 (Honma et al., 2000; Morris, 2002); aged NPCs with decreased p53 activity display increased numbers of micronuclei and H2AX foci (Mikheev et al., 2012). In addition, agerelated shortening of telomeres may contribute to loss of genetic stability (Ferron et al., 2009). "
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    Aging cell 05/2013; 12(5). DOI:10.1111/acel.12104 · 6.34 Impact Factor
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    ABSTRACT: In a syngeneic mouse model increased "age" of neural stem and progenitor cells (NSPCs) prior to transformation pre-determined the malignancy of gliomas regardless of host age. NSPC malignant potential or "geropotency" manifests as increased invasion, genomic instability and tolerance of genotoxic and hypoxic stress in aged transformed and even normal aged NSPCs, phenotypes potentially attributable to differential p53/p16 tumor suppressor function, HIF1 and mTOR activity, H2AX expression and the presence of a subpopulation of aged NSPCs with enhanced cell cycle re-entry. Correlation of age-dependent malignancy and transformed NSPC responses to genotoxic stress (chemotherapy and radiation) and HIF1 regulated gene expression with that observed in human gliomas supports the potential clinical relevance of accounting for NSPC "geropotency" in preclinical glioma models.
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    ABSTRACT: Glioma is the most common form of primary brain tumor. Demographically, the risk of occurrence increases until old age. Here we present a novel computational model to reproduce the probability of glioma incidence across the lifespan. Previous mathematical models explaining glioma incidence are framed in a rather abstract way, and do not directly relate to empirical findings. To decrease this gap between theory and experimental observations, we incorporate recent data on cellular and molecular factors underlying gliomagenesis. Since evidence implicates the adult neural stem cell as the likely cell-of-origin of glioma, we have incorporated empirically-determined estimates of neural stem cell number, cell division rate, mutation rate and oncogenic potential into our model. We demonstrate that our model yields results which match actual demographic data in the human population. In particular, this model accounts for the observed peak incidence of glioma at approximately 80 years of age, without the need to assert differential susceptibility throughout the population. Overall, our model supports the hypothesis that glioma is caused by randomly-occurring oncogenic mutations within the neural stem cell population. Based on this model, we assess the influence of the (experimentally indicated) decrease in the number of neural stem cells and increase of cell division rate during aging. Our model provides multiple testable predictions, and suggests that different temporal sequences of oncogenic mutations can lead to tumorigenesis. Finally, we conclude that four or five oncogenic mutations are sufficient for the formation of glioma.
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