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

Abstract

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 18month 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 3month (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, mirror 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.

The impact of age on oncogenic potential: tumor-initiating cells and the brain microenvironment

“…Aged mouse NPCs that have been oncogenically transformed by overexpression of Ras and simultaneous abrogation of tumor suppressor proteins p53 and Rb, form more malignant gliomas in vivo than their younger counterparts (Mikheev et al ., 2009). The negative impact of increased age on outcome in this model is cell intrinsic; the age of transplanted cells, but not the host age, determines the degree of malignancy based on survival, invasiveness, genomic stability, and responses to genotoxic and hypoxic stress (Mikheev et al ., 2012). These data suggest that normal aging predisposes NPCs to increased malignant potential.…”

“…In vitro studies show that actively cycling NPCs derived from the aged mouse forebrain migrate at similar rates to actively cycling NPCs from the young adult mouse forebrain, while noncycling cells migrate more slowly with age (Stoll et al ., 2011a). By contrast, in a syngeneic transplant model, aging-transformed NPCs demonstrated markedly increased invasive potential in vitro and in vivo compared with young transformed NPCs (Mikheev et al ., 2012). These findings suggest that age-related differences in normal NPCs that are either amplified or ‘unmasked’ upon oncogenic transformation result in age-related increases in invasive potential in mouse models.…”

“…Among these, age-dependent differences in hypoxic response and cellular metabolism may contribute (Mikheev et al ., 2012), as these mechanisms are known to regulate invasiveness in glioma and other cancers (Jensen, 2009; Sottnik et al ., 2011). The decline in p53 activity associated with aging in NPCs (Mikheev et al ., 2009) may also contribute to differential invasiveness, as wild-type p53 inhibits cell migration and invasion (Mukhopadhyay et al ., 2009) while gain-of-function p53 mutants associated with cancer can promote cell invasion (Muller et al ., 2009).…”

“…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, age-related shortening of telomeres may contribute to loss of genetic stability (Ferron et al ., 2009).…”

The Role of the Microenvironmental Niche in Declining Stem-Cell Functions Associated with Biological Aging

“…For example, recent studies suggest the accumulation of DNA damage (as indicated by genomic marks like g-H2AX and 53BP1) in stem-cell populations like the hematopoietic system (Rossi et al 2007) and in the dentate gyrus neurogenic niche (DeCarolis et al 2014). Other reports have suggested the accumulation of mutations in DNA and genomic instability within the NSC pool with age (Mikheev et al 2012;Dong et al 2014) but additional research is needed. Other cell-intrinsic facets of aging have been characterized in peripheral stem-cell pools (LopezOtin et al 2013), including decreased telomerase activity associated with shortened telomeres (Sahin and Depinho 2010), epigenetics changes (Webb et al 2013;Brunet and Berger 2014), and asymmetric nonrandom chromosome segregation (Charville and Rando 2011).…”