title: 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 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.
authors.affiliation: Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Andrei M
authors.initials: AM
authors.lastname: Mikheev
authors.forename: Rohan
authors.initials: R
authors.lastname: Ramakrishna
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Stoll
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Mikheeva
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beyer
authors.forename: David A
authors.initials: DA
authors.lastname: Plotnik
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Schwartz
authors.forename: Jason K
authors.initials: JK
authors.lastname: Rockhill
authors.forename: John R
authors.initials: JR
authors.lastname: Silber
authors.forename: Donald E
authors.initials: DE
authors.lastname: Born
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kosai
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Horner
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rostomily
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence / Q000235:genetics*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000401:mortality / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D058953:Neural Stem Cells / Q000473:pathology / Q000637:transplantation; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D051793:Hypoxia-Inducible Factor 1