Open AccessIncreased age of transformed mouse neural progenitor/stem cells recapitulates age‐dependent clinical features of human glioma malignancy
Author(s) -
Mikheev Andrei M.,
Ramakrishna Rohan,
Stoll Elizabeth A.,
Mikheeva Svetlana A.,
Beyer Richard P.,
Plotnik David A.,
Schwartz Jeffrey L.,
Rockhill Jason K.,
Silber John R.,
Born Donald E.,
Kosai Yoshito,
Horner Philip J.,
Rostomily Robert C.
Publication year - 2012
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12004
Subject(s) - progenitor cell , biology , malignancy , glioma , progenitor , stem cell , cancer research , neural stem cell , senescence , downregulation and upregulation , immunology , gene , microbiology and biotechnology , genetics
Summary 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 ( NSPC s), 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 NSPC s 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 NSPC s. 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 HRG s 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.