Editors' ChoiceCancer

Targeting Glioma Stem Cells

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Science Signaling  12 Jul 2011:
Vol. 4, Issue 181, pp. ec191
DOI: 10.1126/scisignal.4181ec191

Cancer stem cells (CSCs) are cells within a tumor that exhibit sustained self-renewal and the capacity to produce secondary tumors like those of the primary tumors. One potential strategy to treat cancers is to target these CSCs selectively without affecting the proliferation and survival of normal stem cell populations that are necessary for tissue maintenance. Glioma is an especially lethal form of brain cancer, and glioma stem cells (GSCs) have been identified in this form of cancer. Eyler et al. sorted glioma cells from human tumors into GSC and non-GSC populations on the basis of two different GSC markers and found that the GSCs had increased production of nitric oxide (NO) and increased abundance of nitric oxide synthase-2 (NOS2). Disruption of NOS2 function with RNA knockdown or by pharmacological inhibition or reduction of NO by introduction of an NO scavenging protein blocked GSC properties, such as proliferation or neurosphere formation in culture. Comparative microarray analysis of GSCs and GSCs in which NOS2 was knocked down showed that expression of the gene encoding the cell cycle inhibitor CDA1 was reduced in GSC and that this repression depended on NOS2. Knockdown of CDA1 partially restored the proliferative capacity of GSCs in which NOS2 was knocked down, suggesting that NOS2 acts at least partially through repression of CDA1 to mediate its proliferation-promoting effects. There was a correlation between high NOS2 expression and low CDA1 expression and low patient survival. Various data suggest that NOS2 is not essential for normal neural stem cell function: NOS2-knockout mice exhibit normal neural development, and, as shown by Eyler et al., inhibition of NOS2 activity did not affect mouse, human fetal, or human adult neural progenitor cell proliferation or neurosphere formation in culture. Pharmacological inhibition of NOS2 activity reduced tumor growth of intracranial human glioma xenografts in mice without affecting neural progenitor cells in nontumor-bearing mice. These data suggest that targeting NOS2 with selective inhibitors may be an effective strategy for eliminating GSCs without impairing normal neural stem cell populations.

C. E. Eyler, Q. Wu, K. Yan, J. M. MacSwords, D. Changler-Militello, K. L. Misuraca, J. D. Lathia, M. T. Forrester, J. Lee, J. S. Stamler, S. A. Goldman, M. Bredel, R. E. McLendon, A. E. Sloan, A. B. Hjelmeland, J. N. Rich, Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2. Cell 146, 53–66 (2011). [PubMed]

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