Glioma Stem Cell Proliferation and Tumor Growth Are Promoted by Nitric Oxide Synthase-2

SummaryMalignant gliomas are aggressive brain tumors with limited therapeutic options, and improvements in treatment require a deeper molecular understanding of this disease. As in other cancers, recent studies have identified highly tumorigenic subpopulations within malignant gliomas, known generally as cancer stem cells. Here, we demonstrate that glioma stem cells (GSCs) produce nitric oxide via elevated nitric oxide synthase-2 (NOS2) expression. GSCs depend on NOS2 activity for growth and tumorigenicity, distinguishing them from non-GSCs and normal neural progenitors. Gene expression profiling identified many NOS2-regulated genes, including the cell-cycle inhibitor cell division autoantigen-1 (CDA1). Further, high NOS2 expression correlates with decreased survival in human glioma patients, and NOS2 inhibition slows glioma growth in a murine intracranial model. These data provide insight into how GSCs are mechanistically distinct from their less tumorigenic counterparts and suggest that NOS2 inhibition may be an efficacious approach to treating this devastating disease.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (333 K)Download as PowerPoint slideHighlights► Glioma stem cell proliferation is supported by nitric oxide synthase-2 (NOS2) ► Nonstem glioma cells and normal neural stem cells are not dependent on NOS2 ► NOS2 affects glioma stem cell gene expression, including cell-cycle inhibitor CDA1 ► Pharmacological inhibition of NOS2 attenuates glioma growth in vivo