title: Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2.
abstract: Malignant 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.
authors: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Christine E
authors: CE
authors: Eyler
authors: Qiulian
authors: Q
authors: Wu
authors: Kenneth
authors: K
authors: Yan
authors: Jennifer M
authors: JM
authors: MacSwords
authors: Devin
authors: D
authors: Chandler-Militello
authors: Katherine L
authors: KL
authors: Misuraca
authors: Justin D
authors: JD
authors: Lathia
authors: Michael T
authors: MT
authors: Forrester
authors: Jeongwu
authors: J
authors: Lee
authors: Jonathan S
authors: JS
authors: Stamler
authors: Steven A
authors: SA
authors: Goldman
authors: Markus
authors: M
authors: Bredel
authors: Roger E
authors: RE
authors: McLendon
authors: Andrew E
authors: AE
authors: Sloan
authors: Anita B
authors: AB
authors: Hjelmeland
authors: Jeremy N
authors: JN
authors: Rich
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D001324:Autoantigens; C436320:cell division autoantigen-1; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II