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Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2 |
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| Authors: | Eyler Christine E Wu Qiulian Yan Kenneth MacSwords Jennifer M Chandler-Militello Devin Misuraca Katherine L Lathia Justin D Forrester Michael T Lee Jeongwu Stamler Jonathan S Goldman Steven A Bredel Markus McLendon Roger E Sloan Andrew E Hjelmeland Anita B Rich Jeremy N |
| Institution: | 1 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA 2 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA 3 Medical Scientist Training Program, Duke University Medical Center, Durham, NC 27710, USA 4 Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA 5 Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA 6 Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA 7 Institute for Transformative Molecular Medicine and Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH 44106, USA 8 Departments of Neurological Surgery, Pathology, and Translational Neuroscience, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH 44106, USA 9 Department of Molecular Medicine at the Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH 44106, USA 10 Department of Radiation Oncology, University of Alabama Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AB 35249, USA 11 Department of Neurosurgery, Neurocenter and Comprehensive Cancer Center, University of Freiburg, D-79106 Freiburg, Germany |
| 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. |
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