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

被引：271

作者：

Eyler, Christine E. ^{[1
,2
,3
]}

Wu, Qiulian ^{[1
]}

Yan, Kenneth ^{[1
]}

MacSwords, Jennifer M. ^{[1
]}

Chandler-Militello, Devin ^{[5
]}

Misuraca, Katherine L. ^{[2
]}

Lathia, Justin D. ^{[1
]}

Forrester, Michael T. ^{[6
]}

Lee, Jeongwu ^{[1
]}

Stamler, Jonathan S. ^{[7
,8
]}

Goldman, Steven A. ^{[5
]}

Bredel, Markus ^{[13
,14
,15
]}

McLendon, Roger E. ^{[4
]}

Sloan, Andrew E. ^{[9
,10
,11
]}

Hjelmeland, Anita B. ^{[1
]}

Rich, Jeremy N. ^{[1
,12
]}

机构：

[1] Cleveland Clin, Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44195 USA

[2] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA

[3] Duke Univ, Med Ctr, Med Scientist Training Program, Durham, NC 27710 USA

[4] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA

[5] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA

[6] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[7] Case Western Reserve Univ, Sch Med, Inst Transformat Mol Med, Cleveland, OH 44106 USA

[8] Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA

[9] Case Western Reserve Univ, Sch Med, Dept Neurol Surg, Cleveland, OH 44106 USA

[10] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA

[11] Case Western Reserve Univ, Sch Med, Dept Translat Neurosci, Cleveland, OH 44106 USA

[12] Case Western Reserve Univ, Sch Med, Cleveland Clin Lerner Coll Med, Dept Mol Med, Cleveland, OH 44106 USA

[13] Univ Alabama, Ctr Comprehens Canc, Dept Radiat Oncol, Birmingham, AL 35249 USA

[14] Univ Freiburg, Neuroctr, Dept Neurosurg, D-79106 Freiburg, Germany

[15] Univ Freiburg, Ctr Comprehens Canc, D-79106 Freiburg, Germany

来源：

CELL | 2011年 / 146卷 / 01期

基金：

美国国家卫生研究院;

关键词：

LYMPHOCYTIC-LEUKEMIA CELLS; HIGHLY SELECTIVE INHIBITOR; ACUTE MYELOID-LEUKEMIA; ISCHEMIC BRAIN-INJURY; MICE LACKING; IN-VIVO; HUMAN GLIOBLASTOMA; INITIATING CELLS; SEPTIC SHOCK; SELF-RENEWAL;

D O I：

10.1016/j.cell.2011.06.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：53 / 66

页数：14

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