title: Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB signaling in glioblastoma cancer stem cells regulates the Notch pathway.
abstract: Malignant gliomas are locally aggressive, highly vascular tumors that have a dismal prognosis, and present therapies provide little improvement in the disease course and outcome. Many types of malignancies, including glioblastoma, originate from a population of cancer stem cells (CSCs) that are able to initiate and maintain tumors. Although CSCs only represent a small fraction of cells within a tumor, their high tumor-initiating capacity and therapeutic resistance drives tumorigenesis. Therefore, it is imperative to identify pathways associated with CSCs to devise strategies to selectively target them. In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-κB signaling. Glioma CSCs were isolated and maintained in vitro using an adherent culture system, and the biological properties were compared with the traditional cultures of CSCs grown as multicellular spheres under nonadherent culture conditions. Interestingly, both adherent and spheroid glioma CSCs show constitutive activation of the STAT3/NF-κB signaling pathway and up-regulation of STAT3- and NF-κB-dependent genes. Gene expression profiling also identified components of the Notch pathway as being deregulated in glioma CSCs, and the deregulated expression of these genes was sensitive to treatment with STAT3 and NF-κB inhibitors. This finding is particularly important because Notch signaling appears to play a key role in CSCs in a variety of cancers and controls cell fate determination, survival, proliferation, and the maintenance of stem cells. The constitutive activation of STAT3 and NF-κB signaling pathways that leads to the regulation of Notch pathway genes in glioma CSCs identifies novel therapeutic targets for the treatment of glioma.
authors.affiliation: From the Department of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Jo Meagan
authors.initials: JM
authors.lastname: Garner
authors.affiliation: From the Department of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Meiyun
authors.initials: M
authors.lastname: Fan
authors.affiliation: From the Department of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Chuan He
authors.initials: CH
authors.lastname: Yang
authors.affiliation: From the Department of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Ziyun
authors.initials: Z
authors.lastname: Du
authors.affiliation: From the Department of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sims
authors.affiliation: the Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.affiliation: From the Department of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and. Electronic address: lpfeffer@uthsc.edu.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Cancer Stem Cells; Glioblastoma; Glioma; NF-κB (NF-κB); Notch Pathway; STAT3
references.citation: J Biol Chem. 1996 Apr 5;271(14):8057-61
references.pmid: 8626489
references.citation: Nat Cell Biol. 2004 Jun;6(6):547-54
references.pmid: 15156153
references.citation: Science. 1994 Apr 1;264(5155):95-8
references.pmid: 8140422
references.citation: Oncogene. 2000 May 15;19(21):2474-88
references.pmid: 10851046
references.citation: J Biol Chem. 2009 Oct 9;284(41):27808-27815
references.pmid: 19687011
references.citation: Stem Cells Dev. 2008 Feb;17(1):173-84
references.pmid: 18271701
references.citation: Cancer Cell. 2004 Sep;6(3):203-8
references.pmid: 15380510
references.citation: Nat Neurosci. 2011 Jul 17;14(8):957-64
references.pmid: 21765423
references.citation: Breast Cancer Res. 2011 Jul 26;13(4):214
references.pmid: 21867572
references.citation: Cancer Res. 2007 Oct 15;67(20):9630-6
references.pmid: 17942891
references.citation: Biomaterials. 2002 Jul;23(13):2773-81
references.pmid: 12059028
references.citation: Science. 1996 Nov 1;274(5288):787-9
references.pmid: 8864120
references.citation: Mol Cancer. 2006 Dec 02;5:67
references.pmid: 17140455
references.citation: Curr Opin Genet Dev. 2009 Feb;19(1):44-50
references.pmid: 19167210
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Science. 1996 Nov 1;274(5288):782-4
references.pmid: 8864118
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: J Neurooncol. 2008 Jan;86(1):31-45
references.pmid: 17611714
references.citation: Nat Rev Cancer. 2005 Apr;5(4):311-21
references.pmid: 15803157
references.citation: J Neuropathol Exp Neurol. 2006 Dec;65(12):1181-8
references.pmid: 17146292
references.citation: J Cell Biochem. 2007 Dec 1;102(5):1087-94
references.pmid: 17910035
references.citation: Science. 1996 Nov 1;274(5288):784-7
references.pmid: 8864119
references.citation: Cell Stem Cell. 2009 Jun 5;4(6):568-80
references.pmid: 19497285
references.citation: J Biol Chem. 2005 Sep 9;280(36):31530-6
references.pmid: 16009713
references.citation: BMC Med. 2010 Nov 15;8:72
references.pmid: 21078177
references.citation: Stem Cells. 2010 Jan;28(1):5-16
references.pmid: 19904829
references.citation: Bioessays. 2007 Oct;29(10):1039-47
references.pmid: 17876798
references.citation: Nature. 1995 Jul 13;376(6536):167-70
references.pmid: 7603567
references.citation: J Biol Chem. 2006 Apr 28;281(17):11678-84
references.pmid: 16517601
references.citation: Nat Neurosci. 2005 Jun;8(6):723-9
references.pmid: 15908947
references.citation: Oncogene. 2000 Dec 27;19(56):6613-26
references.pmid: 11426647
references.citation: Nature. 2006 Aug 17;442(7104):823-6
references.pmid: 16799564
references.citation: Cancer Res. 2006 Oct 1;66(19):9339-44
references.pmid: 16990346
references.citation: Cell. 1994 Apr 8;77(1):63-71
references.pmid: 7512451
references.citation: Cytokine Growth Factor Rev. 2010 Feb;21(1):11-9
references.pmid: 20018552
references.citation: Genes Dev. 2003 May 15;17(10):1253-70
references.pmid: 12756227
references.citation: J Clin Invest. 2011 Jul;121(7):2723-35
references.pmid: 21633165
references.citation: N Engl J Med. 2005 Mar 10;352(10):987-96
references.pmid: 15758009
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D412-6
references.pmid: 18940858