title: Stem cell quiescence.
abstract: Adult stem cells are maintained in a quiescent state but are able to exit quiescence and rapidly expand and differentiate in response to stress. The quiescent state appears to be necessary for preserving the self-renewal of stem cells and is a critical factor in the resistance of cancer stem cells (CSCs) to chemotherapy and targeted therapies. Limited knowledge about quiescence mechanisms has prevented significant advances in targeting of drug-resistant quiescent CSCs populations in the clinic. Thus, an improved understanding of the molecular mechanisms of quiescence in adult stem cells is critical for the development of molecularly targeted therapies against quiescent CSCs in different cancers. Recent studies have provided a better understanding of the intrinsic and extrinsic regulatory mechanisms that control stem cell quiescence. It is now appreciated that the p53 gene plays a critical role in regulating stem cell quiescence. Other intrinsic regulatory mechanisms include the FoxO, HIF-1α, and NFATc1 transcription factors and signaling through ATM and mTOR. Extrinsic microenvironmental regulatory mechanisms include angiopoietin-1, TGF-β, bone morphogenic protein, thrombopoietin, N-cadherin, and integrin adhesion receptors; Wnt/β-catenin signaling; and osteopontin. In this article, we review current advances in understanding normal stem cell quiescence, their significance for CSC quiescence and drug resistance, and the potential clinical applications of these findings.
authors: Authors' Affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, California, USA.
authors: Ling
authors: L
authors: Li
authors: Ravi
authors: R
authors: Bhatia
references: Nat Rev Immunol. 2006 Feb;6(2):93-106
references: 16491134
references: Cancer Cell. 2006 Mar;9(3):175-87
references: 16530702
references: Cell. 2007 Jan 26;128(2):325-39
references: 17254970
references: Blood. 2008 Dec 15;112(13):4793-807
references: 19064739
references: Nature. 2004 Oct 21;431(7011):997-1002
references: 15496926
references: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12753-8
references: 14530387
references: Cancer Cell. 2010 May 18;17(5):427-42
references: 20478526
references: Nat Biotechnol. 2010 Mar;28(3):275-80
references: 20160717
references: Oncogene. 2004 Sep 2;23(40):6693-701
references: 15235588
references: Cell Stem Cell. 2010 Jul 2;7(1):78-89
references: 20621052
references: J Biol Chem. 2002 Jul 26;277(30):26729-32
references: 12048180
references: Cell. 2007 Jun 15;129(6):1097-110
references: 17574023
references: Blood. 2003 Jun 15;101(12):4701-7
references: 12576334
references: Science. 2004 Mar 26;303(5666):2011-5
references: 14976264
references: Stem Cells. 2007 Apr;25(4):836-43
references: 17170062
references: Leukemia. 2009 Oct;23(10):1708-15
references: 19641523
references: Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1195-200
references: 9448308
references: Nature. 2001 Nov 1;414(6859):98-104
references: 11689954
references: Cell Stem Cell. 2008 Mar 6;2(3):274-83
references: 18371452
references: Exp Hematol. 2011 May;39(5):511-20
references: 21288477
references: J Leukoc Biol. 2001 Jun;69(6):912-20
references: 11404376
references: Nat Med. 2009 Jun;15(6):696-700
references: 19483695
references: Nature. 2004 Oct 21;431(7011):1002-7
references: 15457180
references: J Clin Oncol. 2011 Feb 10;29(5):591-9
references: 21220598
references: Cell Stem Cell. 2010 Sep 3;7(3):391-402
references: 20804974
references: Nature. 2009 Apr 16;458(7240):904-8
references: 19212321
references: Proc Natl Acad Sci U S A. 1990 Jun;87(12):4473-5
references: 1693772
references: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3120-5
references: 10077647
references: Blood. 2010 Jun 24;115(25):5131-6
references: 20237318
references: Stem Cells. 2009 May;27(5):1109-19
references: 19415781
references: Nature. 2003 Oct 23;425(6960):836-41
references: 14574412
references: Science. 2004 Jan 16;303(5656):359-63
references: 14671312
references: Cell Stem Cell. 2009 Jan 9;4(1):37-48
references: 19128791
references: Nature. 2006 May 25;441(7092):518-22
references: 16633340
references: Cell Stem Cell. 2010 Sep 3;7(3):380-90
references: 20804973
references: Physiology (Bethesda). 2005 Oct;20:349-56
references: 16174874
references: Clin Cancer Res. 2010 Jun 15;16(12):3153-62
references: 20530697
references: J Exp Med. 2008 Jun 9;205(6):1395-408
references: 18474632
references: Cell. 2007 Oct 19;131(2):324-36
references: 17956733
references: Cell. 2004 Jul 23;118(2):149-61
references: 15260986
references: Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12682-7
references: 15314234
references: Development. 2007 Mar;134(6):1071-80
references: 17287246
references: Cell Stem Cell. 2007 Dec 13;1(6):685-97
references: 18371409
references: Nature. 2001 Nov 1;414(6859):105-11
references: 11689955
references: J Exp Med. 2005 Jun 6;201(11):1781-91
references: 15928197
references: Nature. 2008 Jun 19;453(7198):1072-8
references: 18469801
references: Blood. 2008 Jan 15;111(2):492-503
references: 17914027
references: Cell. 2008 Jan 25;132(2):299-310
references: 18243104
references: Leukemia. 2009 Jun;23(6):1199-201
references: 19262595
references: Leuk Res. 2008 Feb;32(2):255-61
references: 17692911
references: Cell Stem Cell. 2007 Dec 13;1(6):671-84
references: 18371408
references: Blood. 2009 Jun 11;113(24):6206-14
references: 19050309
references: Blood. 2005 Aug 15;106(4):1232-9
references: 15845900
references: Nature. 2006 May 25;441(7092):475-82
references: 16598206
references: Nat Med. 2006 Oct;12(10):1181-4
references: 17013383
references: Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1908-13
references: 9050878
references: Nat Immunol. 2006 Oct;7(10):1048-56
references: 16951689
references: Biochem Pharmacol. 2007 Sep 1;74(5):659-71
references: 17498667
references: Blood. 1998 Jul 15;92(2):348-51; discussion 352
references: 9657728
references: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10063-8
references: 17553962
references: Science. 2000 Mar 10;287(5459):1804-8
references: 10710306
references: Blood. 2007 Jan 1;109(1):58-60
references: 16973963