title: Cancer stem cells in the development of liver cancer.
abstract: Liver cancer is an aggressive disease with a poor outcome. Several hepatic stem/progenitor markers are useful for isolating a subset of liver cells with stem cell features, known as cancer stem cells (CSCs). These cells are responsible for tumor relapse, metastasis, and chemoresistance. Liver CSCs dictate a hierarchical organization that is shared in both organogenesis and tumorigenesis. An increased understanding of the molecular signaling events that regulate cellular hierarchy and stemness, and success in defining key CSC-specific genes, have opened up new avenues to accelerate the development of novel diagnostic and treatment strategies. This Review highlights recent advances in understanding the pathogenesis of liver CSCs and discusses unanswered questions about the concept of liver CSCs.
authors: Department of General Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan. taroy@m-kanazawa.jp
authors: Taro
authors: T
authors: Yamashita
authors: Xin Wei
authors: XW
authors: Wang
mesh_terms: D000818:Animals; D019070:Cell Lineage; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010641:Phenotype; D011379:Prognosis; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology
references: Nature. 2009 Aug 27;460(7259):1132-5
references: 19668191
references: Cell Stem Cell. 2012 Apr 6;10(4):362-9
references: 22482502
references: Cell Stem Cell. 2012 Sep 7;11(3):429-39
references: 22958934
references: Hepatology. 2012 Feb;55(2):563-74
references: 21953633
references: Nat Rev Cancer. 2011 Sep 23;11(10):726-34
references: 21941284
references: Cancer Res. 2012 Jul 1;72(13):3414-23
references: 22552294
references: Gastroenterology. 2012 Dec;143(6):1660-1669.e7
references: 22974708
references: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9912-7
references: 16782807
references: J Clin Invest. 2012 Aug;122(8):2911-5
references: 22797301
references: N Engl J Med. 2009 Oct 8;361(15):1437-47
references: 19812400
references: Gastroenterology. 2005 Jan;128(1):33-42
references: 15633121
references: Cell. 2008 May 16;133(4):704-15
references: 18485877
references: Oncogene. 2010 Sep 9;29(36):4989-5005
references: 20639898
references: Cancer Lett. 2007 Jul 18;252(2):157-70
references: 17188425
references: Nature. 2009 Aug 27;460(7259):1149-53
references: 19668189
references: Oncogene. 2007 Apr 2;26(15):2166-76
references: 17401425
references: Nat Rev Cancer. 2004 Nov;4(11):839-49
references: 15516957
references: Hepatology. 2012 Jun;55(6):2041-2
references: 22262236
references: Nature. 2011 Jan 20;469(7330):314-22
references: 21248838
references: J Hepatol. 2001 May;34(5):690-8
references: 11434615
references: Hepatology. 2008 Mar;47(3):919-28
references: 18275073
references: Hepatology. 2009 Aug;50(2):472-80
references: 19585654
references: N Engl J Med. 2006 Sep 21;355(12):1253-61
references: 16990388
references: Hepatology. 2009 Jan;49(1):318-29
references: 19111019
references: Hepatology. 2008 May;47(5):1544-56
references: 18393293
references: Cancer Res. 2007 Nov 15;67(22):10831-9
references: 18006828
references: Cancer Cell. 2012 Sep 11;22(3):291-303
references: 22975373
references: Gastroenterology. 2011 Mar;140(3):1063-70
references: 21094160
references: Science. 1999 Jun 18;284(5422):1998-2003
references: 10373120
references: Stem Cells Dev. 2012 May 1;21(7):1124-33
references: 21861758
references: Cell. 2006 Aug 25;126(4):663-76
references: 16904174
references: Hepatology. 2011 Mar;53(3):854-64
references: 21319186
references: Anat Rec A Discov Mol Cell Evol Biol. 2004 Sep;280(1):910-23
references: 15382010
references: J Hepatol. 2012 Sep;57(3):613-20
references: 22612999
references: Hepatology. 2012 Jan;55(1):121-31
references: 21898503
references: Gastroenterology. 2008 Mar;134(3):823-32
references: 18262526
references: Nat Med. 2006 Apr;12(4):410-6
references: 16532004
references: Hepatology. 2013 Apr;57(4):1458-68
references: 23175471
references: Hepatology. 2008 Feb;47(2):636-47
references: 18023068
references: J Hepatol. 2012;56 Suppl 1:S75-87
references: 22300468
references: J Cell Sci. 2003 May 1;116(Pt 9):1775-86
references: 12665558
references: Exp Cell Res. 2002 Oct 1;279(2):330-43
references: 12243758
references: J Virol. 2011 Dec;85(23):12292-303
references: 21937640
references: Gastroenterology. 2009 Mar;136(3):1012-24
references: 19150350
references: Hepatology. 2012 Nov;56(5):1792-803
references: 22707408
references: Biochim Biophys Acta. 1976 Oct 12;458(3):283-321
references: 1067873
references: Stem Cells Dev. 2011 Dec;20(12):2177-88
references: 21361791
references: Clin Biochem. 2011 Jun;44(8-9):582-9
references: 21376027
references: Hepatology. 2005 Mar;41(3):535-44
references: 15726663
references: Nat Genet. 2012 May 06;44(6):694-8
references: 22561517
references: Nat Rev Cancer. 2006 Sep;6(9):674-87
references: 16929323
references: Nat Genet. 2011 Aug 07;43(9):828-9
references: 21822264
references: Hepatology. 2008 Jan;47(1):247-58
references: 18038450
references: Cell Stem Cell. 2012 Sep 7;11(3):415-28
references: 22958933
references: Semin Liver Dis. 2004 Feb;24(1):43-8
references: 15085485
references: Gastroenterology. 2007 Jun;132(7):2542-56
references: 17570225
references: Hepatology. 2008 Dec;48(6):1964-78
references: 18837044
references: J Exp Med. 2011 Sep 26;208(10):1963-76
references: 21875955
references: Oncogene. 2006 Jun 26;25(27):3818-22
references: 16799623
references: Cell. 2009 Dec 24;139(7):1315-26
references: 20064377
references: Hepatology. 2007 May;45(5):1298-305
references: 17464972
references: Nat Med. 1997 Jul;3(7):730-7
references: 9212098
references: Cancer Res. 2008 Jun 1;68(11):4287-95
references: 18519688
references: Histopathology. 2008 Jan;52(2):224-32
references: 18184271
references: J Hepatol. 1998 Sep;29(3):455-63
references: 9764994
references: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references: 21296855
references: Nature. 2009 Aug 27;460(7259):1145-8
references: 19668190
references: Nature. 2006 Jun 29;441(7097):1075-9
references: 16810242
references: Semin Cell Dev Biol. 2002 Dec;13(6):419-24
references: 12468242
references: Cancer Res. 2009 Sep 15;69(18):7385-92
references: 19723656
references: Carcinogenesis. 2012 Sep;33(9):1791-6
references: 22696594
references: J Hepatol. 1995;22(2 Suppl):28-36
references: 7665846
references: J Clin Invest. 2010 Sep;120(9):3326-39
references: 20697159
references: Hepatology. 2008 May;47(5):1702-13
references: 18398918
references: Ann Surg Oncol. 2012 Sep;19(9):2877-87
references: 22461131
references: J Cell Physiol. 2007 Nov;213(2):286-300
references: 17559071
references: Cell Stem Cell. 2011 Jul 8;9(1):50-63
references: 21726833
references: Nature. 2011 Jan 20;469(7330):362-7
references: 21248843
references: J Biol Chem. 2011 Sep 23;286(38):33520-32
references: 21799003
references: J Clin Invest. 2005 Feb;115(2):209-18
references: 15690074
references: Hepatology. 2007 Jun;45(6):1462-70
references: 17538966
references: Biochim Biophys Acta. 2002 Nov 11;1592(3):303-12
references: 12421674
references: Proc Natl Acad Sci U S A. 2011 May 10;108(19):7950-5
references: 21498687
references: Cancer Res. 2011 May 15;71(10):3701-8
references: 21464043
references: Cell Stem Cell. 2010 Dec 3;7(6):694-707
references: 21112564
references: Nat Genet. 2002 Aug;31(4):339-46
references: 12149612
references: Gastroenterology. 2003 Jan;124(1):202-16
references: 12512043
references: Virology. 2003 Jul 20;312(1):245-53
references: 12890637
references: Am J Pathol. 2007 Feb;170(2):478-89
references: 17255316
references: Hepatology. 2012 Oct;56(4):1331-41
references: 22505225
references: Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20471-6
references: 21059911
references: Science. 1977 Aug 26;197(4306):893-5
references: 887927
references: Gut. 2008 Aug;57(8):1129-38
references: 18417531
references: Hepatology. 2006 Jul;44(1):240-51
references: 16799977
references: Science. 1976 Oct 1;194(4260):23-8
references: 959840
references: J Exp Med. 2007 Aug 6;204(8):1973-87
references: 17664288
references: Stem Cells. 2007 Oct;25(10):2419-29
references: 17585168
references: Cancer Res. 2010 Jun 1;70(11):4687-97
references: 20484035
references: Cancer Res. 2006 Feb 15;66(4):1883-90; discussion 1895-6
references: 16488983
references: Nature. 1994 Feb 17;367(6464):645-8
references: 7509044
references: Hepatology. 2012 Apr;55(4):1215-26
references: 22095660
references: Nat Cell Biol. 2009 Feb;11(2):162-71
references: 19136966
references: Mol Cancer Ther. 2012 Mar;11(3):629-38
references: 22238367
references: Cancer Cell. 2012 Mar 20;21(3):283-96
references: 22439924
references: N Engl J Med. 2008 Nov 6;359(19):1995-2004
references: 18923165
references: Hepatology. 2005 Apr;41(4):809-18
references: 15793848
references: Gastroenterology. 2004 Oct;127(4):1110-22
references: 15480989
references: Hepatology. 2012 Dec;56(6):2255-67
references: 22898879
references: Gut. 2010 Jul;59(7):953-62
references: 20442200
references: Hepatology. 2013 Apr;57(4):1484-97
references: 23174907
references: Cancer Cell. 2011 Mar 8;19(3):387-400
references: 21397861
references: Hepatology. 2010 Apr;51(4):1373-82
references: 20131405
references: Hepatology. 2012 Mar;55(3):807-20
references: 21994122
references: Genes Dev. 2005 Aug 15;19(16):1849-54
references: 16103213
references: Cancer Cell. 2006 Aug;10(2):99-111
references: 16904609
references: Hepatology. 2001 Jun;33(6):1387-93
references: 11391527
references: Gastroenterology. 2001 Feb;120(2):534-44
references: 11159894
references: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2445-50
references: 18263735
references: Cell. 2011 Aug 19;146(4):633-44
references: 21854987
references: Nat Genet. 2012 May 27;44(7):760-4
references: 22634756
references: J Clin Oncol. 2008 Jun 10;26(17):2800-5
references: 18539957
references: Cell. 2007 Nov 30;131(5):861-72
references: 18035408
references: Gastroenterology. 2007 Sep;133(3):937-50
references: 17673212
references: Hepatology. 2008 Jan;47(1):288-95
references: 17929301
references: Hepatology. 2007 Oct;46(4):1236-45
references: 17647294
references: Cancer Res. 2012 Aug 15;72(16):4276-85
references: 22773665
references: Cancer Cell. 2012 Sep 11;22(3):279-80
references: 22975368
references: Cancer Res. 2008 Mar 1;68(5):1451-61
references: 18316609
references: Gastroenterology. 2010 Jul;139(1):335-43.e2
references: 20399781
references: Hepatology. 2010 Sep;52(3):945-53
references: 20564331
references: Oncogene. 2008 Mar 13;27(12):1749-58
references: 17891174
references: Curr Opin Genet Dev. 2004 Oct;14(5):582-90
references: 15380251
references: Gastroenterology. 2002 Feb;122(2):366-75
references: 11832451
references: Hepatology. 2011 Nov;54(5):1707-17
references: 22045674
references: Cell. 2006 Jun 30;125(7):1253-67
references: 16814713
references: Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2230-4
references: 8134379
references: J Hepatol. 2001 May;34(5):683-9
references: 11434614
references: Hepatology. 2010 May;51(5):1635-44
references: 20196115
references: Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1548-53
references: 19171902
references: Hepatology. 1999 Feb;29(2):520-7
references: 9918930
references: Semin Oncol. 2012 Aug;39(4):461-72
references: 22846863
references: J Clin Oncol. 2011 Aug 10;29(23):3140-5
references: 21730269
references: Genes Dev. 2001 Aug 1;15(15):1998-2009
references: 11485993
references: Hepatology. 2011 Jan;53(1):160-70
references: 20979057
references: Am J Pathol. 1997 Nov;151(5):1273-80
references: 9358753
references: Nature. 2006 Aug 10;442(7103):688-91
references: 16799568
references: Mol Cancer Res. 2008 Jul;6(7):1146-53
references: 18644979
references: Biochim Biophys Acta. 2008 Feb;1782(2):61-74
references: 18187050
references: Cancer Cell. 2008 Feb;13(2):153-66
references: 18242515