title: Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways.
abstract: Epigenetic mechanisms play critical roles in stem cell biology by maintaining pluripotency of stem cells and promoting differentiation of more mature derivatives. If similar mechanisms are relevant for the cancer stem cell (CSC) model, then epigenetic modulation might enrich the CSC population, thereby facilitating CSC isolation and rigorous evaluation. To test this hypothesis, primary human cancer cells and liver cancer cell lines were treated with zebularine (ZEB), a potent DNA methyltransferase-1 inhibitor, and putative CSCs were isolated using the side population (SP) approach. The CSC properties of ZEB-treated and untreated subpopulations were tested using standard in vitro and in vivo assays. Whole transcriptome profiling of isolated CSCs was performed to generate CSC signatures. Clinical relevance of the CSC signatures was evaluated in diverse primary human cancers. Epigenetic modulation increased frequency of cells with CSC properties in the SP fraction isolated from human cancer cells as judged by self-renewal, superior tumor-initiating capacity in serial transplantations, and direct cell tracking experiments. Integrative transcriptome analysis revealed common traits enriched for stemness-associated genes, although each individual CSC gene expression signature exhibited activation of different oncogenic pathways (e.g., EGFR, SRC, and MYC). The common CSC signature was associated with malignant progression, which is enriched in poorly differentiated tumors, and was highly predictive of prognosis in liver and other cancers.
  
  
  CONCLUSIONS
  Epigenetic modulation may provide a tool for prospective isolation and in-depth analysis of CSC. The liver CSC gene signatures are defined by a pernicious interaction of unique oncogene-specific and common stemness traits. These data should facilitate the identifications of therapeutic tools targeting both unique and common features of CSCs.
authors: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Jens U
authors: JU
authors: Marquardt
authors: Chiara
authors: C
authors: Raggi
authors: Jesper B
authors: JB
authors: Andersen
authors: Daekwan
authors: D
authors: Seo
authors: Itzhak
authors: I
authors: Avital
authors: David
authors: D
authors: Geller
authors: Yun-Han
authors: YH
authors: Lee
authors: Mitsuteru
authors: M
authors: Kitade
authors: Agnes
authors: A
authors: Holczbauer
authors: Matthew C
authors: MC
authors: Gillen
authors: Elizabeth A
authors: EA
authors: Conner
authors: Valentina M
authors: VM
authors: Factor
authors: Snorri S
authors: SS
authors: Thorgeirsson
references: N Engl J Med. 2008 Jul 24;359(4):378-90
references: 18650514
references: Hepatology. 2004 Sep;40(3):667-76
references: 15349906
references: N Engl J Med. 2006 Sep 21;355(12):1253-61
references: 16990388
references: Gastroenterology. 2009 Mar;136(3):1012-24
references: 19150350
references: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references: 12629218
references: Gastroenterology. 2007 Jun;132(7):2542-56
references: 17570225
references: Cancer Res. 2008 Jun 1;68(11):4287-95
references: 18519688
references: J Clin Oncol. 2008 Jun 10;26(17):2813-20
references: 18539959
references: Hepatology. 2006 Jul;44(1):240-51
references: 16799977
references: Cancer Res. 2006 Oct 1;66(19):9339-44
references: 16990346
references: J Mol Biol. 1987 Jul 20;196(2):261-82
references: 3656447
references: Nat Rev Cancer. 2004 Jun;4(6):470-80
references: 15170449
references: Blood. 2008 Aug 1;112(3):568-75
references: 18523148
references: Nature. 2008 Dec 4;456(7222):593-8
references: 19052619
references: Nat Med. 2006 Apr;12(4):410-6
references: 16532004
references: Cell Stem Cell. 2010 Jul 2;7(1):127-33
references: 20621056
references: Stem Cell Rev. 2005;1(3):253-60
references: 17142862
references: Cell Stem Cell. 2010 Jul 2;7(1):2-4
references: 20621039
references: Hepatology. 2008 Oct;48(4):1312-27
references: 18821591
references: Cancer Res. 2009 Apr 1;69(7):2775-82
references: 19276364
references: Cancer Cell. 2004 Aug;6(2):151-8
references: 15324698
references: J Histochem Cytochem. 2002 Aug;50(8):1131-4
references: 12133915
references: J Exp Med. 1996 Apr 1;183(4):1797-806
references: 8666936
references: Cell Stem Cell. 2008 Apr 10;2(4):333-44
references: 18397753
references: Cell Mol Life Sci. 2003 Aug;60(8):1647-58
references: 14504655
references: Cell. 2007 Feb 23;128(4):683-92
references: 17320506
references: J Clin Invest. 2010 Jan;120(1):41-50
references: 20051635
references: Mol Biol Cell. 2002 Jun;13(6):1977-2000
references: 12058064
references: Nat Rev Genet. 2006 Jan;7(1):21-33
references: 16369569
references: Stem Cells. 2006 Mar;24(3):506-13
references: 16239320
references: Sci Transl Med. 2010 Oct 20;2(54):54ra77
references: 20962331
references: Nat Genet. 2008 May;40(5):499-507
references: 18443585
references: Nature. 2001 Nov 1;414(6859):105-11
references: 11689955
references: Nature. 2006 May 25;441(7092):431-6
references: 16724054
references: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13784-9
references: 11707590
references: Neoplasia. 2004 Jan-Feb;6(1):1-6
references: 15068665
references: Cell Stem Cell. 2009 Nov 6;5(5):504-14
references: 19896441
references: BMC Genomics. 2006 Apr 27;7:96
references: 16643655
references: Cancer Cell. 2008 Feb;13(2):153-66
references: 18242515