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Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways.

 Jens U. Marquardt  ;  Chiara Raggi  ;  Jesper B. Andersen  ;  Daekwan Seo  ;  Itzhak Avital  ;  David Geller  ;  Yun-Han Lee  ;  Mitsuteru Kitade  ;  Agnes Holczbauer  ;  Matthew C. Gillen  ;  Elizabeth A. Conner  ;  Valentina M. Factor  ;  Snorri S. Thorgeirsson 
 HEPATOLOGY, Vol.54(3) : 1031-1042, 2011 
Journal Title
Issue Date
Animals ; Cell Line, Tumor ; Cytidine/analogs & derivatives ; Cytidine/pharmacology ; Epigenesis, Genetic ; Gene Expression Profiling* ; Humans ; Liver Neoplasms/etiology* ; Liver Neoplasms/mortality ; Liver Neoplasms/pathology ; Mice ; Neoplastic Stem Cells/metabolism*
Cancer Stem Cells ; Liver Cancer ; Side-population ; Epigenetics
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. CONCLUSION: 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.
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1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Lee, Yun Han(이윤한)
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