title: Epigenetic regulation of cancer stem cells in liver cancer: current concepts and clinical implications.
abstract: The two dominant models of carcinogenesis postulate stochastic (clonal evolution) or hierarchic organization of tumor (cancer stem cell model). According to the latter, at the germinal center of tumor evolution is a cancer stem cell (CSC) which, similar to normal adult stem cells, possesses the capacity of self-renewal and a differentiation potential. Over the past few years, compelling evidence has emerged in support of the hierarchic cancer model for many solid tumors including hepatocellular cancers. The CSCs are posited to be responsible not only for tumor initiation but also for the generation of distant metastasis and relapse after therapy. These characteristics are particularly relevant for a multi-resistant tumor entity like human hepatocellular carcinoma and may herald a paradigm shift in the management of this deadly disease. Identification and detailed characterization of liver CSCs is therefore imperative for improving prevention approaches, enhancing early detection, and extending the limited treatment options. Despite the current progress in understanding the contribution of CSCs to the generation of heterogeneity of tumors, the molecular complexity and exact regulation of CSCs is poorly understood. This review focuses on the genetic and epigenetic mechanisms that regulate and define the unique CSC properties with an emphasis on key regulatory pathways of liver CSCs and their clinical significance.
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, MD, USA.
authors.forename: J U
authors.initials: JU
authors.lastname: Marquardt
authors.forename: V M
authors.initials: VM
authors.lastname: Factor
authors.forename: S S
authors.initials: SS
authors.lastname: Thorgeirsson
mesh_terms: D000071916:AC133 Antigen; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002455:Cell Division; D002469:Cell Separation / Q000379:methods; D044127:Epigenesis, Genetic; D000071858:Epithelial Cell Adhesion Molecule; D016259:Genes, myc; D006023:Glycoproteins / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics; D008954:Models, Biological; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction; D018800:Thy-1 Antigens / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C069077:BMI1 protein, human; C495270:CTNNB1 protein, human; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins; D053823:Hedgehog Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; D051880:Receptors, Notch; D012097:Repressor Proteins; C509239:SHH protein, human; D018800:Thy-1 Antigens; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin; D000444:Aldehyde Dehydrogenase; D063150:Polycomb Repressive Complex 1