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Role of cancer stem cells in hepatocarcinogenesis

By Bo Wang and Samson T Jacob


There has been considerable interest in cancer stem cells (CSCs) among cancer biologists and clinicians, most likely because of their role in the heterogeneity of cancer and their potential application in cancer therapeutics. Recent studies suggest that CSCs play a key role in liver carcinogenesis. A small subpopulation of cancer cells with CSC properties has been identified and characterized from hepatocellular carcinoma (HCC) cell lines, animal models and human primary HCCs. Considering the high mortality and ineffectiveness of current therapies for HCC, understanding the characteristics and function of CSCs is likely to lead to development of new therapies resulting in improvement of patient survival. This review summarizes recent progress in liver cancer stem cell research with regard to the identification, cell origin, regulation of self-renewal capacity, and therapeutic implications of liver CSCs

Topics: Review
Publisher: BioMed Central
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Provided by: PubMed Central

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  1. (2006). Aberger F: GLI transcription factors: mediators of oncogenic Hedgehog signalling.
  2. (2007). Alman BA: Side population cells isolated from mesenchymal neoplasms have tumor initiating potential. Cancer Res
  3. (2004). Aster JC: Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev
  4. (2004). Brivanlou AH: Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med
  5. (2006). Cancer stem cells.
  6. (2010). Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma.
  7. (2003). Cao X: Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res
  8. (2007). CD133-positive hepatocellular carcinoma cells possess high capacity for tumorigenicity.
  9. (2008). Chang HY: Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell
  10. (2009). Clevers H: Crypt stem cells as the cells-of-origin of intestinal cancer.
  11. (2005). Defining the role of Wnt/β-catenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells. Stem Cells
  12. (2006). Diehl AM: Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis
  13. (2004). Dirks PB: Identification of human brain tumour initiating cells. Nature
  14. (2007). Dontu G: ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell
  15. (1997). DW: AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood
  16. (2002). EA: Generation and characterization of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma. Carcinogenesis
  17. (2007). Eberhart CG: Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells
  18. (2010). Eberhart CG: NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells
  19. (2004). Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity
  20. (2007). Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med
  21. (2008). Fan ST: Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell
  22. (1985). Fausto N: Expression of c-Ki-ras, c-Ha-ras, and c-myc in specific cell types during hepatocarcinogenesis. Mol Cell Biol
  23. (2000). Fausto N: Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice.
  24. (2000). Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver. Hepatology
  25. (2008). Frank MH: Identification of cells initiating human melanomas. Nature
  26. (2008). G: IL-4-mediated drug resistance in colon cancer stem cells. Cell Cycle
  27. (2006). Gastrointestinal stem cells. III. Emergent themes of liver stem cell biology: niche, quiescence, self-renewal, and plasticity.
  28. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature
  29. (1996). Ha-rasVal12 but not p53Ser247 leads to a significant neoplastic transformation rate of the putative rat liver stem cells (oval cell). Carcinogenesis
  30. (2007). Hebrok M: Liver-specific loss of betacatenin results in delayed hepatocyte proliferation after partial hepatectomy. Hepatology
  31. (2007). Heeschen C: Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell
  32. (1997). Huttner WB: Prominin, a novel microvillispecific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells.
  33. (2000). Huttner WB: The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions.
  34. (2000). IL: Direct isolation of human central nervous system stem cells.
  35. (2001). IL: Stem cells, cancer, and cancer stem cells. Nature
  36. (1994). JE: A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature
  37. (2007). JE: A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.
  38. (2000). JW: Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response.
  39. (2007). KL: Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology
  40. (2010). L: Targeting Notch to target cancer stem cells. Clin Cancer Res
  41. (2007). La Porta CA: Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential.
  42. (1996). Lalani EN: Liver damage in the rat induces hepatocyte stem cells from biliary epithelial cells. Gastroenterology
  43. (2008). Lindeman GJ: Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer
  44. (2004). Llovet JM: Focus on hepatocellular carcinoma. Cancer Cell
  45. (2007). LM: Human hepatic stem cells from fetal and postnatal donors. J Med
  46. (2009). marks intestinal stem cells that are susceptible to neoplastic transformation. Nature
  47. (2007). MF: Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U A
  48. (2003). MF: Prospective identification of tumorigenic breast cancer cells.
  49. (2008). Olynyk JK: C-kit inhibition by imatinib mesylate attenuates progenitor cell expansion and inhibits liver tumor formation in mice. Gastroenterology
  50. (1999). Olynyk JK: Oval cell numbers in human chronic liver diseases are directly related to disease severity.
  51. (1972). Quantitative study on foci of altered liver cells induced in the rat by a single dose of diethylnitrosamine and partial hepatectomy.
  52. (2007). Radovanovic I, Ruiz i Altaba A: HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol
  53. (2006). SA: Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature
  54. (2008). SC: Expansion of liver cancer stem cells during aging in methionine adenosyltransferase 1Adeficient mice. Hepatology
  55. (1993). Shafritz DA: Models for hepatic progenitor cell activation. Proc Soc Exp Biol Med
  56. (2006). Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology
  57. (2007). Simeone DM: Identification of pancreatic cancer stem cells. Cancer Res
  58. (2009). SM: Down-regulation of Notch1 signaling inhibits tumor growth in human hepatocellular carcinoma.
  59. (2009). SP: Cancer stem cells - from initiation to elimination, how far have we reached?
  60. (2007). Taniguchi H: Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation. Gastroenterology
  61. (2010). Targeting Hedgehog - a cancer stem cell pathway. Clin Cancer Res
  62. (1976). The clonal evolution of tumor cell populations. Science
  63. The origin and liver repopulating capacity of murine oval cells.
  64. (2005). Theise ND: Dose- and time-dependent oval cell reaction in acetaminophen-induced murine liver injury. Hepatology
  65. (2006). Thorgeirsson SS: A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med
  66. (1987). Thorgeirsson SS: A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis
  67. (2008). WF: Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4alpha gene. Hepatology
  68. (2006). Wicha MS: Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res
  69. (2003). Wicha MS: In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev
  70. (2008). Wnt/β-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res
  71. (2008). Xia JC: Increased polycomb-group oncogene Bmi-1 expression correlates with poor prognosis in hepatocellular carcinoma.
  72. (2009). XW: EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology
  73. (2007). XY: Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology
  74. (2004). Zhang W: Function of oval cells in hepatocellular carcinoma in rats.