Cancer Stem Cells in Hepatocellular Carcinoma



Hepatocellular carcinoma is one of the most common cancers and the second leading cause of cancer-related deaths worldwide. Only a small proportion of patients benefit from curative treatment and the prognosis is very poor for the majority of cases due to late presentation, resistance to chemotherapy and high recurrence rate. In recent years, progress in stem cell biology allowed us to explain that hierarchically organized cancer stem cells (CSCs) drive histological and functional heterogeneity of hematological malignancies and solid tumors.

Methods and Results

Also referred to as tumor-initiating cells, CSCs have been isolated from both hepatocellular carcinoma (HCC) cell lines and primary tumors by using hepatic progenitor markers. Although there is still no consensus on cancer stem cell phenotype in HCC, single or combined use of CSC markers defines a minor population of tumor cells with the capacity of self-renewing and the ability to recapitulate the original tumor heterogeneity.


This review focuses on the biological features of CSCs and their potential as diagnostic/prognostic tools and therapeutic targets in HCC.

This is a preview of subscription content, log in to check access.

Fig. 1


  1. 1.

    Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8.

    CAS  Article  Google Scholar 

  2. 2.

    Reya T, et al. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.

    CAS  Article  Google Scholar 

  3. 3.

    Soltysova A, Altanerova V, Altaner C. Cancer stem cells. Neoplasma. 2005;52(6):435.

    CAS  Google Scholar 

  4. 4.

    Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717–28.

    CAS  Article  Google Scholar 

  5. 5.

    Hamburger AW, Salmon SE. Primary bioassay of human tumor stem cells. Science. 1977;197(4302):461–3.

    CAS  Article  Google Scholar 

  6. 6.

    Dick D. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature med. 1997;3(730–737):1.

    Google Scholar 

  7. 7.

    Al-Hajj M, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci. 2003;100(7):3983–8.

    CAS  Article  Google Scholar 

  8. 8.

    Dalerba P, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci. 2007;104(24):10158–63.

    CAS  Article  Google Scholar 

  9. 9.

    O’Brien CA, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445(7123):106–10.

    Article  Google Scholar 

  10. 10.

    Ricci-Vitiani L, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.

    CAS  Article  Google Scholar 

  11. 11.

    Li C, et al. Identification of pancreatic cancer stem cells. Cancer res. 2007;67(3):1030–7.

    CAS  Article  Google Scholar 

  12. 12.

    Singh SK, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401.

    CAS  Article  Google Scholar 

  13. 13.

    Bao S, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.

    CAS  Article  Google Scholar 

  14. 14.

    Piccirillo S, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006;444(7120):761–5.

    CAS  Article  Google Scholar 

  15. 15.

    Chiba T, et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell–like properties. Hepatology. 2006;44(1):240–51.

    CAS  Article  Google Scholar 

  16. 16.

    Haraguchi N, et al. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells. 2006;24(3):506–13.

    CAS  Article  Google Scholar 

  17. 17.

    Yang ZF, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell. 2008;13(2):153–66.

    CAS  Article  Google Scholar 

  18. 18.

    Zhang S, et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer res. 2008;68(11):4311–20.

    CAS  PubMed Central  Article  Google Scholar 

  19. 19.

    Curley MD, et al. CD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells. 2009;27(12):2875–83.

    CAS  Google Scholar 

  20. 20.

    Sugihara E, Saya H. Complexity of cancer stem cells. Int J Cancer. 2013;132(6):1249–59.

    CAS  Article  Google Scholar 

  21. 21.

    Clevers H. The cancer stem cell: premises, promises and challenges. Nat med. 2011:313–9.

    CAS  Article  Google Scholar 

  22. 22.

    Zhou B-BS, et al. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat rev Drug Discov. 2009;8(10):806–23.

    CAS  Article  Google Scholar 

  23. 23.

    Patel P, Chen E. Cancer stem cells, tumor dormancy, and metastasis. Front Endocrinol. 2012;3:125.

    Article  Google Scholar 

  24. 24.

    Mani SA, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15.

    CAS  PubMed Central  Article  Google Scholar 

  25. 25.

    Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29(34):4741–51.

    CAS  PubMed Central  Article  Google Scholar 

  26. 26.

    Torre LA, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.

    Article  Google Scholar 

  27. 27.

    London W, McGlynn K. Liver cancer. Cancer Epidemiology and Prevention. 2006;3:763–86.

    Article  Google Scholar 

  28. 28.

    Jemal A, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  Google Scholar 

  29. 29.

    Yeh MM. Pathology of combined hepatocellular-cholangiocarcinoma. J Gastroenterol Hepatol. 2010;25(9):1485–92.

    Article  Google Scholar 

  30. 30.

    Ma S, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007;132(7):2542–56.

    CAS  Article  Google Scholar 

  31. 31.

    Suetsugu A, et al. Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys res Commun. 2006;351(4):820–4.

    CAS  Article  Google Scholar 

  32. 32.

    Yamashita T, et al. Activation of hepatic stem cell marker EpCAM by Wnt–β-catenin signaling in hepatocellular carcinoma. Cancer res. 2007;67(22):10831–9.

    CAS  Article  Google Scholar 

  33. 33.

    Turner R, et al. Human hepatic stem cell and maturational liver lineage biology. Hepatology. 2011;53(3):1035–45.

    CAS  PubMed Central  Article  Google Scholar 

  34. 34.

    Zhang L, et al. The stem cell niche of human livers: symmetry between development and regeneration. Hepatology. 2008;48(5):1598–607.

    CAS  Article  Google Scholar 

  35. 35.

    Tang Y, et al. Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling. Proc Natl Acad Sci. 2008;105(7):2445–50.

    CAS  Article  Google Scholar 

  36. 36.

    Chen Y, et al. Mature hepatocytes exhibit unexpected plasticity by direct dedifferentiation into liver progenitor cells in culture. Hepatology. 2012;55(2):563–74.

    CAS  PubMed Central  Article  Google Scholar 

  37. 37.

    Yin S, et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer. 2007;120(7):1444–50.

    CAS  Article  Google Scholar 

  38. 38.

    Yang ZF, et al. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology. 2008;47(3):919–28.

    CAS  Article  Google Scholar 

  39. 39.

    Yamashita T, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136(3):1012–1024. e4.

    CAS  Article  Google Scholar 

  40. 40.

    Haraguchi N, et al. CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest. 2010;120(9):3326–39.

    CAS  PubMed Central  Article  Google Scholar 

  41. 41.

    Yin AH, et al. AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood. 1997;90(12):5002–12.

    CAS  Google Scholar 

  42. 42.

    Grosse-Gehling P, et al. CD133 as a biomarker for putative cancer stem cells in solid tumours: limitations, problems and challenges. J Pathol. 2013;229(3):355–78.

    CAS  Article  Google Scholar 

  43. 43.

    Zheng Y-W, et al. The CD133+ CD44+ precancerous subpopulation of oval cells is a therapeutic target for hepatocellular carcinoma. Stem Cells dev. 2014;23(18):2237–49.

    CAS  PubMed Central  Article  Google Scholar 

  44. 44.

    Tang KH, et al. CD133+ liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology. 2012;55(3):807–20.

    CAS  Article  Google Scholar 

  45. 45.

    Marhaba R, Zöller M. CD44 in cancer progression: adhesion, migration and growth regulation. J Mol Histol. 2004;35(3):211–31.

    CAS  Article  Google Scholar 

  46. 46.

    Afify A, Purnell P, Nguyen L. Role of CD44s and CD44v6 on human breast cancer cell adhesion, migration, and invasion. Exp Mol Pathol. 2009;86(2):95–100.

    CAS  Article  Google Scholar 

  47. 47.

    van der Windt GJ, et al. CD44 is protective during hyperoxia-induced lung injury. Am J Respir Cell Mol Biol. 2011;44(3):377–83.

    Article  Google Scholar 

  48. 48.

    Zhu Z, et al. Cancer stem/progenitor cells are highly enriched in CD133+ CD44+ population in hepatocellular carcinoma. Int J Cancer. 2010;126(9):2067–78.

    CAS  Google Scholar 

  49. 49.

    Reif AE, Allen JM. The AKR thymic antigen and its distribution in leukemias and nervous tissues. J Exp med. 1964;120(3):413–33.

    CAS  PubMed Central  Article  Google Scholar 

  50. 50.

    Mima K, et al. CD44s regulates the TGF-β–mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer res. 2012;72(13):3414–23.

    CAS  Article  Google Scholar 

  51. 51.

    Ishimoto T, et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc− and thereby promotes tumor growth. Cancer Cell. 2011;19(3):387–400.

    CAS  Article  Google Scholar 

  52. 52.

    Lu J-W, et al. Overexpression of Thy1/CD90 in human hepatocellular carcinoma is associated with HBV infection and poor prognosis. Acta Histochem. 2011;113(8):833–8.

    CAS  Article  Google Scholar 

  53. 53.

    Went PT, et al. Frequent EpCam protein expression in human carcinomas. Hum Pathol. 2004;35(1):122–8.

    CAS  Article  Google Scholar 

  54. 54.

    Kim JW, et al. Cancer-associated molecular signature in the tissue samples of patients with cirrhosis. Hepatology. 2004;39(2):518–27.

    CAS  Article  Google Scholar 

  55. 55.

    Yamashita T, et al. Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma. Hepatology. 2013;57(4):1484–97.

    CAS  Article  Google Scholar 

  56. 56.

    Kurtz J-E, Dufour P. Adecatumumab: an anti-EpCAM monoclonal antibody, from the bench to the bedside. Expert Opin Biol Ther. 2010;10(6):951–8.

    CAS  Article  Google Scholar 

  57. 57.

    Gires O, Bauerle PA. EpCAM as a target in cancer therapy. J Clin Oncol. 2010;28(15):e239–40.

    Article  Google Scholar 

  58. 58.

    Mina-Osorio P. The moonlighting enzyme CD13: old and new functions to target. Trends Mol med. 2008;14(8):361–71.

    CAS  Article  Google Scholar 

  59. 59.

    Kim HM, et al. Increased CD13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial–mesenchymal transition-like phenomenon. Ann Surg Oncol. 2012;19(3):539–48.

    Article  Google Scholar 

Download references


The study was supported by a grant of The Scientific and Technological Research Council of Turkey (TUBITAK) to Tamer Yagci (111S484). The authors apologize to those investigators whose meritorious works were not cited due to space limitations.

Author information



Corresponding author

Correspondence to Tamer Yagci.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yagci, T., Cetin, M. & Ercin, P.B. Cancer Stem Cells in Hepatocellular Carcinoma. J Gastrointest Canc 48, 241–245 (2017).

Download citation


  • Hepatocellular carcinoma
  • Cancer stem cells
  • Cancer stem cell markers
  • Tumor heterogeneity
  • Tumor recurrence
  • Metastasis