Liver Tumor-Initiating Cells/Cancer Stem Cells: Past Studies, Current Status, and Future Perspectives



In the past decade, the hypothesis of tumor-initiating cell (TIC) or cancer stem cell (CSC)-driven tumorigenesis has been widely acknowledged in both hematological malignancies as well as solid epithelial tumors. In this chapter, we will first review in detail the current scientific knowledge in CSC research in hepatocellular carcinoma (HCC) and the molecular machinery underlying CSC-driven hepatocarcinogenesis. We will then discuss the relevance of liver cancer stem cells to the diagnosis and treatment of the disease and finally, consider the outstanding challenges and potential opportunities that remain ahead of us.


Cancer Stem Cell Side Population Huh7 Cell Side Population Cell Liver Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Bracken AP, Helin K (2009) Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer 9:773–784.PubMedCrossRefGoogle Scholar
  2. Budhu A, Jia HL, Forgues M et al (2008) Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 47:897–907.PubMedCrossRefGoogle Scholar
  3. Challen GA, Little MH (2006) A side order of stem cells: the SP phenotype. Stem Cells 24:3–12.PubMedCrossRefGoogle Scholar
  4. Chiba T, Kita K, Zheng YW, et al (2006) Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 44:240–251.PubMedCrossRefGoogle Scholar
  5. Chiba T, Miyagi S, Saraya A, et al (2008) The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res 68: 7742–7749.PubMedCrossRefGoogle Scholar
  6. de Boer CJ, van Krieken JH, Janssen-van Rhijn CM, et al (1999) Expression of Ep-CAM in normal, regenerating, metaplastic, and neoplastic liver. J Pathol 188:201–206.PubMedCrossRefGoogle Scholar
  7. deSano JT, Xu L (2009) microRNA regulation of cancer stem cells and therapeutic implications. The AAPS Journal 11:682–692.PubMedCrossRefGoogle Scholar
  8. Esquela-Kerscher A, Slack FJ (2006) Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 6:259–269.PubMedCrossRefGoogle Scholar
  9. Frank NY, Schatton T, Frank MH (2010) The therapeutic promise of the cancer stem cell concept. J Clin Invest 120:41–50.PubMedCrossRefGoogle Scholar
  10. Goodell MA, Brose K, Paradis G, et al (1996) Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183:1797–1806.PubMedCrossRefGoogle Scholar
  11. Haraguchi N, Utsunomiya T, Inoue H, et al (2006) Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 24:506–513.PubMedCrossRefGoogle Scholar
  12. Hess DA, Wirthlin L, Craft TP, et al (2006) Selection based on CD133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells. Blood 107: 2162–2169.PubMedCrossRefGoogle Scholar
  13. Iwama A, Oguro H, Negishi M, et al (2004) Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21:843–851.PubMedCrossRefGoogle Scholar
  14. Ji J, Yamashita T, Budhu A, et al (2009) Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology 50:472–480.PubMedCrossRefGoogle Scholar
  15. Kim JW, Ye Q, Forgues M, et al (2004) Cancer-associated molecular signature in the tissue samples of patients with cirrhosis. Hepatology 39:518–527.PubMedCrossRefGoogle Scholar
  16. Ma S, Chan KW, Hu L, et al (2007) Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132:2542–2556.PubMedCrossRefGoogle Scholar
  17. Ma S, Lee TK, Zheng BJ, et al (2008a) CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27:1749–1758.PubMedCrossRefGoogle Scholar
  18. Ma S, Chan KW, Lee TK, et al (2008b) Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res 6:1146–1153.PubMedCrossRefGoogle Scholar
  19. Ma S, Tang KH, Chan YP, et al (2010) miR-130b promotes CD133+ liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell 7:694–707.PubMedCrossRefGoogle Scholar
  20. Molofsky AV, Pardal R, Iwashita T, et al (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425:962–967.PubMedCrossRefGoogle Scholar
  21. Moserle L, Ghisi M, Amadori A, et al (2010) Side population and cancer stem cells: therapeutic implications. Cancer Lett 288:1–9.PubMedCrossRefGoogle Scholar
  22. Park IK, Qian D, Kiel M, et al (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423:302–305.PubMedCrossRefGoogle Scholar
  23. Pearce DJ, Taussig D, Simpson C, et al (2005) Characterization of cells with a high aldehyde dehydrogenase activity from cord blood and acute myeloid leukemia samples. Stem Cells 23:752–60.PubMedCrossRefGoogle Scholar
  24. Song W, Li H, Tao K, et al (2008) Expression and clinical significance of the stem cell marker CD133 in hepatocellular carcinoma. Int J Clin Pract 62:1212–1218.PubMedCrossRefGoogle Scholar
  25. Suetsugu A, Nagaki M, Aoki H, et al (2006) Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun 351:820–824.PubMedCrossRefGoogle Scholar
  26. Tang Y, Kitisin K, Jogunoori W, et al (2008) Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling. Proc Natl Acad Sci USA 105:2445–2450.PubMedCrossRefGoogle Scholar
  27. Yamashita T, Forgues M, Wang W, et al (2008) EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 68:1451–1461.PubMedCrossRefGoogle Scholar
  28. Yamashita T, Ji J, Budhu A, et al (2009) EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 136:1012–1024.PubMedCrossRefGoogle Scholar
  29. Yang W, Yan HX, Chen L, et al (2008a) Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res 68:4287–4295.PubMedCrossRefGoogle Scholar
  30. Yang ZF, Ngai P, Ho DW, et al (2008b) Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 47:919–928.PubMedCrossRefGoogle Scholar
  31. Yang ZF, Ho DW, Ng MN, et al (2008c) Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13:153–166.PubMedCrossRefGoogle Scholar
  32. Yin S, Li J, Hu C, et al (2007) CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 120:1444–1450.PubMedCrossRefGoogle Scholar
  33. You H, Ding W, Rountree CB (2010) Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-beta. Hepatology 51:1635–1644.PubMedCrossRefGoogle Scholar
  34. Zhou BB, Zhang H, Damelin M, et al (2009) Tumor-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 8:806–823.PubMedCrossRefGoogle Scholar
  35. Zhu Z, Hao X, Yan M, et al (2010) Cancer stem/progenitor cells are highly enriched in CD133(+)CD44(+) population in hepatocellular carcinoma. Int J Cancer 126:2067–2078.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Pathology , Li Ka Shing Faculty of Medicine, Queen Mary HospitalThe University of Hong KongPok Fu LamHong Kong
  2. 2.Department of Clinical Oncology , Li Ka Shing Faculty of Medicine, Queen Mary HospitalThe University of Hong KongPok Fu LamHong Kong

Personalised recommendations