Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Turning Hepatic Cancer Stem Cells Inside Out - A Deeper Understanding through Multiple Perspectives

  • Chan, Lok-Hei (Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong) ;
  • Luk, Steve T. (Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong) ;
  • Ma, Stephanie (Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong)
  • Received : 2014.12.30
  • Accepted : 2015.01.02
  • Published : 2015.03.31
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Abstract

Hepatocellular carcinoma (HCC), a highly malignant disease and the third leading cause of all cancer mortalities worldwide, often responses poorly to current treatments and results in dismal outcomes due to frequent chemoresistance and tumor relapse. The heterogeneity of HCC is an important attribute of the disease. It is the outcome of many factors, including the cross-talk between tumor cells within the tumor microenvironment and the acquisition and accumulation of genetic and epigenetic alterations in tumor cells. In addition, there is accumulating evidence in recent years to show that the malignancy of HCC can be attributed partly to the presence of cancer stem cell (CSC). CSCs are capable to self-renew, differentiate and initiate tumor formation. The regulation of the stem cell-like properties by several important signaling pathways have been found to endow the tumor cells with an increased level of tumorigenicity, chemoresistance, and metastatic ability. In this review, we will discuss the recent findings on hepatic CSCs, with special emphasis on their putative origins, relationship with hepatitis viruses, regulatory signaling networks, tumor microenvironment, and how these factors control the stemness of hepatic CSCs. We will also discuss some novel therapeutic strategies targeted at hepatic CSCs for combating HCC and perspectives of future investigation.

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References

  1. Akita, H., Marquardt, J.U., Durkin, M.E., Kitade, M., Seo, D., Conner, E.A., Andersen, J.B., Factor, V.M., and Thorgeirsson, S.S. (2014). MYC activates stem-like cell potential in hepatocarcinoma by a p53-dependent mechanism. Cancer Res. 74, 5903-5913. https://doi.org/10.1158/0008-5472.CAN-14-0527
  2. Ali, N., Allam, H., May, R., Sureban, S.M., Bronze, M.S., Bader, T., Umar, S., Anant, S., and Houchen, C.W. (2011). Hepatitis C virus-induced cancer stem cell-like signatures in cell culture and murine tumor xenografts. J. Virol. 85, 12292-12303. https://doi.org/10.1128/JVI.05920-11
  3. Altekruse, S.F., McGlynn, K.A., and Reichman, M.E. (2009). Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J. Clin. Oncol. 27, 1485-1491. https://doi.org/10.1200/JCO.2008.20.7753
  4. Arzumanyan, A., Friedman, T., Ng, I., Clayton, M., Lian, Z., and Feitelson, M. (2011). Does the hepatitis B antigen HBx promote the appearance of liver cancer stem cells. Cancer Res. 71, 3701-3708 https://doi.org/10.1158/0008-5472.CAN-10-3951
  5. Avila, M.A., Berasain, C., Torres, L., Martin-Duce, A., Corrales, F.J., Yang, H., Prieto, J., Lu, S.C., Caballeria, J., Rodes, J., et al. (2000). Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J. Hepatol. 33, 907-914. https://doi.org/10.1016/S0168-8278(00)80122-1
  6. Bach, P., Abel, T., Hoffmann, C., Gal, Z., Braun, G., Voelker, I., Ball, C.R., Johnston, I.C., Lauer, U.M., Herold-Mende, C., et al. (2013). Specific elimination of CD133+ tumor cells with targeted oncolytic measles virus. Cancer Res. 73, 865-874. https://doi.org/10.1158/0008-5472.CAN-12-2221
  7. Bartosch, B., Thimme, R., Blum, H.E., and Zoulim, F. (2009). Hepatitis C virus-induced hepatocarcinogenesis. J. Hepatol. 51, 810-820. https://doi.org/10.1016/j.jhep.2009.05.008
  8. Cai, J., Sun, W.M., Hwang, J.J., Stain, S.C., and Lu, S.C. (1996). Changes in S-adenosylmethionine synthetase in human liver cancer: molecular characterization and significance. Hepatology 24, 1090-1097 https://doi.org/10.1002/hep.510240519
  9. Chai, S., Tong, M., Ng, K.Y., Kwan, P.S., Chan, Y.P., Fung, T.M., Lee, T.K., Wong, N., Xie, D., Yuan, Y.F., et al. (2014). Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133. Oncotarget 5, 5725-5735. https://doi.org/10.18632/oncotarget.2167
  10. Chen, H., Luo, Z., Dong, L., Tan, Y., Yang, J., Feng, G., Wu, M., Li, Z., and Wang, H. (2013a). CD133/prominin-1-mediated autophagy and glucose uptake beneficial for hepatoma cell survival. PLoS One 8, e56878 https://doi.org/10.1371/journal.pone.0056878
  11. Chen, H., Luo, Z., Sun, W., Zhang, C., Sun, H., Zhao, N., Ding, J., Wu, M., Li, Z., and Wang, H. (2013b). Low glucose promotes CD133 mAb-elicited cell death via inhibition of autophagy in hepatocarcinoma cells. Cancer Lett. 336, 204-212. https://doi.org/10.1016/j.canlet.2013.04.031
  12. Cheung, P.F., Cheng, C.K., Wong, N.C., Ho, J.C., Yip, C.W., Lui, V.C., Cheung, A.N., Fan, S.T., and Cheung, S.T. (2011). Granulin-epithelin precursor is an oncofetal protein defining hepatic cancer stem cells. PLoS One 6, e28246. https://doi.org/10.1371/journal.pone.0028246
  13. Chiba, T., Kita, K., Zheng, Y.W., Yokosuka, O., Saisho, H., Iwama, A., Nakauchi, H., and Taniguchi, H. (2006). Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 44, 240-251.
  14. Chiba, T., Suzuki, E., Negishi, M., Saraya, A., Miyagi, S., Konuma, T., Tanaka, S., Tada, M., Kanai, F., Imazeki, F., et al. (2012). 3-Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor-initiating hepatocellular carcinoma cells. Int. J. Cancer 130, 2557-2567 https://doi.org/10.1002/ijc.26264
  15. Chiba, T., Suzuki, E., Yuki, K., Zen, Y., Oshima, M., Miyagi, S., Saraya, A., Koide, S., Motoyama, T., Ogasawara, S., et al. (2014). Disulfiram eradicates tumor-initiating hepatocellular carcinoma cells in ROS-p38 MAPK pathway-dependent and-independent manners. PLoS One 9, e84807 https://doi.org/10.1371/journal.pone.0084807
  16. Ding, W., Mouzaki, M., You, H., Laird, J.C., Mato, J., Lu, S.C., and Rountree, C.B. (2009). CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-beta-induced apoptosis. Hepatology 49, 1277-1286. https://doi.org/10.1002/hep.22743
  17. Ezzeldin, M., Borrego-Diaz, E., Taha, M., Esfandyari, T., Wise, A.L., Peng, W., Rouyanian, A., Asvadi Kermani, A., Soleimani, M., Patrad, E., et al. (2014). RalA signaling pathway as a therapeutic target in hepatocellular carcinoma (HCC). Mol. Oncol. 8, 1043-1053. https://doi.org/10.1016/j.molonc.2014.03.020
  18. Fan, Q.M., Jing, Y.Y., Yu, G.F., Kou, X.R., Ye, F., Gao, L., Li, R., Zhao, Q.D., Yang, Y., Lu, Z.H., et al. (2014). Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 352, 160-168 https://doi.org/10.1016/j.canlet.2014.05.008
  19. Gleiberman, A.S., Encinas, J.M., Mignone, J.L., Michurina, T., Rosenfeld, M.G., and Enikolopov, G. (2005). Expression of nestin-green fluorescent protein transgene marks oval cells in the adult liver. Dev. Dyn. 234, 413-421. https://doi.org/10.1002/dvdy.20536
  20. Hagiwara, S., Kudo, M., Nagai, T., Inoue, T., Ueshima, K., Nishida, N., Watanabe, T., and Sakurai, T. (2012). Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma. Br. J. Cancer 106, 1997-2003. https://doi.org/10.1038/bjc.2012.145
  21. Haraguchi, N., Ishii, H., Mimori, K., Tanaka, F., Ohkuma, M., Kim, H.M., Akita, H., Takiuchi, D., Hatano, H., Nagano, H., et al. (2010). CD13 is a therapeutic target in human liver cancer stem cells. J. Clin. Invest. 120, 3326-3339 https://doi.org/10.1172/JCI42550
  22. He, G., Dhar, D., Nakagawa, H., Font-Burgada, J., Ogata, H., Jiang, Y., Shalapour, S., Seki, E., Yost, S.E., Jepsen, K., et al. (2013). Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 155, 384-396. https://doi.org/10.1016/j.cell.2013.09.031
  23. Holczbauer, A., Factor, V.M., Andersen, J.B., Marquardt, J.U., Kleiner, D.E., Raggi, C., Kitade, M., Seo, D., Akita, H., Durkin, M.E., et al. (2013). Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types. Gastroenterology 145, 221-231. https://doi.org/10.1053/j.gastro.2013.03.013
  24. Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E., and Forman, D. (2011). Global cancer statistics. CA Cancer J. Clin. 61, 69-90. https://doi.org/10.3322/caac.20107
  25. Kreso, A. and Dick, J.E. (2014). Evolution of the cancer stem cell model. Cell Stem Cell 14, 275-291. https://doi.org/10.1016/j.stem.2014.02.006
  26. Lai, K.P., Chen, J., He, M., Ching, A.K., Lau, C., Lai, P.B., To, K.F., and Wong, N. (2014). Overexpression of ZFX confers self-renewal and chemoresistance properties in hepatocellular carcinoma. Int. J. Cancer 135, 1790-1799 https://doi.org/10.1002/ijc.28819
  27. Lee, T.K., Castilho, A., Cheung, V.C., Tang, K.H., Ma, S., and Ng, I.O. (2011). CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell 9, 50-63. https://doi.org/10.1016/j.stem.2011.06.005
  28. Lee, T.K., Cheung, V.C., Lu, P., Lau, E.Y., Ma, S., Tang, K.H., Tong, M., Lo, J., and Ng, I.O. (2014a). Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology 60, 179-191. https://doi.org/10.1002/hep.27070
  29. Lee, Y.H., Seo, D., Choi, K.J., Andersen, J.B., Won, M.A., Kitade, M., Gomez-Quiroz, L.E., Judge, A.D., Marquardt, J.U., Raggi, C., et al. (2014b). Antitumor effects in hepatocarcinoma of isoformselective inhibition of HDAC2. Cancer Res. 74, 4752-4761. https://doi.org/10.1158/0008-5472.CAN-13-3531
  30. Levrero, M. (2006). Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene 25, 3834-3847 https://doi.org/10.1038/sj.onc.1209562
  31. Li, C.H., Wang, Y.J., Dong, W., Xiang, S., Liang, H.F., Wang, H.Y., Dong, H.H., Chen, L., and Chen, X.P. (2011). Hepatic oval cell lines generate hepatocellular carcinoma following transfection with HBx gene and treatment with aflatoxin B1 in vivo. Cancer Lett. 311, 1-10. https://doi.org/10.1016/j.canlet.2011.05.035
  32. Li, L., Liu, Y., Guo, Y., Liu, B., Zhao, Y., Li, P., Song, F., Zheng, H., Yu, J., Song, T., et al. (2014). Regulatory miR-148a-ACVR1/BMP circuit defines a cancer stem cell-like aggressive subtype of hepatocellular carcinoma. Hepatology [Epub ahead of print].
  33. Liu, C., Liu, L., Shan, J., Shen, J., Xu, Y., Zhang, Q., Yang, Z., Wu, L., Xia, F., Bie, P., et al. (2013a). Histone deacetylase 3 participates in self-renewal of liver cancer stem cells through histone modification. Cancer Lett. 339, 60-69 https://doi.org/10.1016/j.canlet.2013.07.022
  34. Liu, L., Yang, Z., Xu, Y., Li, J., Xu, D., Zhang, L., Sun, J., Xia, S., Zou, F., and Liu, Y. (2013b). Inhibition of oxidative stress-elicited AKT activation facilitates PPARgamma agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells. PLoS One 8, e73038 https://doi.org/10.1371/journal.pone.0073038
  35. Liu, A.Y., Cai, Y., Mao, Y., Lin, Y., Zheng, H., Wu, T., Huang, Y., Fang, X., Lin, S., Feng, Q., et al. (2014). Twist2 promotes selfrenewal of liver cancer stem-like cells by regulating CD24. Carcinogenesis 35, 537-545. https://doi.org/10.1093/carcin/bgt364
  36. Ma, S., Chan, K.W., Hu, L., Lee, T.K., Wo, J.Y., Ng, I.O., Zheng, B.J., and Guan, X.Y. (2007). Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132, 2542-2556. https://doi.org/10.1053/j.gastro.2007.04.025
  37. Ma, S., Chan, K.W., Lee, T.K., Tang, K.H., Wo, J.Y., Zheng, B.J., and Guan, X.Y. (2008a). Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol. Cancer Res. 6, 1146-1153. https://doi.org/10.1158/1541-7786.MCR-08-0035
  38. Ma, S., Lee, T.K., Zheng, B.J., Chan, K.W., and Guan, X.Y. (2008b). CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27, 1749-1758 https://doi.org/10.1038/sj.onc.1210811
  39. Ma, S., Tang, K.H., Chan, Y.P., Lee, T.K., Kwan, P.S., Castilho, A., Ng, I., Man, K., Wong, N., To, K.F., et al. (2010). miR-130b Promotes CD133(+) liver tumor-initiating cell growth and selfrenewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell 7, 694-707 https://doi.org/10.1016/j.stem.2010.11.010
  40. Marquardt, J.U., Raggi, C., Andersen, J.B., Seo, D., Avital, I., Geller, D., Lee, Y.H., Kitade, M., Holczbauer, A., Gillen, M.C., et al. (2011). Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways. Hepatology 54, 1031-1042. https://doi.org/10.1002/hep.24454
  41. Martin-Padura, I., Marighetti, P., Agliano, A., Colombo, F., Larzabal, L., Redrado, M., Bleau, A.M., Prior, C., Bertolini, F., and Calvo, A. (2012). Residual dormant cancer stem-cell foci are responsible for tumor relapse after antiangiogenic metronomic therapy in hepatocellular carcinoma xenografts. Lab. Invest. 92, 952-966. https://doi.org/10.1038/labinvest.2012.65
  42. Mima, K., Okabe, H., Ishimoto, T., Hayashi, H., Nakagawa, S., Kuroki, H., Watanabe, M., Beppu, T., Tamada, M., Nagano, O., et al. (2012). CD44s regulates the TGF-beta-mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res. 72, 3414-3423. https://doi.org/10.1158/0008-5472.CAN-12-0299
  43. Mokkapati, S., Niopek, K., Huang, L., Cunniff, K.J., Ruteshouser, E.C., deCaestecker, M., Finegold, M.J., and Huff, V. (2014). Betacatenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma. Cancer Res. 74, 4515-4525. https://doi.org/10.1158/0008-5472.CAN-13-3275
  44. Morris, S.M., Carter, K.T., Baek, J.Y., Koszarek, A., Yeh, M.M., Knoblaugh, S.E., and Grady, W.M. (2014). TGF-beta signaling alters the pattern of liver tumorigenesis induced by Pten inactivation. Oncogene [Epub ahead of print].
  45. Neuveut, C., Wei, Y., and Buendia, M.A. (2010). Mechanisms of HBV-related hepatocarcinogenesis. J. Hepatol. 52, 594-604. https://doi.org/10.1016/j.jhep.2009.10.033
  46. Nik-Zainal, S., Van Loo, P., Wedge, D.C., Alexandrov, L.B., Greenman, C.D., Lau, K.W., Raine, K., Jones, D., Marshall, J., Ramakrishna, M., et al. (2012). The life history of 21 breast cancers. Cell 149, 994-1007 https://doi.org/10.1016/j.cell.2012.04.023
  47. Piao, L.S., Hur, W., Kim, T.K., Hong, S.W., Kim, S.W., Choi, J.E., Sung, P.S., Song, M.J., Lee, B.C., Hwang, D., et al. (2012). CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer Lett. 315, 129-137 https://doi.org/10.1016/j.canlet.2011.10.012
  48. Raggi, C., Factor, V.M., Seo, D., Holczbauer, A., Gillen, M.C., Marquardt, J.U., Andersen, J.B., Durkin, M., and Thorgeirsson, S.S. (2014). Epigenetic reprogramming modulates malignant properties of human liver cancer. Hepatology 59, 2251-2262. https://doi.org/10.1002/hep.27026
  49. Rountree, C.B., Senadheera, S., Mato, J.M., Crooks, G.M., and Lu, S.C. (2008). Expansion of liver cancer stem cells during aging in methionine adenosyltransferase 1A-deficient mice. Hepatology 47, 1288-1297
  50. Saito, T., Chiba, T., Yuki, K., Zen, Y., Oshima, M., Koide, S., Motoyama, T., Ogasawara, S., Suzuki, E., Ooka, Y., et al. (2013). Metformin, a diabetes drug, eliminates tumor-initiating hepatocellular carcinoma cells. PLoS One 8, e70010. https://doi.org/10.1371/journal.pone.0070010
  51. Schrader, J., Gordon-Walker, T.T., Aucott, R.L., van Deemter, M., Quaas, A., Walsh, S., Benten, D., Forbes, S.J., Wells, R.G., and Iredale, J.P. (2011). Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology 53, 1192-1205. https://doi.org/10.1002/hep.24108
  52. Shan, J., Shen, J., Liu, L., Xia, F., Xu, C., Duan, G., Xu, Y., Ma, Q., Yang, Z., Zhang, Q., et al. (2012) Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma. Hepatology 56, 1004-1014. https://doi.org/10.1002/hep.25745
  53. Song, Y.J., Zhang, S.S., Guo, X.L., Sun, K., Han, Z.P., Li, R., Zhao, Q.D., Deng, W.J., Xie, X.Q., Zhang, J.W., et al. (2013). Autophagy contributes to the survival of CD133+ liver cancer stem cells in the hypoxic and nutrient-deprived tumor microenvironment. Cancer Lett. 339, 70-81. https://doi.org/10.1016/j.canlet.2013.07.021
  54. Sosa, M.S., Bragado, P., and Aguirre-Ghiso, J.A. (2014). Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat. Rev. Cancer 14, 611-622. https://doi.org/10.1038/nrc3793
  55. Sun, Z., Lu, P., Gail, M., Pee, D., Zhang, Q., Ming, L., Wang, J., Wu, Y., Liu, G., and Zhu, Y. (1999). Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. Hepatology 30, 379-383. https://doi.org/10.1002/hep.510300204
  56. Sun, J.C., Pan, K., Chen, M.S., Wang, Q.J., Wang, H., Ma, H.Q., Li, Y.Q., Liang, X.T., Li, J.J., Zhao, J.J., et al. (2010). Dendritic cells-mediated CTLs targeting hepatocellular carcinoma stem cells. Cancer Biol. Ther. 10, 368-375. https://doi.org/10.4161/cbt.10.4.12440
  57. Sun, Y.F., Xu, Y., Yang, X.R., Guo, W., Zhang, X., Qiu, S.J., Shi, R.Y., Hu, B., Zhou, J., and Fan, J. (2013). Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology 57, 1458-1468 https://doi.org/10.1002/hep.26151
  58. Tang, H., Delgermaa, L., Huang, F., Oishi, N., Liu, L., He, F., Zhao, L., and Murakami, S. (2005). The transcriptional transactivation function of HBx protein is important for its augmentation role in hepatitis B virus replication. J. Virol. 79, 5548-5556. https://doi.org/10.1128/JVI.79.9.5548-5556.2005
  59. Tang, K.H., Ma, S., Lee, T.K., Chan, Y.P., Kwan, P.S., Tong, C.M., Ng, I.O., Man, K., To, K.F., Lai, P.B., et al. (2012). CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology 55, 807-820. https://doi.org/10.1002/hep.24739
  60. Tschaharganeh, D.F., Xue, W., Calvisi, D.F., Evert, M., Michurina, T.V., Dow, L.E., Banito, A., Katz, S.F., Kastenhuber, E.R., Weissmueller, S., et al. (2014). p53-dependent nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell 158, 579-592. https://doi.org/10.1016/j.cell.2014.05.051
  61. Wan, S., Zhao, E., Kryczek, I., Vatan, L., Sadovskaya, A., Ludema, G., Simeone, D.M., Zou, W., and Welling, T.H. (2014). Tumorassociated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147, 1393-1404. https://doi.org/10.1053/j.gastro.2014.08.039
  62. Wang, X.Q., Ongkeko, W.M., Chen, L., Yang, Z.F., Lu, P., Chen, K.K., Lopez, J.P., Poon, R.T., and Fan, S.T. (2010). Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4-AKT-ATP-binding cassette G2 pathway. Hepatology 52, 528-539 https://doi.org/10.1002/hep.23692
  63. Wang, C., Yang, W., Yan, H.X., Luo, T., Zhang, J., Tang, L., Wu, F.Q., Zhang, H.L., Yu, L.X., Zheng, L.Y., et al. (2012). Hepatitis B virus X (HBx) induces tumorigenicity of hepatic progenitor cells in 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated HBx transgenic mice. Hepatology 55, 108-120. https://doi.org/10.1002/hep.24675
  64. Wang, X.Q., Ng, R.K., Ming, X., Zhang, W., Chen, L., Chu, A.C., Pang, R., Lo, C.M., Tsao, S.W., Liu, X., et al. (2013). Epigenetic regulation of pluripotent genes mediates stem cell features in human hepatocellular carcinoma and cancer cell lines. PLoS One 8, e72435. https://doi.org/10.1371/journal.pone.0072435
  65. Wu, K., Ding, J., Chen, C., Sun, W., Ning, B.F., Wen, W., Huang, L., Han, T., Yang, W., Wang, C., et al. (2012). Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development. Hepatology 56, 2255-2267 https://doi.org/10.1002/hep.26007
  66. Wurmbach, E., Chen, Y.B., Khitrov, G., Zhang, W., Roayaie, S., Schwartz, M., Fiel, I., Thung, S., Mazzaferro, V., Bruix, J., et al. (2007). Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 45, 938-947 https://doi.org/10.1002/hep.21622
  67. Xia, H., Ooi, L.L., and Hui, K.M. (2013). MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology 58, 629-641. https://doi.org/10.1002/hep.26369
  68. Xu, X., Xing, B., Hu, M., Xu, Z., Xie, Y., Dai, G., Gu, J., Wang, Y., and Zhang, Z. (2010). Recurrent hepatocellular carcinoma cells with stem cell-like properties: possible targets for immunotherapy. Cytotherapy 12, 190-200. https://doi.org/10.3109/14653240903390803
  69. Yamashita, T., Ji, J., Budhu, A., Forgues, M., Yang, W., Wang, H.Y., Jia, H., Ye, Q., Qin, L.X., Wauthier, E., et al. (2009). EpCAMpositive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 136, 1012-1024. https://doi.org/10.1053/j.gastro.2008.12.004
  70. Yang, Z.F., Ho, D.W., Ng, M.N., Lau, C.K., Yu, W.C., Ngai, P., Chu, P.W., Lam, C.T., Poon, R.T., and Fan, S.T. (2008). Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13, 153-166. https://doi.org/10.1016/j.ccr.2008.01.013
  71. Yang, Z., Zhang, L., Ma, A., Liu, L., Li, J., Gu, J., and Liu, Y. (2011). Transient mTOR inhibition facilitates continuous growth of liver tumors by modulating the maintenance of CD133+ cell populations. PLoS One 6, e28405. https://doi.org/10.1371/journal.pone.0028405
  72. Yang, W., Wang, C., Lin, Y., Liu, Q., Yu, L.X., Tang, L., Yan, H.X., Fu, J., Chen, Y., Zhang, H.L., et al. (2012). OV6(+) tumorinitiating cells contribute to tumor progression and invasion in human hepatocellular carcinoma. J. Hepatol. 57, 613-620. https://doi.org/10.1016/j.jhep.2012.04.024
  73. You, H., Ding, W., and Rountree, C.B. (2010). Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-beta. Hepatology 51, 1635-1644. https://doi.org/10.1002/hep.23544
  74. Zhang, L., Sun, H., Zhao, F., Lu, P., Ge, C., Li, H., Hou, H., Yan, M., Chen, T., Jiang, G., et al. (2012). BMP4 administration induces differentiation of CD133+ hepatic cancer stem cells, blocking their contributions to hepatocellular carcinoma. Cancer Res. 72, 4276-4285. https://doi.org/10.1158/0008-5472.CAN-12-1013
  75. Zhang, L., Li, H., Ge, C., Li, M., Zhao, F.Y., Hou, H.L., Zhu, M.X., Tian, H., Zhang, L.X., Chen, T.Y., et al. (2014). Inhibitory effects of transcription factor Ikaros on the expression of liver cancer stem cell marker CD133 in hepatocellular carcinoma. Oncotarget 15, 10621-10635.
  76. Zhao, W., Wang, L., Han, H., Jin, K., Lin, N., Guo, T., Chen, Y., Cheng, H., Lu, F., Fang, W., et al. (2013). 1B50-1, a mAb raised against recurrent tumor cells, targets liver tumor-initiating cells by binding to the calcium channel ${\alpha}2{\delta}1$ subunit. Cancer Cell 23, 541-556. https://doi.org/10.1016/j.ccr.2013.02.025

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