Table of Contents Author Guidelines Submit a Manuscript
Analytical Cellular Pathology
Volume 2017, Article ID 5108653, 9 pages
https://doi.org/10.1155/2017/5108653
Review Article

The Recent Advances on Liver Cancer Stem Cells: Biomarkers, Separation, and Therapy

1Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu 225300, China
2School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, Hubei 430000, China

Correspondence should be addressed to Mei Lin; moc.361@iem_l

Received 21 March 2017; Accepted 5 July 2017; Published 27 July 2017

Academic Editor: Neng Wang

Copyright © 2017 Yanhong Xiao et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. R. de Lope, S. Tremosini, A. Forner, M. Reig, and J. Bruix, “Management of HCC,” Journal of Hepatology, vol. 56, Supplement 1, pp. S75–S87, 2012. View at Google Scholar
  2. A. Forner, J. M. Llovet, and J. Bruix, “Hepatocellular carcinoma,” Lancet, vol. 379, pp. 1245–1255, 2012. View at Publisher · View at Google Scholar · View at Scopus
  3. T. Reya, S. J. Morrison, M. F. Clarke, and I. L. Weissman, “Stem cells, cancer, and cancer stem cells,” Nature, vol. 414, no. 6859, pp. 105–111, 2011. View at Google Scholar
  4. W. Song, H. Li, K. Tao et al., “Expression and clinical significance of the stem cell marker CD133 in hepatocellular carcinoma,” International Journal of Clinical Practice, vol. 62, no. 8, pp. 1212–1218, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. Y. Hori, “Prominin-1 (CD133) reveals new faces of pancreatic progenitor cells and cancer stem cells: current knowledge and therapeutic perspectives,” Advances in Experimental Medicine and Biology, vol. 777, pp. 185–196, 2013. View at Google Scholar
  6. A. Suetsugu, M. Nagaki, H. Aoki, T. Motohashi, T. Kunisada, and H. Moriwaki, “Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells,” Biochemical and Biophysical Research Communications, vol. 351, pp. 820–824, 2006. View at Publisher · View at Google Scholar · View at Scopus
  7. C. B. Rountree, W. Ding, L. He, and B. Stiles, “Expansion of CD133-expressing liver cancer stem cells in liver-specific phosphatase and tensin homolog deleted on chromosome 10-deleted mice,” Stem Cells, vol. 27, no. 2, pp. 290–299, 2009. View at Publisher · View at Google Scholar · View at Scopus
  8. K. H. Tang, S. Ma, T. K. Lee et al., “CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling,” Hepatology, vol. 55, no. 3, pp. 807–820, 2012. View at Publisher · View at Google Scholar · View at Scopus
  9. Y. M. Liu, X. F. Li, H. Liu, and X. L. Wu, “Ultrasound-targeted microbubble destruction-mediated downregulation of CD133 inhibits epithelial-mesenchymal transition, stemness and migratory ability of liver cancer stem cells,” Oncology Reports, vol. 34, no. 6, pp. 2977–2986, 2015. View at Publisher · View at Google Scholar · View at Scopus
  10. J. Li, J. N. Chen, T. T. Zeng et al., “CD133+ liver cancer stem cells resist interferon-gamma-induced autophagy,” BMC Cancer, vol. 16, p. 15, 2016. View at Google Scholar
  11. W. Ding, M. Mouzaki, H. You et al., “CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-beta-induced apoptosis,” Hepatology, vol. 49, no. 4, pp. 1277–1286, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. S. Ma, T. K. Lee, B. J. Zheng, K. W. Chan, and X. Y. Guan, “CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway,” Oncogene, vol. 27, no. 12, pp. 1749–1758, 2008. View at Google Scholar
  13. S. Ma, K. W. Chan, T. K. Lee et al., “Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations,” Molecular Cancer Research, vol. 6, pp. 1146–1153, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. Z. F. Yang, D. W. Ho, M. N. Ng et al., “Significance of CD90+ cancer stem cells in human liver cancer,” Cancer Cell, vol. 13, pp. 153–166, 2008. View at Publisher · View at Google Scholar · View at Scopus
  15. Z. Zhu, X. Hao, M. Yan et al., “Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma,” International Journal of Cancer, vol. 126, pp. 2067–2078, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. K. Williams, K. Motiani, P. V. Giridhar, and S. Kasper, “CD44 integrates signaling in normal stem cell, cancer stem cell and (pre)metastatic niches,” Experimental Biology and Medicine (Maywood, N.J.), vol. 238, pp. 324–338, 2013. View at Publisher · View at Google Scholar · View at Scopus
  17. B. D. Chen, Y. F. Hui, H. B. Zhang, L. F. Fan, M. H. Si, and G. S. Yang, “Expression of CD90/EpCAM/CD24 in hepatocellular carcinoma cell lines at various stages of differentiation,” Zhonghua Gan Zang Bing Za Zhi, vol. 21, pp. 688–691, 2013. View at Google Scholar
  18. Z. F. Yang, P. Ngai, D. W. Ho et al., “Identification of local and circulating cancer stem cells in human liver cancer,” Hepatology, vol. 47, pp. 919–928, 2008. View at Publisher · View at Google Scholar · View at Scopus
  19. Q. Jia, X. Zhang, T. Deng, and J. Gao, “Positive correlation of Oct4 and ABCG2 to chemotherapeutic resistance in CD90(+)CD133(+) liver cancer stem cells,” Cellular Reprogramming, vol. 15, pp. 143–150, 2013. View at Publisher · View at Google Scholar · View at Scopus
  20. N. Haraguchi, H. Ishii, K. Mimori et al., “CD13 is a therapeutic target in human liver cancer stem cells,” The Journal of Clinical Investigation, vol. 120, pp. 3326–3339, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. H. M. Kim, N. Haraguchi, H. Ishii et al., “Increased CD13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon,” Annals of Surgical Oncology, vol. 19, Supplement 3, pp. S539–S548, 2012. View at Publisher · View at Google Scholar · View at Scopus
  22. M. Yamashita, H. Wada, H. Eguchi et al., “A CD13 inhibitor, ubenimex, synergistically enhances the effects of anticancer drugs in hepatocellular carcinoma,” International Journal of Oncology, vol. 49, pp. 89–98, 2016. View at Publisher · View at Google Scholar · View at Scopus
  23. T. Roskams, R. De Vos, P. Van Eyken, H. Myazaki, B. Van Damme, and V. Desmet, “Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man,” Journal of Hepatology, vol. 29, no. 3, pp. 455–463. View at Publisher · View at Google Scholar · View at Scopus
  24. W. Yang, H. X. Yan, L. Chen et al., “Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells,” Cancer Research, vol. 68, pp. 4287–4295, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. W. Yang, C. Wang, Y. Lin et al., “OV6(+) tumor-initiating cells contribute to tumor progression and invasion in human hepatocellular carcinoma,” Journal of Hepatology, vol. 57, pp. 613–620, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. T. Yamashita, A. Budhu, M. Forgues, and X. W. Wang, “Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma,” Cancer Research, vol. 67, pp. 10831–10839, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. T. Yamashita, J. Ji, A. Budhu et al., “EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features,” Gastroenterology, vol. 136, pp. 1012–1024, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. B. Terris, C. Cavard, and C. Perret, “EpCAM, a new marker for cancer stem cells in hepatocellular carcinoma,” Journal of Hepatology, vol. 52, pp. 280-281, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. T. Yamashita, M. Honda, Y. Nakamoto et al., “Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma,” Hepatology, vol. 57, pp. 1484–1497, 2013. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Zhou, J. D. Schuetz, K. D. Bunting et al., “The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype,” Nature Medicine, vol. 7, pp. 1028–1034, 2001. View at Publisher · View at Google Scholar · View at Scopus
  31. G. Zhang, Z. Wang, W. Luo, H. Jiao, J. Wu, and C. Jiang, “Expression of potential cancer stem cell marker ABCG2 is associated with malignant behaviors of hepatocellular carcinoma,” Gastroenterology Research and Practice, vol. 2013, Article ID 782581, 12 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  32. T. K. Lee, A. Castilho, V. C. Cheung, K. H. Tang, S. Ma, and I. O. Ng, “CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation,” Cell Stem Cell, vol. 9, pp. 50–63, 2011. View at Publisher · View at Google Scholar · View at Scopus
  33. A. Y. Liu, Y. Cai, Y. Mao et al., “Twist2 promotes self-renewal of liver cancer stem-like cells by regulating CD24,” Carcinogenesis, vol. 35, pp. 537–545, 2014. View at Publisher · View at Google Scholar · View at Scopus
  34. J. Huang, X. Zhang, M. Zhang et al., “Up-regulation of DLK1 as an imprinted gene could contribute to human hepatocellular carcinoma,” Carcinogenesis, vol. 28, pp. 1094–1103, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. H. Li, M. L. Cui, T. Y. Chen et al., “Serum DLK1 is a potential prognostic biomarker in patients with hepatocellular carcinoma,” Tumour Biology, vol. 36, pp. 8399–8404, 2015. View at Publisher · View at Google Scholar · View at Scopus
  36. H. Kim, G. H. Choi, D. C. Na et al., “Human hepatocellular carcinomas with “Stemness”-related marker expression: keratin 19 expression and a poor prognosis,” Hepatology, vol. 54, pp. 1707–1717, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. J. S. Bae, H. N. Choi, S. J. Noh et al., “Expression of K19 and K7 in dysplastic nodules and hepatocellular carcinoma,” Oncology Letters, vol. 4, pp. 213–220, 2012. View at Publisher · View at Google Scholar · View at Scopus
  38. T. Kawai, K. Yasuchika, T. Ishii et al., “Keratin 19, a cancer stem cell marker in human hepatocellular carcinoma,” Clinical Cancer Research, vol. 21, pp. 3081–3091, 2015. View at Publisher · View at Google Scholar · View at Scopus
  39. K. Fujio, Z. Hu, R. P. Evarts, E. R. Marsden, C. H. Niu, and S. S. Thorgeirsson, “Coexpression of stem cell factor and c-kit in embryonic and adult liver,” Experimental Cell Research, vol. 224, pp. 243–250, 1996. View at Publisher · View at Google Scholar · View at Scopus
  40. H. A. Crosby, D. A. Kelly, and A. J. Strain, “Human hepatic stem-like cells isolated using c-kit or CD34 can differentiate into biliary epithelium,” Gastroenterology, vol. 120, pp. 534–544, 2001. View at Publisher · View at Google Scholar
  41. E. S. Lee, E. M. Han, Y. S. Kim et al., “Occurrence of c-kit+ tumor cells in hepatitis B virus-associated hepatocellular carcinoma,” American Journal of Clinical Pathology, vol. 124, pp. 31–36, 2005. View at Publisher · View at Google Scholar
  42. J. Xiong, “SALL4: engine of cell stemness,” Current Gene Therapy, vol. 14, pp. 400–411, 2014. View at Publisher · View at Google Scholar
  43. B. Jones, “Liver cancer: SALL4—a cancer marker and target,” Nature Reviews. Clinical Oncology, vol. 10, p. 426, 2013. View at Publisher · View at Google Scholar · View at Scopus
  44. S. X. Han, J. L. Wang, X. J. Guo et al., “Serum SALL4 is a novel prognosis biomarker with tumor recurrence and poor survival of patients in hepatocellular carcinoma,” Journal of Immunology Research, vol. 2014, Article ID 262385, 7 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  45. E. Yakaboski, A. Jares, and Y. Ma, “Stem cell gene SALL4 in aggressive hepatocellular carcinoma: a cancer stem cell-specific target?” Hepatology, vol. 60, pp. 419–421, 2014. View at Publisher · View at Google Scholar · View at Scopus
  46. S. Liu, N. Li, X. Yu et al., “Expression of intercellular adhesion molecule 1 by hepatocellular carcinoma stem cells and circulating tumor cells,” Gastroenterology, vol. 144, pp. 1031–1041, 2013. View at Publisher · View at Google Scholar · View at Scopus
  47. W. Zhao, L. Wang, H. Han et al., “1B50-1, a mAb raised against recurrent tumor cells, targets liver tumor-initiating cells by binding to the calcium channel α2δ1 subunit,” Cancer Cell, vol. 23, pp. 541–556, 2013. View at Publisher · View at Google Scholar · View at Scopus
  48. J. Shan, J. Shen, L. Liu et al., “Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma,” Hepatology, vol. 56, no. 3, pp. 1004–1014, 2012. View at Publisher · View at Google Scholar · View at Scopus
  49. Y. Miyoshi, K. Iwao, Y. Nagasawa et al., “Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3,” Cancer Research, vol. 58, pp. 2524–2527, 1998. View at Google Scholar
  50. H. Huang, H. Fujii, A. Sankila et al., “Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection,” The American Journal of Pathology, vol. 155, pp. 1795–1801, 1999. View at Publisher · View at Google Scholar
  51. C. M. Wong, S. T. Fan, and I. O. Ng, “Beta-catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance,” Cancer, vol. 92, pp. 136–145, 2001. View at Google Scholar
  52. C. N. Guan, X. M. Chen, H. Q. Lou, X. H. Liao, B. Y. Chen, and P. W. Zhang, “Clinical significance of axin and beta-catenin protein expression in primary hepatocellular carcinomas,” Asian Pacific Journal of Cancer Prevention, vol. 13, pp. 677–681, 2012. View at Publisher · View at Google Scholar · View at Scopus
  53. J. Gao, Z. Song, Y. Chen et al., “Deregulated expression of notch receptors in human hepatocellular carcinoma,” Digestive and Liver Disease, vol. 40, pp. 114–121, 2008. View at Publisher · View at Google Scholar · View at Scopus
  54. A. Villanueva, C. Alsinet, K. Yanger et al., “Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice,” Gastroenterology, vol. 143, pp. 1660–1669, 2012. View at Publisher · View at Google Scholar · View at Scopus
  55. M. A. Patil, J. Zhang, C. Ho, S. T. Cheung, S. T. Fan, and X. Chen, “Hedgehog signaling in human hepatocellular carcinoma,” Cancer Biology & Therapy, vol. 5, pp. 111–117, 2006. View at Google Scholar
  56. G. M. Philips, I. S. Chan, M. Swiderska et al., “Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer,” PloS One, vol. 6, no. 9, article e23943, 2011. View at Publisher · View at Google Scholar · View at Scopus
  57. M. Ikeguchi, A. Iwamoto, K. Taniguchi, K. Katano, and Y. Hirooka, “The gene expression level of transforming growth factor-beta (TGF-beta) as a biological prognostic marker of hepatocellular carcinoma,” Journal of Experimental & Clinical Cancer Research, vol. 24, pp. 415–421, 2005. View at Google Scholar
  58. J. Marx, “Cancer research. Mutant stem cells may seed cancer,” Science, vol. 301, pp. 1308–1310, 2003. View at Publisher · View at Google Scholar · View at Scopus
  59. R. Pardal, M. F. Clarke, and S. J. Morrison, “Applying the principles of stem-cell biology to cancer,” Nature Reviews Cancer, vol. 3, pp. 895–902, 2003. View at Publisher · View at Google Scholar
  60. M. A. Goodell, K. Brose, G. Paradis, A. S. Conner, and R. C. Mulligan, “Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo,” The Journal of Experimental Medicine, vol. 183, pp. 1797–1806, 1996. View at Publisher · View at Google Scholar · View at Scopus
  61. N. A. Franken, H. M. Rodermond, J. Stap, J. Haveman, and C. van Bree, “Clonogenic assay of cells in vitro,” Nature Protocols, vol. 1, pp. 2315–2319, 2006. View at Publisher · View at Google Scholar · View at Scopus
  62. E. Pastrana, V. Silva-Vargas, and F. Doetsch, “Eyes wide open: a critical review of sphere-formation as an assay for stem cells,” Cell Stem Cell, vol. 8, pp. 486–498, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. Y. Ohi, Y. Umekita, T. Yoshioka et al., “Aldehyde dehydrogenase 1 expression predicts poor prognosis in triplenegative breast cancer,” Histopathology, vol. 59, pp. 776–780, 2011. View at Publisher · View at Google Scholar · View at Scopus
  64. C. Udomsakdi, C. J. Eaves, H. J. Sutherland, and P. M. Lansdorp, “Separation of functionally distinct subpopulations of primitive human hematopoietic cells using rhodamine-123,” Experimental Hematology, vol. 19, pp. 338–342, 1991. View at Google Scholar
  65. A. Kreso, P. van Galen, N. M. Pedley et al., “Self-renewal as a therapeutic target in human colorectal cancer,” Nature Medicine, vol. 20, pp. 29–36, 2014. View at Publisher · View at Google Scholar · View at Scopus
  66. M. L. Suva, N. Riggi, M. Janiszewska et al., “EZH2 is essential for glioblastoma cancer stem cell maintenance,” Cancer Research, vol. 69, pp. 9211–9218, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. C. Raggi, V. M. Factor, D. Seo et al., “Epigenetic reprogramming modulates malignant properties of human liver cancer,” Hepatology, vol. 59, pp. 2251–2262, 2014. View at Publisher · View at Google Scholar · View at Scopus
  68. K. J. Yong, C. Gao, J. S. Lim et al., “Oncofetal gene SALL4 in aggressive hepatocellular carcinoma,” The New England Journal of Medicine, vol. 368, pp. 2266–2276, 2013. View at Publisher · View at Google Scholar · View at Scopus
  69. S. S. Zeng, T. Yamashita, M. Kondo et al., “The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma,” Journal of Hepatology, vol. 60, pp. 127–134, 2014. View at Publisher · View at Google Scholar · View at Scopus
  70. M. P. Deonarain, C. A. Kousparou, and A. A. Epenetos, “Antibodies targeting cancer stem cells: a new paradigm in immunotherapy?” MABS, vol. 1, pp. 12–25, 2009. View at Google Scholar
  71. K. Ogawa, S. Tanaka, S. Matsumura et al., “EpCAM-targeted therapy for human hepatocellular carcinoma,” Annals of Surgical Oncology, vol. 21, pp. 1314–1322, 2014. View at Publisher · View at Google Scholar · View at Scopus
  72. C. Yin, Y. Lin, X. Zhang et al., “Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4alpha gene,” Hepatology, vol. 48, pp. 1528–1539, 2008. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Fiorillo, A. F. Verre, M. Iliut et al., “Graphene oxide selectively targets cancer stem cells, across multiple tumor types: implications for non-toxic cancer treatment, via "differentiation-based nano-therapy",” Oncotarget, vol. 6, pp. 3553–3562, 2015. View at Publisher · View at Google Scholar
  74. X. Mao, J. Liu, Z. Gong et al., “iRGD-conjugated DSPE-PEG2000 nanomicelles for targeted delivery of salinomycin for treatment of both liver cancer cells and cancer stem cells,” Nanomedicine (London, England), vol. 10, pp. 2677–2695, 2015. View at Publisher · View at Google Scholar · View at Scopus
  75. Z. Wang, J. Tan, C. Mc Conville et al., “Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells,” Nanomedicine, vol. 13, no. 2, pp. 641–657, 2016. View at Publisher · View at Google Scholar
  76. L. S. Piao, W. Hur, T. K. Kim et al., “CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma,” Cancer Letters, vol. 315, no. 2, pp. 129–137, 2012. View at Publisher · View at Google Scholar · View at Scopus
  77. H. Sun, S. He, B. Wen, W. Jia, E. Fan, and Y. Zheng, “Effect of Biejiajian pills on Wnt signal pathway molecules beta-catenin and GSK-3beta and the target genes CD44v6 and VEGF in hepatocellular carcinoma cells,” Nan Fang Yi Ke da Xue Xue Bao, vol. 34, pp. 1454–1458, 2014. View at Google Scholar
  78. Y. Y. Lu, J. J. Wang, X. K. Zhang, W. B. Li, and X. L. Guo, “1118-20, an indazole diarylurea compound, inhibits hepatocellular carcinoma HepG2 proliferation and tumour angiogenesis involving Wnt/beta-catenin pathway and receptor tyrosine kinases,” The Journal of Pharmacy and Pharmacology, vol. 67, pp. 1393–1405, 2015. View at Publisher · View at Google Scholar · View at Scopus
  79. T. T. Huynh, Y. K. Rao, W. H. Lee et al., “Destruxin B inhibits hepatocellular carcinoma cell growth through modulation of the Wnt/beta-catenin signaling pathway and epithelial-mesenchymal transition,” Toxicology in Vitro, vol. 28, pp. 552–561, 2014. View at Publisher · View at Google Scholar · View at Scopus
  80. X. Ke, Y. Zhao, X. Lu et al., “TQ inhibits hepatocellular carcinoma growth in vitro and in vivo via repression of Notch signaling,” Oncotarget, vol. 6, pp. 32610–32621, 2015. View at Publisher · View at Google Scholar · View at Scopus
  81. R. Dhanasekaran, I. Nakamura, C. Hu et al., “Activation of the transforming growth factor-beta/SMAD transcriptional pathway underlies a novel tumor-promoting role of sulfatase 1 in hepatocellular carcinoma,” Hepatology, vol. 61, pp. 1269–1283, 2015. View at Publisher · View at Google Scholar · View at Scopus