Литература

  1. Torre, L.A.; Siegel, R.L.; Ward, E.M.; Jemal, A. Global cancer incidence and mortality rates and trends—An update. Cancer Epidemiol. Biomark. Prev. 2016, 25, 16–27.
  2. Davila, J.A.; Morgan, R.O.; Shaib, Y.; McGlynn, K.A.; El-Serag, H.B. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: A population-based study. Gastroenterology 2004, 127, 1372–1380.
  3. Yang, J.D.; Harmsen, W.S.; Slettedahl, S.W.; Chaiteerakij, R.; Enders, F.T.; Therneau, T.M.; Orsini, L.; Kim, W.R.; Roberts, L.R. Factors that affect risk for hepatocellular carcinoma and effects of surveillance. Clin. Gastroenterol. Hepatol. 2011, 9, 617–623.
  4. Beasley, R.P. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 1988, 61, 1942–1956.
  5. Yu, S.Z. Primary prevention of hepatocellular carcinoma. J. Gastroenterol. Hepatol. 1995, 10, 674–682.
  6. Ghebranious, N.; Sell, S. Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice. Hepatology 1998, 27, 383–391.
  7. Tsai, J.F.; Jeng, J.E.; Chuang, L.Y.; Ho, M.S.; Ko, Y.C.; Lin, Z.Y.; Hsieh, M.Y.; Chen, S.C.; Chuang, W.L.; Wang, L.Y.; et al. Habitual betel quid chewing as a risk factor for cirrhosis: A case-control study. Medicine 2003, 82, 365–372.
  8. Tsai, J.F.; Chuang, L.Y.; Jeng, J.E.; Ho, M.S.; Hsieh, M.Y.; Lin, Z.Y.; Wang, L.Y. Betel quid chewing as a risk factor for hepatocellular carcinoma: A case-control study. Br. J. Cancer 2001, 84, 709–713.
  9. Chu, Y.J.; Yang, H.I.; Wu, H.C.; Liu, J.; Wang, L.Y.; Lu, S.N.; Lee, M.H.; Jen, C.L.; You, S.L.; Santella, R.M.; et al. Aflatoxin B1 exposure increases the risk of cirrhosis and hepatocellular carcinoma in chronic hepatitis B virus carriers. Int. J. Cancer 2017, 141, 711–720.
  10. Bressac, B.; Kew, M.; Wands, J.; Ozturk, M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 1991, 350, 429–431.
  11. Unsal, H.; Yakicier, C.; Marcais, C.; Kew, M.; Volkmann, M.; Zentgraf, H.; Isselbacher, K.J.; Ozturk, M. Genetic heterogeneity of hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA 1994, 91, 822–826.
  12. Yan, R.Q.; Su, J.J.; Huang, D.R.; Gan, Y.C.; Yang, C.; Huang, G.H. Human hepatitis B virus and hepatocellular carcinoma. II. Experimental induction of hepatocellular carcinoma in tree shrews exposed to hepatitis B virus and aflatoxin B1. J. Cancer Res. Clin. Oncol. 1996, 122, 289–295.
  13. Marquardt, J.U.; Andersen, J.B.; Thorgeirsson, S.S. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat. Rev. Cancer 2015, 15, 653–667.
  14. Alizadeh, A.A.; Aranda, V.; Bardelli, A.; Blanpain, C.; Bock, C.; Borowski, C.; Caldas, C.; Califano, A.; Doherty, M.; Elsner, M.; et al. Toward understanding and exploiting tumor heterogeneity. Nat. Med. 2015, 21, 846–853.
  15. Schulze, K. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 2015, 47, 505–511.
  16. Guichard, C.; Amaddeo, G.; Imbeaud, S.; Ladeiro, Y.; Pelletier, L.; Maad, I.B.; Calderaro, J.; Bioulac-Sage, P.; Letexier, M.; Degos, F.; et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat. Genet. 2012, 44, 694–698.
  17. Hartmann, D.; Srivastava, U.; Thaler, M.; Kleinhans, K.N.; N’Kontchou, G.; Scheffold, A.; Bauer, K.; Kratzer, R.F.; Kloos, N.; Katz, S.F.; et al. Telomerase gene mutations are associated with cirrhosis formation. Hepatology 2011, 53, 1608–1617.
  18. Calado, R.T.; Brudno, J.; Mehta, P.; Kovacs, J.J.; Wu, C.; Zago, M.A.; Chanock, S.J.; Boyer, T.D.; Young, N.S. Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology 2011, 53, 1600–1607.
  19. Rudolph, K.L.; Chang, S.; Millard, M.; Schreiber-Agus, N.; DePinho, R.A. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 2000, 287, 1253–1258.
  20. Wege, H.; Brummendorf, T.H. Telomerase activation in liver regeneration and hepatocarcinogenesis: Dr. Jekyll or Mr. Hyde? Curr. Stem Cell Res. Ther. 2007, 2, 31–38.
  21. Wiemann, S.U.; Satyanarayana, A.; Tsahuridu, M.; Tillmann, H.L.; Zender, L.; Klempnauer, J.; Flemming, P.; Franco, S.; Blasco, M.A.; Manns, M.P.; et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 2002, 16, 935–942.
  22. Farazi, P.A.; Glickman, J.; Jiang, S.; Yu, A.; Rudolph, K.L.; DePinho, R.A. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res. 2003, 63, 5021–5027.
  23. Nault, J.C.; Calderaro, J.; Di Tommaso, L.; Balabaud, C.; Zafrani, E.S.; Bioulac-Sage, P.; Roncalli, M.; Zucman-Rossi, J. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology 2014, 60, 1983–1992.
  24. Ahn, S.M.; Jang, S.J.; Shim, J.H.; Kim, D.; Hong, S.M.; Sung, C.O.; Baek, D.; Haq, F.; Ansari, A.A.; Lee, S.Y.; et al. Genomic portrait of resectable hepatocellular carcinomas: Implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 2014, 60, 1972–1982.
  25. Nault, J.C.; Mallet, M.; Pilati, C.; Calderaro, J.; Bioulac-Sage, P.; Laurent, C.; Laurent, A.; Cherqui, D.; Balabaud, C.; Zucman-Rossi, J. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat. Commun. 2013, 4, 2218.
  26. Block, T.M.; Mehta, A.S.; Fimmel, C.J.; Jordan, R. Molecular viral oncology of hepatocellular carcinoma. Oncogene 2003, 22, 5093–5107.
  27. Tokino, T.; Tamura, H.; Hori, N.; Matsubara, K. Chromosome deletions associated with hepatitis B virus integration. Virology 1991, 185, 879–882.
  28. Murakami, Y.; Saigo, K.; Takashima, H.; Minami, M.; Okanoue, T.; Brechot, C.; Paterlini-Brechot, P. Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut 2005, 54, 1162–1168.
  29. Tarn, C.; Lee, S.; Hu, Y.; Ashendel, C.; Andrisani, O.M. Hepatitis B virus X protein differentially activates RAS-RAF-MAPK and JNK pathways in X-transforming versus non-transforming AML12 hepatocytes. J. Biol. Chem. 2001, 276, 34671–34680.
  30. Nijhara, R.; Jana, S.S.; Goswami, S.K.; Rana, A.; Majumdar, S.S.; Kumar, V.; Sarkar, D.P. Sustained activation of mitogen-activated protein kinases and activator protein 1 by the hepatitis B virus X protein in mouse hepatocytes in vivo. J. Virol. 2001, 75, 10348–10358.
  31. Nijhara, R.; Jana, S.S.; Goswami, S.K.; Kumar, V.; Sarkar, D.P. An internal segment (residues 58–119) of the hepatitis B virus X protein is sufficient to activate MAP kinase pathways in mouse liver. FEBS Lett. 2001, 504, 59–64.
  32. Feitelson, M.A.; Sun, B.; Satiroglu Tufan, N.L.; Liu, J.; Pan, J.; Lian, Z. Genetic mechanisms of hepatocarcinogenesis. Oncogene 2002, 21, 2593–2604.
  33. Yu, D.Y.; Moon, H.B.; Son, J.K.; Jeong, S.; Yu, S.L.; Yoon, H.; Han, Y.M.; Lee, C.S.; Park, J.S.; Lee, C.H.; et al. Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein. J. Hepatol. 1999, 31, 123–132.
  34. Kim, C.-M.; Koike, K.; Saito, I.; Miyamura, T.; Jay, G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 1991, 351, 317–320.
  35. Wieland, S.; Thimme, R.; Purcell, R.H.; Chisari, F.V. Genomic analysis of the host response to hepatitis B virus infection. Proc. Natl. Acad. Sci. USA 2004, 101, 6669–6674.
  36. Rehermann, B.; Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat. Rev. Immunol. 2005, 5, 215–229.
  37. Farazi, P.A.; DePinho, R.A. Hepatocellular carcinoma pathogenesis: From genes to environment. Nat. Rev. Immunol. 2006, 6, 674–687.
  38. Lindenbach, B.D.; Rice, C.M. Unravelling hepatitis C virus replication from genome to function. Nature 2005, 436, 933–938.
  39. Lindenbach, B.D.; Evans, M.J.; Syder, A.J.; Wolk, B.; Tellinghuisen, T.L.; Liu, C.C.; Maruyama, T.; Hynes, R.O.; Burton, D.R.; McKeating, J.A.; et al. Complete replication of hepatitis C virus in cell culture. Science 2005, 309, 623–626.
  40. Wakita, T.; Pietschmann, T.; Kato, T.; Date, T.; Miyamoto, M.; Zhao, Z.; Murthy, K.; Habermann, A.; Krausslich, H.G.; Mizokami, M.; et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat. Med. 2005, 11, 791–796.
  41. Vilchez, V.; Turcios, L.; Marti, F.; Gedaly, R. Targeting Wnt/beta-catenin pathway in hepatocellular carcinoma treatment. World J. Gastroenterol. 2016, 22, 823–832.
  42. Harada, N.; Oshima, H.; Katoh, M.; Tamai, Y.; Oshima, M.; Taketo, M.M. Hepatocarcinogenesis in mice with beta-catenin and Ha-ras gene mutations. Cancer Res. 2004, 64, 48–54.
  43. Clevers, H.; Nusse, R. Wnt/beta-catenin signaling and disease. Cell 2012, 149, 1192–1205.
  44. Qiao, L.; Zhang, H.; Yu, J.; Francisco, R.; Dent, P.; Ebert, M.P.; Rocken, C.; Farrell, G. Constitutive activation of NF-kappaB in human hepatocellular carcinoma: Evidence of a cytoprotective role. Hum. Gene Ther. 2006, 17, 280–290.
  45. Papa, S.; Bubici, C.; Zazzeroni, F.; Franzoso, G. Mechanisms of liver disease: Cross-talk between the NF-kappaB and JNK pathways. Biol. Chem. 2009, 390, 965–976.
  46. Barre, B.; Perkins, N.D. A cell cycle regulatory network controlling NF-kappaB subunit activity and function. EMBO J. 2007, 26, 4841–4855.
  47. Johnson, R.F.; Witzel, I.I.; Perkins, N.D. p53-dependent regulation of mitochondrial energy production by the RelA subunit of NF-kappaB. Cancer Res. 2011, 71, 5588–5597.
  48. Alves, A.; Mamede, A.C.; Alves, M.; Oliveira, P.F.; Rocha, S.M.; Botelho, F.; Maia, C.J. Glycolysis inhibition as a strategy for hepatocellular carcinoma treatment? Curr. Cancer Drug Targets 2018.
  49. Lei, S.; Yang, J.; Chen, C.; Sun, J.; Yang, L.; Tang, H.; Yang, T.; Chen, A.; Zhao, H.; Li, Y.; et al. FLIP(L) is critical for aerobic glycolysis in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 2016, 35, 79.
  50. Asgharzadeh, M.R.; Barar, J.; Pourseif, M.M.; Eskandani, M.; Jafari Niya, M.; Mashayekhi, M.R.; Omidi, Y. Molecular machineries of pH dysregulation in tumor microenvironment: Potential targets for cancer therapy. Bioimpacts 2017, 7, 115–133.
  51. Kretzmann, N.A.; Chiela, E.; Matte, U.; Marroni, N.; Marroni, C.A. N-acetylcysteine improves antitumoural response of Interferon alpha by NF-kB downregulation in liver cancer cells. Comp. Hepatol. 2012, 11, 4.
  52. Eltzschig, H.K.; Carmeliet, P. Hypoxia and inflammation. N. Engl. J. Med. 2011, 364, 656–665.
  53. Nizet, V.; Johnson, R.S. Interdependence of hypoxic and innate immune responses. Nat. Rev. Immunol. 2009, 9, 609–617.
  54. DiGiacomo, J.W.; Gilkes, D.M. Tumor hypoxia as an enhancer of inflammation-mediated metastasis: Emerging therapeutic strategies. Target. Oncol. 2018, 13, 157–173.
  55. Barry, E.R.; Morikawa, T.; Butler, B.L.; Shrestha, K.; de la Rosa, R.; Yan, K.S.; Fuchs, C.S.; Magness, S.T.; Smits, R.; Ogino, S.; et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 2013, 493, 106–110.
  56. Rizvi, S.; Fischbach, S.R.; Bronk, S.F.; Hirsova, P.; Krishnan, A.; Dhanasekaran, R.; Smadbeck, J.B.; Smoot, R.L.; Vasmatzis, G.; Gores, G.J. YAP-associated chromosomal instability and cholangiocarcinoma in mice. Oncotarget 2018, 9, 5892–5905.
  57. Hayashi, H.; Higashi, T.; Yokoyama, N.; Kaida, T.; Sakamoto, K.; Fukushima, Y.; Ishimoto, T.; Kuroki, H.; Nitta, H.; Hashimoto, D.; et al. An imbalance in TAZ and YAP expression in hepatocellular carcinoma confers cancer stem cell-like behaviors contributing to disease progression. Cancer Res. 2015, 75, 4985–4997.
  58. Wu, H.; Liu, Y.; Jiang, X.W.; Li, W.F.; Guo, G.; Gong, J.P.; Ding, X. Clinicopathological and prognostic significance of Yes-associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma. Tumor Biol. 2016, 37, 13499–13508.
  59. Camargo, F.D.; Gokhale, S.; Johnnidis, J.B.; Fu, D.; Bell, G.W.; Jaenisch, R.; Brummelkamp, T.R. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Biol. 2007, 17, 2054–2060.
  60. Yin, F.; Yu, J.; Zheng, Y.; Chen, Q.; Zhang, N.; Pan, D. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell 2013, 154, 1342–1355.
  61. Kerbel, R.S. Tumor angiogenesis: Past, present and the near future. Carcinogenesis 2000, 21, 505–515.
  62. Andisheh-Tadbir, A.; Hamzavi, M.; Rezvani, G.; Ashraf, M.J.; Fattahi, M.J.; Khademi, B.; Kamali, F. Tissue expression, serum and salivary levels of vascular endothelial growth factor in patients with HNSCC. Braz. J. Otorhinolaryngol. 2014, 80, 503–507.
  63. Rahbari, N.N.; Kedrin, D.; Incio, J.; Liu, H.; Ho, W.W.; Nia, H.T.; Edrich, C.M.; Jung, K.; Daubriac, J.; Chen, I.; et al. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci. Transl. Med. 2016, 8, 360ra135.
  64. Yang, Y.; Zhang, Y.; Iwamoto, H.; Hosaka, K.; Seki, T.; Andersson, P.; Lim, S.; Fischer, C.; Nakamura, M.; Abe, M.; et al. Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. Nat. Commun. 2016, 7, 12680.
  65. Kutluer, G.; Cicek, N.M.; Moraloglu, O.; Ertargin, P.; Sarikaya, E.; Artar, I.; Erdem, O. Low VEGF expression in conceptus material and maternal serum AFP and beta-hCG levels as indicators of defective angiogenesis in first-trimester miscarriages. J. Turk. Ger. Gynecol. Assoc. 2012, 13, 111–117.
  66. Ye, S.; Mao, B.; Yang, L.; Fu, W.; Hou, J. Thrombosis recanalization by paeoniflorin through the upregulation of urokinasetype plasminogen activator via the MAPK signaling pathway. Mol. Med. Rep. 2016, 13, 4593–4598.
  67. Santibanez, J.F. Urokinase type plasminogen activator and the molecular mechanisms of its regulation in cancer. Protein Pept. Lett. 2017, 24, 936–946.
  68. Mauro, C.D.; Pesapane, A.; Formisano, L.; Rosa, R.; D’Amato, V.; Ciciola, P.; Servetto, A.; Marciano, R.; Orsini, R.C.; Monteleone, F.; et al. Urokinase-type plasminogen activator receptor (uPAR) expression enhances invasion and metastasis in RAS mutated tumors. Sci. Rep. 2017, 7, 9388.
  69. Pavon, M.A.; Arroyo-Solera, I.; Cespedes, M.V.; Casanova, I.; Leon, X.; Mangues, R. uPA/uPAR and SERPINE1 in head and neck cancer: Role in tumor resistance, metastasis, prognosis and therapy. Oncotarget 2016, 7, 57351–57366.
  70. Markl, B.; Hardt, J.; Franz, S.; Schaller, T.; Schenkirsch, G.; Kriening, B.; Hoffmann, R.; Ruth, S. Tumor budding, uPA, and PAI-1 in colorectal cancer: Update of a prospective study. Gastroenterol. Res. Pract. 2017, 2017, 6504960.
  71. Andres, S.A.; Edwards, A.B.; Wittliff, J.L. Expression of urokinase-type plasminogen activator (uPA), its receptor (uPAR), and inhibitor (PAI-1) in human breast carcinomas and their clinical relevance. J. Clin. Lab. Anal. 2012, 26, 93–103.
  72. Rubina, K.A.; Sysoeva, V.Y.; Zagorujko, E.I.; Tsokolaeva, Z.I.; Kurdina, M.I.; Parfyonova, Y.V.; Tkachuk, V.A. Increased expression of uPA, uPAR, and PAI-1 in psoriatic skin and in basal cell carcinomas. Arch. Dermatol. Res. 2017, 309, 433–442.
  73. Montuori, N.; Ragno, P. Role of uPA/uPAR in the modulation of angiogenesis. Chem. Immunol. Allergy 2014, 99, 105–122.
  74. Wu, Y.; Qiao, X.; Qiao, S.; Yu, L. Targeting integrins in hepatocellular carcinoma. Expert Opin. Ther. Targets 2011, 15, 421–437.
  75. Weis, S.M.; Cheresh, D.A. αV integrins in angiogenesis and cancer. Cold Spring Harb. Perspect. Med. 2011, 1, a006478.
  76. Soejima, Y.; Inoue, M.; Takahashi, Y.; Uozaki, H.; Sawabe, M.; Fukusato, T. Integrins αvβ6, α6β4 and α3β1 are down-regulated in cholangiolocellular carcinoma but not cholangiocarcinoma. Hepatol. Res. 2014, 44, 320–334.
  77. Lijuan, W.; Liu, X.; Yu, H.; Zhou, F.; Chen, H.; Liu, Q. Integrins mediate the migration of HepG2 cells induced by low shear stress. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2014, 31, 336–340.
  78. Tian, T.; Li, C.L.; Fu, X.; Wang, S.H.; Lu, J.; Guo, H.; Yao, Y.; Nan, K.J.; Yang, Y.J. beta1 integrin-mediated multicellular resistance in hepatocellular carcinoma through activation of the FAK/Akt pathway. J. Int. Med. Res. 2018, 46, 1311–1325.
  79. Feng, T.; Yu, H.; Xia, Q.; Ma, Y.; Yin, H.; Shen, Y.; Liu, X. Cross-talk mechanism between endothelial cells and hepatocellular carcinoma cells via growth factors and integrin pathway promotes tumor angiogenesis and cell migration. Oncotarget 2017, 8, 69577–69593.
  80. Kainuma, M.; Takada, I.; Makishima, M.; Sano, K. Farnesoid X receptor activation enhances transforming growth factor beta-induced epithelial-mesenchymal transition in hepatocellular carcinoma cells. Int. J. Mol. Sci. 2018, 19, 1898.
  81. Huang, W.; Ma, K.; Zhang, J.; Qatanani, M.; Cuvillier, J.; Liu, J.; Dong, B.; Huang, X.; Moore, D.D. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 2006, 312, 233–236.
  1. Huang, X.F.; Zhao, W.Y.; Huang, W.D. FXR and liver carcinogenesis. Acta Pharmacol. Sin. 2015, 36, 37–43.
  2. Deuschle, U.; Schuler, J.; Schulz, A.; Schluter, T.; Kinzel, O.; Abel, U.; Kremoser, C. FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model. PLoS ONE 2012, 7, e43044.
  3. Yang, F.; Huang, X.; Yi, T.; Yen, Y.; Moore, D.D.; Huang, W. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 2007, 67, 863–867.
  4. Fujino, T.; Takeuchi, A.; Maruko-Ohtake, A.; Ohtake, Y.; Satoh, J.; Kobayashi, T.; Tanaka, T.; Ito, H.; Sakamaki, R.; Kashimura, R.; et al. Critical role of farnesoid X receptor for hepatocellular carcinoma cell proliferation. J. Biochem. 2012, 152, 577–586.
  5. Kim, I.; Morimura, K.; Shah, Y.; Yang, Q.; Ward, J.M.; Gonzalez, F.J. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 2007, 28, 940–946.
  6. Niu, Y.; Xu, M.; Slagle, B.L.; Huang, H.; Li, S.; Guo, G.L.; Shi, G.; Qin, W.; Xie, W. Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein-induced hepatocarcinogenesis. Hepatology 2017, 65, 893–906.
  7. Llovet, J.M.; Zucman-Rossi, J.; Pikarsky, E.; Sangro, B.; Schwartz, M.; Sherman, M.; Gores, G. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 2016, 2, 16018.
  8. Gores, G.J. Apoptosis and hepatic necroinflammation. Gastroenterol. Hepatol. 2008, 4, 394–395. [Google Scholar]
  9. Ringelhan, M.; Pfister, D.; O’Connor, T.; Pikarsky, E.; Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 2018, 19, 222–232.
  10. Linkermann, A.; Stockwell, B.R.; Krautwald, S.; Anders, H.J. Regulated cell death and inflammation: An auto-amplification loop causes organ failure. Nat. Rev. Immunol. 2014, 14, 759–767.
  11. Guo, H.; Callaway, J.B.; Ting, J.P.Y. Inflammasomes: Mechanism of action, role in disease, and therapeutics. Nat. Med. 2015, 21, 677.
  12. Ting, J.P.; Duncan, J.A.; Lei, Y. How the noninflammasome NLRs function in the innate immune system. Science 2010, 327, 286–290.
  13. Gross, O.; Yazdi, A.S.; Thomas, C.J.; Masin, M.; Heinz, L.X.; Guarda, G.; Quadroni, M.; Drexler, S.K.; Tschopp, J. Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity 2012, 36, 388–400.
  14. Ghiringhelli, F.; Apetoh, L.; Tesniere, A.; Aymeric, L.; Ma, Y.; Ortiz, C.; Vermaelen, K.; Panaretakis, T.; Mignot, G.; Ullrich, E.; et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat. Med. 2009, 15, 1170–1178.
  15. Cassel, S.L.; Joly, S.; Sutterwala, F.S. The NLRP3 inflammasome: A sensor of immune danger signals. Semin. Immunol. 2009, 21, 194–198.
  16. Lukens, J.R.; Kanneganti, T.D. Beyond canonical inflammasomes: Emerging pathways in IL-1-mediated autoinflammatory disease. Semin. Immunopathol. 2014, 36, 595–609.
  17. Zhang, J.; Fu, S.; Sun, S.; Li, Z.; Guo, B. Inflammasome activation has an important role in the development of spontaneous colitis. Mucosal Immunol. 2014, 7, 1139–1150.
  18. Lamkanfi, M.; Dixit, V.M. Mechanisms and functions of inflammasomes. Cell 2014, 157, 1013–1022.
  19. Zitvogel, L.; Kepp, O.; Galluzzi, L.; Kroemer, G. Inflammasomes in carcinogenesis and anticancer immune responses. Nat. Immunol. 2012, 13, 343–351.
  20. Kawai, T.; Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011, 34, 637–650.
  21. Kawasaki, T.; Kawai, T. Toll-like receptor signaling pathways. Front. Immunol. 2014, 5, 461.
  22. Martinon, F.; Burns, K.; Tschopp, J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 2002, 10, 417–426.
  23. Martinon, F.; Mayor, A.; Tschopp, J. The inflammasomes: Guardians of the body. Ann. Rev. Immunol. 2009, 27, 229–265.
  24. Ye, Z.; Ting, J.P. NLR, the nucleotide-binding domain leucine-rich repeat containing gene family. Curr. Opin. Immunol. 2008, 20, 3–9.
  25. Bauernfeind, F.; Ablasser, A.; Bartok, E.; Kim, S.; Schmid-Burgk, J.; Cavlar, T.; Hornung, V. Inflammasomes: Current understanding and open questions. Cell. Mol. Life Sci. CMLS 2011, 68, 765–783.
  26. Cayrol, C.; Girard, J.P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc. Natl. Acad. Sci. USA 2009, 106, 9021–9026.
  27. Schroder, K.; Tschopp, J. The inflammasomes. Cell 2010, 140, 821–832.
  28. Csak, T.; Ganz, M.; Pespisa, J.; Kodys, K.; Dolganiuc, A.; Szabo, G. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 2011, 54, 133–144.
  29. Boaru, S.G.; Borkham-Kamphorst, E.; Tihaa, L.; Haas, U.; Weiskirchen, R. Expression analysis of inflammasomes in experimental models of inflammatory and fibrotic liver disease. J. Inflamm. 2012, 9, 49.
  30. He, G.; Karin, M. NF-κB and STAT3–key players in liver inflammation and cancer. Cell Res. 2011, 21, 159–168.
  31. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674.
  32. Luedde, T.; Schwabe, R.F. NF-κB in the liver—Linking injury, fibrosis and hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 2011, 8, 108–118.
  33. Takeda, K.; Akira, S. STAT family of transcription factors in cytokine-mediated biological responses. Cytokine Growth Factor Rev. 2000, 11, 199–207.
  34. Hirano, T.; Ishihara, K.; Hibi, M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 2000, 19, 2548–2556.
  35. Li, C.J.; Liao, W.T.; Wu, M.Y.; Chu, P.Y. New insights into the role of autophagy in tumor immune microenvironment. Int. J. Mol. Sci. 2017, 18, 1566.
  36. Matsui, M.; Machida, S.; Itani-Yohda, T.; Akatsuka, T. Downregulation of the proteasome subunits, transporter, and antigen presentation in hepatocellular carcinoma, and their restoration by interferon-gamma. J. Gastroenterol. Hepatol. 2002, 17, 897–907.
  37. Ormandy, L.A.; Hillemann, T.; Wedemeyer, H.; Manns, M.P.; Greten, T.F.; Korangy, F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 2005, 65, 2457–2464.
  38. Unitt, E.; Rushbrook, S.M.; Marshall, A.; Davies, S.; Gibbs, P.; Morris, L.S.; Coleman, N.; Alexander, G.J. Compromised lymphocytes infiltrate hepatocellular carcinoma: The role of T-regulatory cells. Hepatology 2005, 41, 722–730.
  39. Cariani, E.; Pilli, M.; Zerbini, A.; Rota, C.; Olivani, A.; Pelosi, G.; Schianchi, C.; Soliani, P.; Campanini, N.; Silini, E.M.; et al. Immunological and molecular correlates of disease recurrence after liver resection for hepatocellular carcinoma. PLoS ONE 2012, 7, e32493.
  40. Hoechst, B.; Ormandy, L.A.; Ballmaier, M.; Lehner, F.; Kruger, C.; Manns, M.P.; Greten, T.F.; Korangy, F. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 2008, 135, 234–243.
  41. Zhu, X.D.; Zhang, J.B.; Zhuang, P.Y.; Zhu, H.G.; Zhang, W.; Xiong, Y.Q.; Wu, W.Z.; Wang, L.; Tang, Z.Y.; Sun, H.C. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2008, 26, 2707–2716.
  42. Yeung, O.W.; Lo, C.M.; Ling, C.C.; Qi, X.; Geng, W.; Li, C.X.; Ng, K.T.; Forbes, S.J.; Guan, X.Y.; Poon, R.T.; et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J. Hepatol. 2015, 62, 607–616.
  43. Ding, T.; Xu, J.; Wang, F.; Shi, M.; Zhang, Y.; Li, S.P.; Zheng, L. High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum. Pathol. 2009, 40, 381–389.
  44. Behboudi, S.; Alisa, A.; Boswell, S.; Anastassiou, J.; Pathan, A.A.; Williams, R. Expansion of anti-AFP Th1 and Tc1 responses in hepatocellular carcinoma occur in different stages of disease. Br. J. Cancer 2010, 102, 748–753.
  45. Wu, M.-Y.; Li, C.-J.; Hou, M.-F.; Chu, P.-Y. New insights into the role of inflammation in the pathogenesis of atherosclerosis. Int. J. Mol. Sci. 2017, 18, 2034.
  46. Yu, L.-X.; Ling, Y.; Wang, H.-Y. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis. Oncol. 2018, 2, 6.
  47. Budhu, A.; Forgues, M.; Ye, Q.H.; Jia, H.L.; He, P.; Zanetti, K.A.; Kammula, U.S.; Chen, Y.; Qin, L.X.; Tang, Z.Y.; et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 2006, 10, 99–111.
  48. Hattori, E.; Okumoto, K.; Adachi, T.; Takeda, T.; Ito, J.; Sugahara, K.; Watanabe, H.; Saito, K.; Saito, T.; Togashi, H.; et al. Possible contribution of circulating interleukin-10 (IL-10) to anti-tumor immunity and prognosis in patients with unresectable hepatocellular carcinoma. Hepatol. Res. Off. J. Jpn Soc. Hepatol. 2003, 27, 309–314.
  49. Kim, C.; Chung, S.; Yuchun, L.; Kim, M.C.; Chan, J.K.; Asada, H.H.; Kamm, R.D. In vitro angiogenesis assay for the study of cell-encapsulation therapy. Lab Chip 2012, 12, 2942–2950.
  50. Won, C.; Kim, B.H.; Yi, E.H.; Choi, K.J.; Kim, E.K.; Jeong, J.M.; Lee, J.H.; Jang, J.J.; Yoon, J.H.; Jeong, W.I.; et al. Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma. Hepatology 2015, 62, 1160–1173.
  51. Ray, K. Diagnosis: Programmed probiotics light up liver cancer in urine. Nat. Rev. Gastroenterol. Hepatol. 2015, 12, 429.
  52. Dapito, D.H.; Mencin, A.; Gwak, G.Y.; Pradere, J.P.; Jang, M.K.; Mederacke, I.; Caviglia, J.M.; Khiabanian, H.; Adeyemi, A.; Bataller, R.; et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012, 21, 504–516.
  53. Yao, J.; Chang, L.; Yuan, L.; Duan, Z. Nutrition status and small intestinal bacterial overgrowth in patients with virus-related cirrhosis. Asia Pac. J. Clin. Nutr. 2016, 25, 283–291.
  54. Lin, A.; Wang, G.; Zhao, H.; Zhang, Y.; Han, Q.; Zhang, C.; Tian, Z.; Zhang, J. TLR4 signaling promotes a COX-2/PGE2/STAT3 positive feedback loop in hepatocellular carcinoma (HCC) cells. Oncoimmunology 2016, 5, e1074376.
  55. Tampaki, E.C.; Tampakis, A.; Alifieris, C.E.; Krikelis, D.; Pazaiti, A.; Kontos, M.; Trafalis, D.T. Efficacy and Safety of neoadjuvant treatment with bevacizumab, liposomal doxorubicin, cyclophosphamide and paclitaxel combination in locally/regionally advanced, HER2-negative, Grade III at premenopausal status breast cancer: A Phase II Study. Clin. Drug Investig. 2018.
  56. Gonzalez-Vacarezza, N.; Alonso, I.; Arroyo, G.; Martinez, J.; De Andres, F.; LLerena, A.; Estevez-Carrizo, F. Predictive biomarkers candidates for patients with metastatic colorectal cancer treated with bevacizumab-containing regimen. Drug Metab. Pers. Ther. 2016, 31, 83–90.
  57. Pinter, M.; Ulbrich, G.; Sieghart, W.; Kolblinger, C.; Reiberger, T.; Li, S.; Ferlitsch, A.; Muller, C.; Lammer, J.; Peck-Radosavljevic, M. Hepatocellular carcinoma: A Phase II randomized controlled double-blind trial of transarterial chemoembolization in combination with biweekly intravenous administration of bevacizumab or a placebo. Radiology 2015, 277, 903–912.
  58. Pokuri, V.K.; Tomaszewski, G.M.; Ait-Oudhia, S.; Groman, A.; Khushalani, N.I.; Lugade, A.A.; Thanavala, Y.; Ashton, E.A.; Grande, C.; Fetterly, G.J.; et al. Efficacy, safety, and potential biomarkers of sunitinib and transarterial chemoembolization (TACE) combination in advanced hepatocellular carcinoma (HCC): Phase II trial. Am. J. Clin. Oncol. 2018, 41, 332–338.
  59. Cheng, A.L.; Kang, Y.K.; Lin, D.Y.; Park, J.W.; Kudo, M.; Qin, S.; Chung, H.C.; Song, X.; Xu, J.; Poggi, G.; et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: Results of a randomized phase III trial. J. Clin. Oncol. 2013, 31, 4067–4075.
  60. Yau, T.; Chan, P.; Pang, R.; Ng, K.; Fan, S.T.; Poon, R.T. Phase 1-2 trial of PTK787/ZK222584 combined with intravenous doxorubicin for treatment of patients with advanced hepatocellular carcinoma: Implication for antiangiogenic approach to hepatocellular carcinoma. Cancer 2010, 116, 5022–5029.
  61. Yu, W.C.; Zhang, K.Z.; Chen, S.G.; Liu, W.F. Efficacy and Safety of apatinib in patients with intermediate/advanced hepatocellular carcinoma: A prospective observation study. Medicine 2018, 97, e9704.
  62. Kong, Y.; Sun, L.; Hou, Z.; Zhang, Y.; Chen, P.; Cui, Y.; Zhu, X.; Song, T.; Li, Q.; Li, H.; et al. Apatinib is effective for treatment of advanced hepatocellular carcinoma. Oncotarget 2017, 8, 105596–105605.
  63. Cainap, C.; Qin, S.; Huang, W.T.; Chung, I.J.; Pan, H.; Cheng, Y.; Kudo, M.; Kang, Y.K.; Chen, P.J.; Toh, H.C.; et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: Results of a randomized phase III trial. J. Clin. Oncol. 2015, 33, 172–179.
  64. Chiu, Y.L.; Carlson, D.M.; Pradhan, R.S.; Ricker, J.L. Exposure-response (safety) analysis to identify linifanib dose for a Phase III study in patients with hepatocellular carcinoma. Clin. Ther. 2013, 35, 1770–1777.
  65. Hatemi, I.; Hatemi, G.; Pamuk, O.N.; Erzin, Y.; Celik, A.F. TNF-alpha antagonists and thalidomide for the management of gastrointestinal Behcet’s syndrome refractory to the conventional treatment modalities: A case series and review of the literature. Clin. Exp. Rheumatol. 2015, 33 (Suppl. 94), S129–S137.
  66. Segarra, M.; Lozano, E.; Corbera-Bellalta, M.; Vilardell, C.; Cibeira, M.T.; Esparza, J.; Izco, N.; Blade, J.; Cid, M.C. Thalidomide decreases gelatinase production by malignant B lymphoid cell lines through disruption of multiple integrin-mediated signaling pathways. Haematologica 2010, 95, 456–463.
  67. Cao, D.D.; Xu, H.L.; Liu, L.; Zheng, Y.F.; Gao, S.F.; Xu, X.M.; Ge, W. Thalidomide combined with transcatheter artierial chemoembolzation for primary hepatocellular carcinoma: A systematic review and meta-analysis. Oncotarget 2017, 8, 44976–44993.
  68. Matsuda, Y.; Fukumoto, M. Sorafenib: Complexities of Raf-dependent and Raf-independent signaling are now unveiled. Med. Mol. Morphol. 2011, 44, 183–189.
  69. Gauthier, A.; Ho, M. Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol. Res. 2013, 43, 147–154.
  70. Palmer, D.H. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 2008, 359, 378–390. [Google Scholar]
  71. Abdel-Rahman, O. Impact of baseline characteristics on outcomes of advanced HCC patients treated with sorafenib: A secondary analysis of a phase III study. J. Cancer Res. Clin. Oncol. 2018, 144, 901–908.
  72. Villanueva, A.; Chiang, D.Y.; Newell, P.; Peix, J.; Thung, S.; Alsinet, C.; Tovar, V.; Roayaie, S.; Minguez, B.; Sole, M.; et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008, 135, 1972–1983.
  73. Liu, Y.N.; Wan, R.Z.; Liu, Z.P. Recent developments of small molecule PI3K/mTOR dual inhibitors. Mini Rev. Med. Chem. 2013, 13, 2047–2059.
  74. Wang, Z.; Zhou, J.; Fan, J.; Tan, C.J.; Qiu, S.J.; Yu, Y.; Huang, X.W.; Tang, Z.Y. Sirolimus inhibits the growth and metastatic progression of hepatocellular carcinoma. J. Cancer Res. Clin. Oncol. 2009, 135, 715–722.
  75. Geissler, E.K.; Schnitzbauer, A.A.; Zulke, C.; Lamby, P.E.; Proneth, A.; Duvoux, C.; Burra, P.; Jauch, K.W.; Rentsch, M.; Ganten, T.M.; et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: A randomized, multicenter, open-label Phase 3 trial. Transplantation 2016, 100, 116–125.
  76. Koeberle, D.; Dufour, J.F.; Demeter, G.; Li, Q.; Ribi, K.; Samaras, P.; Saletti, P.; Roth, A.D.; Horber, D.; Buehlmann, M.; et al. Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): A randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29). Ann. Oncol. 2016, 27, 856–861.
  77. Wong, C.M.; Fan, S.T.; Ng, I.O. β-Catenin mutation and overexpression in hepatocellular carcinoma: Clinicopathologic and prognostic significance. Cancer 2001, 92, 136–145.
  78. Hwang, S.Y.; Deng, X.; Byun, S.; Lee, C.; Lee, S.J.; Suh, H.; Zhang, J.; Kang, Q.; Zhang, T.; Westover, K.D.; et al. Direct targeting of beta-catenin by a small molecule stimulates proteasomal degradation and suppresses oncogenic Wnt/beta-catenin signaling. Cell Rep. 2016, 16, 28–36.
  79. Arsura, M.; Cavin, L.G. Nuclear factor-kappaB and liver carcinogenesis. Cancer Lett. 2005, 229, 157–169.
  80. Wahl, K.; Siegemund, M.; Lehner, F.; Vondran, F.; Nussler, A.; Langer, F.; Krech, T.; Kontermann, R.; Manns, M.P.; Schulze-Osthoff, K.; et al. Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib. Hepatology 2013, 57, 625–636.
  81. Kim, G.P.; Mahoney, M.R.; Szydlo, D.; Mok, T.S.; Marshke, R.; Holen, K.; Picus, J.; Boyer, M.; Pitot, H.C.; Rubin, J.; et al. An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma. Investig. New Drugs 2012, 30, 387–394.
  82. Pardee, A.D.; Butterfield, L.H. Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities. Oncoimmunology 2012, 1, 48–55.
  83. Sangro, B.; Gomez-Martin, C.; de la Mata, M.; Inarrairaegui, M.; Garralda, E.; Barrera, P.; Riezu-Boj, J.I.; Larrea, E.; Alfaro, C.; Sarobe, P.; et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol. 2013, 59, 81–88.
  84. Juliana, C.; Fernandes-Alnemri, T.; Wu, J.; Datta, P.; Solorzano, L.; Yu, J.W.; Meng, R.; Quong, A.A.; Latz, E.; Scott, C.P.; et al. Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J. Biol. Chem. 2010, 285, 9792–9802.
  85. Honda, H.; Nagai, Y.; Matsunaga, T.; Okamoto, N.; Watanabe, Y.; Tsuneyama, K.; Hayashi, H.; Fujii, I.; Ikutani, M.; Hirai, Y.; et al. Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation. J. Leukoc. Biol. 2014, 96, 1087–1100.
  86. Zhang, A.H.; Liu, W.; Jiang, N.; Xu, Q.; Tan, R.X. Spirodalesol, an NLRP3 Inflammasome Activation Inhibitor. Org. Lett. 2016, 18, 6496–6499.
  87. Yu, S.X.; Chen, W.; Hu, X.Z.; Feng, S.Y.; Li, K.Y.; Qi, S.; Lei, Q.Q.; Hu, G.Q.; Li, N.; Zhou, F.H.; et al. Liver X receptors agonists suppress NLRP3 inflammasome activation. Cytokine 2017, 91, 30–37.
  88. Yang, G.; Lee, H.E.; Lee, J.Y. A pharmacological inhibitor of NLRP3 inflammasome prevents non-alcoholic fatty liver disease in a mouse model induced by high fat diet. Sci. Rep. 2016, 6, 24399.
  89. Youm, Y.H.; Nguyen, K.Y.; Grant, R.W.; Goldberg, E.L.; Bodogai, M.; Kim, D.; D’Agostino, D.; Planavsky, N.; Lupfer, C.; Kanneganti, T.D.; et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 2015, 21, 263–269.
  90. Coll, R.C.; Robertson, A.A.; Chae, J.J.; Higgins, S.C.; Munoz-Planillo, R.; Inserra, M.C.; Vetter, I.; Dungan, L.S.; Monks, B.G.; Stutz, A.; et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 2015, 21, 248–255.
  91. Gris, D.; Ye, Z.; Iocca, H.A.; Wen, H.; Craven, R.R.; Gris, P.; Huang, M.; Schneider, M.; Miller, S.D.; Ting, J.P. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J. Immunol. 2010, 185, 974–981.
  92. Inoue, M.; Williams, K.L.; Gunn, M.D.; Shinohara, M.L. NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 2012, 109, 10480–10485.
  93. Inoue, M.; Williams, K.L.; Oliver, T.; Vandenabeele, P.; Rajan, J.V.; Miao, E.A.; Shinohara, M.L. Interferon-beta therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome. Sci. Signal. 2012, 5, ra38.
  94. Llovet, J.M.; Sala, M.; Castells, L.; Suarez, Y.; Vilana, R.; Bianchi, L.; Ayuso, C.; Vargas, V.; Rodes, J.; Bruix, J. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology 2000, 31, 54–58.
  95. Ikeda, K.; Arase, Y.; Saitoh, S.; Kobayashi, M.; Suzuki, Y.; Suzuki, F.; Tsubota, A.; Chayama, K.; Murashima, N.; Kumada, H. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer. Hepatology 2000, 32, 228–232.
  96. Sakon, M.; Nagano, H.; Dono, K.; Nakamori, S.; Umeshita, K.; Yamada, A.; Kawata, S.; Imai, Y.; Iijima, S.; Monden, M. Combined intraarterial 5-fluorouracil and subcutaneous interferon-alpha therapy for advanced hepatocellular carcinoma with tumor thrombi in the major portal branches. Cancer 2002, 94, 435–442.
  97. Kubo, S.; Nishiguchi, S.; Hirohashi, K.; Tanaka, H.; Shuto, T.; Yamazaki, O.; Shiomi, S.; Tamori, A.; Oka, H.; Igawa, S.; et al. Effects of long-term postoperative interferon-alpha therapy on intrahepatic recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. A randomized, controlled trial. Ann. Intern. Med. 2001, 134, 963–967.
  98. Reinisch, W.; Holub, M.; Katz, A.; Herneth, A.; Lichtenberger, C.; Schoniger-Hekele, M.; Waldhoer, T.; Oberhuber, G.; Ferenci, P.; Gangl, A.; et al. Prospective pilot study of recombinant granulocyte-macrophage colony-stimulating factor and interferon-gamma in patients with inoperable hepatocellular carcinoma. J. Immunother. 2002, 25, 489–499.
  99. Palmieri, G.; Montella, L.; Milo, M.; Fiore, R.; Biondi, E.; Bianco, A.R.; Martignetti, A. Ultra-low-dose interleukin-2 in unresectable hepatocellular carcinoma. Am. J. Clin. Oncol. 2002, 25, 224–226.
  100. Cui, J.; Wang, N.; Zhao, H.; Jin, H.; Wang, G.; Niu, C.; Terunuma, H.; He, H.; Li, W. Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma. Int. J. Cancer 2014, 134, 342–351.
  101. Qiu, Y.; Xu, M.B.; Yun, M.M.; Wang, Y.Z.; Zhang, R.M.; Meng, X.K.; Ou-Yang, X.H.; Yun, S. Hepatocellular carcinoma-specific immunotherapy with synthesized alpha1,3-galactosyl epitope-pulsed dendritic cells and cytokine-induced killer cells. World J. Gastroenterol. 2011, 17, 5260–5266.
  102. Kamiya, T.; Chang, Y.H.; Campana, D. Expanded and activated natural killer cells for immunotherapy of hepatocellular carcinoma. Cancer Immunol. Res. 2016, 4, 574–581.
  103. Sawada, Y.; Yoshikawa, T.; Nobuoka, D.; Shirakawa, H.; Kuronuma, T.; Motomura, Y.; Mizuno, S.; Ishii, H.; Nakachi, K.; Konishi, M.; et al. Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: Immunologic evidence and potential for improving overall survival. Clin. Cancer Res. 2012, 18, 3686–3696.
  104. Voron, T.; Colussi, O.; Marcheteau, E.; Pernot, S.; Nizard, M.; Pointet, A.L.; Latreche, S.; Bergaya, S.; Benhamouda, N.; Tanchot, C.; et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 2015, 212, 139–148.
  105. Chan, A.W.; Tong, J.H.; Chan, S.L.; Lai, P.B.; To, K.F. Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology 2014, 64, 935–950.
  106. Vesely, M.D.; Kershaw, M.H.; Schreiber, R.D.; Smyth, M.J. Natural innate and adaptive immunity to cancer. Ann. Rev. Immunol. 2011, 29, 235–271.
  107. Collins, A.V.; Brodie, D.W.; Gilbert, R.J.; Iaboni, A.; Manso-Sancho, R.; Walse, B.; Stuart, D.I.; van der Merwe, P.A.; Davis, S.J. The interaction properties of costimulatory molecules revisited. Immunity 2002, 17, 201–210.
  108. Duffy, A.G.; Ulahannan, S.V.; Makorova-Rusher, O.; Rahma, O.; Wedemeyer, H.; Pratt, D.; Davis, J.L.; Hughes, M.S.; Heller, T.; ElGindi, M.; et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J. Hepatol. 2017, 66, 545–551.
  109. Shi, L.; Chen, S.; Yang, L.; Li, Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J. Hematol. Oncol. 2013, 6, 74.
  110. Dai, S.; Jia, R.; Zhang, X.; Fang, Q.; Huang, L. The PD-1/PD-Ls pathway and autoimmune diseases. Cell. Immunol. 2014, 290, 72–79.
  111. Hamanishi, J.; Mandai, M.; Ikeda, T.; Minami, M.; Kawaguchi, A.; Murayama, T.; Kanai, M.; Mori, Y.; Matsumoto, S.; Chikuma, S.; et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J. Clin. Oncol. 2015, 33, 4015–4022.
  112. El-Khoueiry, A.B.; Sangro, B.; Yau, T.; Crocenzi, T.S.; Kudo, M.; Hsu, C.; Kim, T.Y.; Choo, S.P.; Trojan, J.; Welling, T.H.R.; et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017, 389, 2492–2502.
  113. Iwai, Y.; Ishida, M.; Tanaka, Y.; Okazaki, T.; Honjo, T.; Minato, N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl. Acad. Sci. USA 2002, 99, 12293–12297.
  114. Zhong, F.; Cheng, X.; Sun, S.; Zhou, J. Transcriptional activation of PD-L1 by Sox2 contributes to the proliferation of hepatocellular carcinoma cells. Oncol. Rep. 2017, 37, 3061–3067.
  115. Liu, J.; Liu, Y.; Meng, L.; Liu, K.; Ji, B. Targeting the PD-L1/DNMT1 axis in acquired resistance to sorafenib in human hepatocellular carcinoma. Oncol. Rep. 2017, 38, 899–907.
  116. Zhang, W.; Liu, J.; Wu, Y.; Xiao, F.; Wang, Y.; Wang, R.; Yang, H.; Wang, G.; Yang, J.; Deng, H.; et al. Immunotherapy of hepatocellular carcinoma with a vaccine based on xenogeneic homologous alpha fetoprotein in mice. Biochem. Biophys. Res. Commun. 2008, 376, 10–14.
  117. Sawada, Y.; Yoshikawa, T.; Ofuji, K.; Yoshimura, M.; Tsuchiya, N.; Takahashi, M.; Nobuoka, D.; Gotohda, N.; Takahashi, S.; Kato, Y.; et al. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. Oncoimmunol. 2016, 5, e1129483.
  118. Takakura, K.; Kajihara, M.; Ito, Z.; Ohkusa, T.; Gong, J.; Koido, S. Dendritic-tumor fusion cells in cancer immunotherapy. Discov. Med. 2015, 19, 169–174.
  119. Zhao, T.; Jia, H.; Cheng, Q.; Xiao, Y.; Li, M.; Ren, W.; Li, C.; Feng, Y.; Feng, Z.; Wang, H.; et al. Nifuroxazide prompts antitumor immune response of TCL-loaded DC in mice with orthotopically-implanted hepatocarcinoma. Oncol. Rep. 2017, 37, 3405–3414.
  120. Wang, X.; Bayer, M.E.; Chen, X.; Fredrickson, C.; Cornforth, A.N.; Liang, G.; Cannon, J.; He, J.; Fu, Q.; Liu, J.; et al. Phase I trial of active specific immunotherapy with autologous dendritic cells pulsed with autologous irradiated tumor stem cells in hepatitis B-positive patients with hepatocellular carcinoma. J. Surg. Oncol. 2015, 111, 862–867.
  121. Brown, Z.J.; Yu, S.J.; Heinrich, B.; Ma, C.; Fu, Q.; Sandhu, M.; Agdashian, D.; Zhang, Q.; Korangy, F.; Greten, T.F. Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma. Cancer Immunol. Immunother. 2018, 67, 1305–1315.
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