1. Liver Cancer Institute, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai 200032, China; 2. Key Labolatory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China; 3. Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
Hepatocellular carcinoma (HCC) is a highly complex disease that is generally resistant to commonly used chemotherapy and radiotherapy. Consequently, there is an urgent need for the development of new treatment strategies for this devastating disease. In the past decade, tremendous progress has been achieved in the molecular stratification of HCCs for diagnosis, prognosis, and therapeutic decision-making. To date, the molecular classification of HCCs has been carried out through transcriptomic, genetic and epigenetic profiling of tumors. Such research has led to identification of several potential molecular targets in HCC, and subsequently, development of novel systemic agents for the treatment of HCC has begun in earnest. In this article, we review the current knowledge of the molecular pathogenesis of HCC and outline potential areas for application of this knowledge in a clinical setting. As a typical virus and inflammation-associated cancer, both host immune response and tumor microenvironment have crucial roles in HCC pathogenesis. In addition, we examine the potential of immunotherapy and strategies targeting various components of the tumor microenvironment, as well as novel molecular and cellular targets in HCC such as cancer stem cells.
Increase in specific CTL frequency and function in 12/14
[90]
Tab.2
Fig.1
1
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61(2): 69-90 doi: 10.3322/caac.20107 pmid:21296855
2
Sherman M. Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis 2010; 30(1): 3-16 doi: 10.1055/s-0030-1247128 pmid:20175029
3
Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53(3): 1020-1022 doi: 10.1002/hep.24199 pmid:21374666
4
Minouchi K, Kaneko S, Kobayashi K. Mutation of p53 gene in regenerative nodules in cirrhotic liver. J Hepatol 2002; 37(2): 231-239 doi: 10.1016/S0168-8278(02)00144-7 pmid:12127428
5
Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors. Oncogene 2006; 25(27): 3778-3786 doi: 10.1038/sj.onc.1209547 pmid:16799619
6
van Malenstein H, van Pelt J, Verslype C. Molecular classification of hepatocellular carcinoma anno 2011. Eur J Cancer 2011; 47(12): 1789-1797 doi: 10.1016/j.ejca.2011.04.027 pmid:21612914
7
Zucman-Rossi J. Molecular classification of hepatocellular carcinoma. Dig Liver Dis 2010; 42(Suppl 3): S235-S241 doi: 10.1016/S1590-8658(10)60511-7 pmid:20547309
8
Maher B. Exome sequencing takes centre stage in cancer profiling. Nature 2009; 459(7244): 146-147 doi: 10.1038/459146b pmid:19444175
9
Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet 2011; 43(9): 828-829 doi: 10.1038/ng.903 pmid:21822264
10
Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, LeBlanc AC, Donovan DJ, Thung SN, Solé M, Tovar V, Alsinet C, Ramos AH, Barretina J, Roayaie S, Schwartz M, Waxman S, Bruix J, Mazzaferro V, Ligon AH, Najfeld V, Friedman SL, Sellers WR, Meyerson M, Llovet JM. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 2008; 68(16): 6779-6788 doi: 10.1158/0008-5472.CAN-08-0742 pmid:18701503
11
Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, Ye SL, Liu YK, Tang ZY, Wang XW. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003; 9(4): 416-423 doi: 10.1038/nm843 pmid:12640447
12
Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, Mikaelyan A, Roberts LR, Demetris AJ, Sun Z, Nevens F, Roskams T, Thorgeirsson SS. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 2006; 12(4): 410-416 doi: 10.1038/nm1377 pmid:16532004
13
Gao Q, Wang XY, Qiu SJ, Zhou J, Shi YH, Zhang BH, Fan J. Tumor stroma reaction-related gene signature predicts clinical outcome in human hepatocellular carcinoma. Cancer Sci 2011; 102(8): 1522-1531 doi: 10.1111/j.1349-7006.2011.01981.x pmid:21564420
14
Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 2006; 6(4): 259-269 doi: 10.1038/nrc1840 pmid:16557279
15
Toffanin S, Hoshida Y, Lachenmayer A, Villanueva A, Cabellos L, Minguez B, Savic R, Ward SC, Thung S, Chiang DY, Alsinet C, Tovar V, Roayaie S, Schwartz M, Bruix J, Waxman S, Friedman SL, Golub T, Mazzaferro V, Llovet JMMicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology 2011;140(5):1618-1628 . e16 doi: 10.1053/j.gastro.2011.02.009 pmid:21324318
16
Zhou J, Yu L, Gao X, Hu J, Wang J, Dai Z, Wang JF, Zhang Z, Lu S, Huang X, Wang Z, Qiu S, Wang X, Yang G, Sun H, Tang Z, Wu Y, Zhu H, Fan J A plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol 2011;29(36):4781-4788 doi: 10.1200/JCO.2011.38.26972 pmid:2105822
17
Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, Zanetti KA, Ye QH, Qin LX, Croce CM, Tang ZY, Wang XW. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 2008; 47(3): 897-907 doi: 10.1002/hep.22160 pmid:18176954
18
Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, Ambs S, Chen Y, Meltzer PS, Croce CM, Qin LX, Man K, Lo CM, Lee J, Ng IO, Fan J, Tang ZY, Sun HC, Wang XW. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 2009; 361(15): 1437-1447 doi: 10.1056/NEJMoa0901282 pmid:19812400
19
Tsai WC, Hsu PW, Lai TC, Chau GY, Lin CW, Chen CM, Lin CD, Liao YL, Wang JL, Chau YP, Hsu MT, Hsiao M, Huang HD, Tsou AP. MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology 2009; 49(5): 1571-1582 doi: 10.1002/hep.22806 pmid:19296470
20
Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS. Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene 2009; 28(40): 3526-3536 doi: 10.1038/onc.2009.211 pmid:19617899
21
Hou J, Lin L, Zhou W, Wang Z, Ding G, Dong Q, Qin L, Wu X, Zheng Y, Yang Y, Tian W, Zhang Q, Wang C, Zhang Q, Zhuang SM, Zheng L, Liang A, Tao W, Cao X. Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell 2011; 19(2): 232-243 doi: 10.1016/j.ccr.2011.01.001 pmid:21316602
22
Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B, Mazzaferro V, Lowe SW, Croce CM, Dejean A. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci USA 2010; 107(1): 264-269 doi: 10.1073/pnas.0907904107 pmid:20018759
23
Li J, Wang Y, Yu W, Chen J, Luo J. Expression of serum miR-221 in human hepatocellular carcinoma and its prognostic significance. Biochem Biophys Res Commun 2011; 406(1): 70-73 doi: 10.1016/j.bbrc.2011.01.111 pmid:21295551
24
Arai E, Ushijima S, Gotoh M, Ojima H, Kosuge T, Hosoda F, Shibata T, Kondo T, Yokoi S, Imoto I, Inazawa J, Hirohashi S, Kanai Y. Genome-wide DNA methylation profiles in liver tissue at the precancerous stage and in hepatocellular carcinoma. Int J Cancer 2009; 125(12): 2854-2862 doi: 10.1002/ijc.24708 pmid:19569176
25
Calvisi DF, Ladu S, Gorden A, Farina M, Lee JS, Conner EA, Schroeder I, Factor VM, Thorgeirsson SS. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. J Clin Invest 2007; 117(9): 2713-2722 doi: 10.1172/JCI31457 pmid:17717605
26
Sherman M. Recurrence of hepatocellular carcinoma. N Engl J Med 2008; 359(19): 2045-2047 doi: 10.1056/NEJMe0807581 pmid:18923166
27
Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, Gupta S, Moore J, Wrobel MJ, Lerner J, Reich M, Chan JA, Glickman JN, Ikeda K, Hashimoto M, Watanabe G, Daidone MG, Roayaie S, Schwartz M, Thung S, Salvesen HB, Gabriel S, Mazzaferro V, Bruix J, Friedman SL, Kumada H, Llovet JM, Golub TR. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008; 359(19): 1995-2004 doi: 10.1056/NEJMoa0804525 pmid:18923165
28
Jiang J, Gusev Y, Aderca I, Mettler TA, Nagorney DM, Brackett DJ, Roberts LR, Schmittgen TD. Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res 2008; 14(2): 419-427 doi: 10.1158/1078-0432.CCR-07-0523 pmid:18223217
29
Lou C, Du Z, Yang B, Gao Y, Wang Y, Fang S. Aberrant DNA methylation profile of hepatocellular carcinoma and surgically resected margin. Cancer Sci 2009; 100(6): 996-1004 doi: 10.1111/j.1349-7006.2009.01138.x pmid:19385975
30
Villanueva A, Hoshida Y, Toffanin S, Lachenmayer A, Alsinet C, Savic R, Cornella H, Llovet JM. New strategies in hepatocellular carcinoma: genomic prognostic markers. Clin Cancer Res 2010; 16(19): 4688-4694 doi: 10.1158/1078-0432.CCR-09-1811 pmid:20713493
31
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, H?ussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, the SISG. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359(4): 378-390 doi: 10.1056/NEJMoa0708857 pmid:18650514
32
Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology 2011; 140(5): 1410-1426 doi: 10.1053/j.gastro.2011.03.006 pmid:21406195
33
Ribatti D, Vacca A, Nico B, Sansonno D, Dammacco F. Angiogenesis and anti-angiogenesis in hepatocellular carcinoma. Cancer Treat Rev 2006; 32(6): 437-444 doi: 10.1016/j.ctrv.2006.06.002 pmid:16870349
34
Zhu AX, Blaszkowsky LS, Ryan DP, Clark JW, Muzikansky A, Horgan K, Sheehan S, Hale KE, Enzinger PC, Bhargava P, Stuart K. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24(12): 1898-1903 doi: 10.1200/JCO.2005.04.9130 pmid:16622265
35
Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Huber J, Nakatani T, Tsujinoue H, Yanase K, Imazu H, Fukui H. Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology 2002; 35(4): 834-842 doi: 10.1053/jhep.2002.32541 pmid:11915029
36
Thomas MB, Chadha R, Glover K, Wang X, Morris J, Brown T, Rashid A, Dancey J, Abbruzzese JL. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 2007; 110(5): 1059-1067 doi: 10.1002/cncr.22886 pmid:17623837
37
Ramanathan RK, Belani CP, Singh DA, Tanaka M, Lenz HJ, Yen Y, Kindler HL, Iqbal S, Longmate J, Mack PC, Lurje G, Gandour-Edwards R, Dancey J, Gandara DR. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 2009; 64(4): 777-783 doi: 10.1007/s00280-009-0927-7 pmid:19169683
38
H?pfner M, Sutter AP, Huether A, Schuppan D, Zeitz M, Scherübl H. Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma. J Hepatol 2004; 41(6): 1008-1016 doi: 10.1016/j.jhep.2004.08.024 pmid:15582135
39
Fuchs BC, Fujii T, Dorfman JD, Goodwin JM, Zhu AX, Lanuti M, Tanabe KK. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res 2008; 68(7): 2391-2399 doi: 10.1158/0008-5472.CAN-07-2460 pmid:18381447
40
Comoglio PM, Giordano S, Trusolino L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 2008; 7(6): 504-516 doi: 10.1038/nrd2530 pmid:18511928
41
Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, Tovar V, Roayaie S, Minguez B, Sole M, Battiston C, Van Laarhoven S, Fiel MI, Di Feo A, Hoshida Y, Yea S, Toffanin S, Ramos A, Martignetti JA, Mazzaferro V, Bruix J, Waxman S, Schwartz M, Meyerson M, Friedman SL, Llovet JM. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008;135(6): 1972-1983 . e1-11 doi: 10.1053/j.gastro.2008.08.008 pmid:18929564
42
Huynh H, Chow KH, Soo KC, Toh HC, Choo SP, Foo KF, Poon D, Ngo VC, Tran E. RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma. J Cell Mol Med 2009; 13(7): 1371-1380 doi: 10.1111/j.1582-4934.2008.00364.x pmid:18466352
43
Zhu AX, Abrams TA, Miksad R, Blaszkowsky LS, Meyerhardt JA, Zheng H, Muzikansky A, Clark JW, Kwak EL, Schrag D, Jors KR, Fuchs CS, Iafrate AJ, Borger DR, Ryan DP. Phase 1/2 study of everolimus in advanced hepatocellular carcinoma. Cancer 2011;117(22):5094-5102 doi: 10.1002/cncr.26165 pmid:21538343.
44
Newell P, Toffanin S, Villanueva A, Chiang DY, Minguez B, Cabellos L, Savic R, Hoshida Y, Lim KH, Melgar-Lesmes P, Yea S, Peix J, Deniz K, Fiel MI, Thung S, Alsinet C, Tovar V, Mazzaferro V, Bruix J, Roayaie S, Schwartz M, Friedman SL, Llovet JM. Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol 2009; 51(4): 725-733 doi: 10.1016/j.jhep.2009.03.028 pmid:19665249
45
Wang Z, Zhou J, Fan J, Tan CJ, Qiu SJ, Yu Y, Huang XW, Tang ZY. Sirolimus inhibits the growth and metastatic progression of hepatocellular carcinoma. J Cancer Res Clin Oncol 2009; 135(5): 715-722 doi: 10.1007/s00432-008-0506-z pmid:19002496
46
Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008; 48(4): 1312-1327 doi: 10.1002/hep.22506 pmid:18821591
47
Shi YH, Ding WX, Zhou J, He JY, Xu Y, Gambotto AA, Rabinowich H, Fan J, Yin XM. Expression of X-linked inhibitor-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence. Hepatology 2008; 48(2): 497-507 doi: 10.1002/hep.22393 pmid:18666224
48
Ding ZB, Shi YH, Zhou J, Qiu SJ, Xu Y, Dai Z, Shi GM, Wang XY, Ke AW, Wu B, Fan J. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res 2008; 68(22): 9167-9175 doi: 10.1158/0008-5472.CAN-08-1573 pmid:19010888
49
Shi YH, Ding ZB, Zhou J, Qiu SJ, Fan J. Prognostic significance of Beclin 1-dependent apoptotic activity in hepatocellular carcinoma. Autophagy 2009; 5(3): 380-382 doi: 10.4161/auto.5.3.7658 pmid:19145109
50
Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol 2011; 21(1): 35-43 doi: 10.1016/j.semcancer.2010.10.007 pmid:20946957
51
Mazzocca A, Fransvea E, Lavezzari G, Antonaci S, Giannelli G. Inhibition of transforming growth factor beta receptor I kinase blocks hepatocellular carcinoma growth through neo-angiogenesis regulation. Hepatology 2009; 50(4): 1140-1151 doi: 10.1002/hep.23118 pmid:19711426
52
Fransvea E, Mazzocca A, Antonaci S, Giannelli G. Targeting transforming growth factor (TGF)-betaRI inhibits activation of beta1 integrin and blocks vascular invasion in hepatocellular carcinoma. Hepatology 2009; 49(3): 839-850 doi: 10.1002/hep.22731 pmid:19115199
53
Fransvea E, Angelotti U, Antonaci S, Giannelli G. Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology 2008; 47(5): 1557-1566 doi: 10.1002/hep.22201 pmid:18318443
54
Ke AW, Shi GM, Zhou J, Huang XY, Shi YH, Ding ZB, Wang XY, Devbhandari RP, Fan JCD151 amplifies signaling by integrin alpha6beta1 to PI3K and induces the epithelial-mesenchymal transition in HCC cells. Gastroenterology 2011;140(5):1629-1641 . e15 21320503 doi: 10.1053/j.gastro.2011.02.008
55
Shi GM, Ke AW, Zhou J, Wang XY, Xu Y, Ding ZB, Devbhandari RP, Huang XY, Qiu SJ, Shi YH, Dai Z, Yang XR, Yang GH, Fan J. CD151 modulates expression of matrix metalloproteinase 9 and promotes neoangiogenesis and progression of hepatocellular carcinoma. Hepatology 2010; 52(1): 183-196 doi: 10.1002/hep.23661 pmid:20578262
56
Ke AW, Shi GM, Zhou J, Wu FZ, Ding ZB, Hu MY, Xu Y, Song ZJ, Wang ZJ, Wu JC, Bai DS, Li JC, Liu KD, Fan J. Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology 2009; 49(2): 491-503 doi: 10.1002/hep.22639 pmid:19065669
57
Gao Y, Yao A, Zhang W, Lu S, Yu Y, Deng L, Yin A, Xia Y, Sun B, Wang X. Human mesenchymal stem cells overexpressing pigment epithelium-derived factor inhibit hepatocellular carcinoma in nude mice. Oncogene 2010; 29(19): 2784-2794 doi: 10.1038/onc.2010.38 pmid:20190814
58
Li YW, Qiu SJ, Fan J, Zhou J, Gao Q, Xiao YS, Xu YF. Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol 2011; 54(3): 497-505 doi: 10.1016/j.jhep.2010.07.044 pmid:21112656
59
Kuang DM, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, Yin XY, Zheng L. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol 2011; 54(5): 948-955 doi: 10.1016/j.jhep.2010.08.041 pmid:21145847
60
Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, Wu WZ, Wang L, Tang ZY, Sun HC. 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 2008; 26(16): 2707-2716 doi: 10.1200/JCO.2007.15.6521 pmid:18509183
61
Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25(18): 2586-2593 doi: 10.1200/JCO.2006.09.4565 pmid:17577038
62
Gao Q, Zhou J, Wang XY, Qiu SJ, Song K, Huang XW, Sun J, Shi YH, Li BZ, Xiao YS, Fan J. Infiltrating memory/Senescent T cell ratio predicts extrahepatic metastasis of hepatocellular carcinoma. Ann Surg Oncol 2012;19(2):455-466 doi: 10.1245/s10434-011-1864-3 pmid:21792513.
63
Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000; 356(9232): 802-807 doi: 10.1016/S0140-6736(00)02654-4 pmid:11022927
64
Greten TF, Manns MP, Korangy F. Immunotherapy of hepatocellular carcinoma. J Hepatol 2006; 45(6): 868-878 doi: 10.1016/j.jhep.2006.09.004 pmid:17046096
65
Llovet JM, Sala M, Castells L, Suarez Y, Vilana R, Bianchi L, Ayuso C, Vargas V, Rodés J, Bruix J. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology 2000; 31(1): 54-58 doi: 10.1002/hep.510310111 pmid:10613728
66
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(2): 228-232 doi: 10.1053/jhep.2000.9409 pmid:10915728
67
Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Yamazaki O, Shiomi S, Tamori A, Oka H, Igawa S, Kuroki T, Kinoshita H. 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(10): 963-967 pmid:11352697
68
Reinisch W, Holub M, Katz A, Herneth A, Lichtenberger C, Schoniger-Hekele M, Waldhoer T, Oberhuber G, Ferenci P, Gangl A, Mueller C. Prospective pilot study of recombinant granulocyte-macrophage colony-stimulating factor and interferon-gamma in patients with inoperable hepatocellular carcinoma. J Immunother 2002; 25(6): 489-499 doi: 10.1097/00002371-200211000-00005 pmid:12439346
69
Palmieri G, Montella L, Milo M, Fiore R, Biondi E, Bianco AR, Martignetti A. Ultra-low-dose interleukin-2 in unresectable hepatocellular carcinoma. Am J Clin Oncol 2002; 25(3): 224-226 doi: 10.1097/00000421-200206000-00003 pmid:12040276
70
Iwashita Y, Tahara K, Goto S, Sasaki A, Kai S, Seike M, Chen CL, Kawano K, Kitano S. A phase I study of autologous dendritic cell-based immunotherapy for patients with unresectable primary liver cancer. Cancer Immunol Immunother 2003; 52(3): 155-161 pmid:12649744
71
Patt YZ, Hassan MM, Lozano RD, Brown TD, Vauthey JN, Curley SA, Ellis LM. Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol 2003; 21(3): 421-427 doi: 10.1200/JCO.2003.10.103 pmid:12560429
72
Feun LG, O’Brien C, Molina E, Rodriguez M, Jeffers L, Schiff ER, Marini A, Savaraj N, Ardalan B. Recombinant leukocyte interferon, doxorubicin, and 5FUDR in patients with hepatocellular carcinoma-A phase II trial. J Cancer Res Clin Oncol 2003; 129(1): 17-20 pmid:12618896
73
Kuang M, Peng BG, Lu MD, Liang LJ, Huang JF, He Q, Hua YP, Totsuka S, Liu SQ, Leong KW, Ohno T. Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res 2004; 10(5): 1574-1579 doi: 10.1158/1078-0432.CCR-03-0071 pmid:15014006
74
Shi M, Zhang B, Tang ZR, Lei ZY, Wang HF, Feng YY, Fan ZP, Xu DP, Wang FS. Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma. World J Gastroenterol 2004; 10(8): 1146-1151 pmid:15069715
75
Chen S, Li B, Xie H, Xu L, Niu G, Fan K, Fan Q. Phase I clinical trial of targeted therapy using 131I-Hepama-1 mAb in patients with hepatocellular carcinoma. Cancer Biother Radiopharm 2004; 19(5): 589-600 pmid:15650451
76
Lee WC, Wang HC, Hung CF, Huang PF, Lia CR, Chen MF. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother 2005; 28(5): 496-504 doi: 10.1097/01.cji.0000171291.72039.e2 pmid:16113606
77
Yin XY, Lü MD, Liang LJ, Lai JM, Li DM, Kuang M. Systemic chemo-immunotherapy for advanced-stage hepatocellular carcinoma. World J Gastroenterol 2005; 11(16): 2526-2529 pmid:15832431
78
Chi KH, Liu SJ, Li CP, Kuo HP, Wang YS, Chao Y, Hsieh SL. Combination of conformal radiotherapy and intratumoral injection of adoptive dendritic cell immunotherapy in refractory hepatoma. J Immunother 2005; 28(2): 129-135 doi: 10.1097/01.cji.0000154248.74383.5e pmid:15725956
79
Butterfield LH, Ribas A, Dissette VB, Lee Y, Yang JQ, De la Rocha P, Duran SD, Hernandez J, Seja E, Potter DM, McBride WH, Finn R, Glaspy JA, Economou JS. A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res 2006; 12(9): 2817-2825 doi: 10.1158/1078-0432.CCR-05-2856 pmid:16675576
80
Chen ZN, Mi L, Xu J, Song F, Zhang Q, Zhang Z, Xing JL, Bian HJ, Jiang JL, Wang XH, Shang P, Qian AR, Zhang SH, Li L, Li Y, Feng Q, Yu XL, Feng Y, Yang XM, Tian R, Wu ZB, Leng N, Mo TS, Kuang AR, Tan TZ, Li YC, Liang DR, Lu WS, Miao J, Xu GH, Zhang ZH, Nan KJ, Han J, Liu QG, Zhang HX, Zhu P. Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/II trials. Int J Radiat Oncol Biol Phys 2006; 65(2): 435-444 doi: 10.1016/j.ijrobp.2005.12.034 pmid:16690431
81
Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Bhoori S, Capussotti L, Calise F, Pellicci R, Belli G, Tagger A, Colombo M, Bonino F, Majno P, Llovet JM. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology 2006; 44(6): 1543-1554 doi: 10.1002/hep.21415 pmid:17133492
82
Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ, Fan J, Zhou XD, Zhou J, Qiu SJ, Shen YF. Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol 2006; 132(7): 458-465 doi: 10.1007/s00432-006-0091-y pmid:16557381
83
Lo CM, Liu CL, Chan SC, Lam CM, Poon RT, Ng IO, Fan ST, Wong J. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg 2007; 245(6): 831-842 doi: 10.1097/01.sla.0000245829.00977.45 pmid:17522506
84
Kudo M, Sakaguchi Y, Chung H, Hatanaka K, Hagiwara S, Ishikawa E, Takahashi S, Kitai S, Inoue T, Minami Y, Ueshima K. Long-term interferon maintenance therapy improves survival in patients with HCV-related hepatocellular carcinoma after curative radiofrequency ablation. A matched case-control study. Oncology 2007; 72(Suppl 1): 132-138 doi: 10.1159/000111719 pmid:18087194
85
Weng DS, Zhou J, Zhou QM, Zhao M, Wang QJ, Huang LX, Li YQ, Chen SP, Wu PH, Xia JC. Minimally invasive treatment combined with cytokine-induced killer cells therapy lower the short-term recurrence rates of hepatocellular carcinomas. J Immunother 2008; 31(1): 63-71 doi: 10.1097/CJI.0b013e31815a121b pmid:18157013
86
Dollinger MM, Behrens CM, Lesske J, Behl S, Behrmann C, Fleig WE. Thymostimulin in advanced hepatocellular carcinoma: a phase II trial. BMC Cancer 2008; 8(1): 72 doi: 10.1186/1471-2407-8-72 pmid:18366627
87
Dong H, Li Q, Wang J, Zhang T, Kong DL. A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis 2009; 41(1): 36-41 doi: 10.1016/j.dld.2008.04.007 pmid:18818130
88
Palmer DH, Midgley RS, Mirza N, Torr EE, Ahmed F, Steele JC, Steven NM, Kerr DJ, Young LS, Adams DH. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 2009; 49(1): 124-132 doi: 10.1002/hep.22626 pmid:18980227
89
Greten TF, Ormandy LA, Fikuart A, H?chst B, Henschen S, H?rning M, Manns MP, Korangy F. Low-dose cyclophosphamide treatment impairs regulatory T cells and unmasks AFP-specific CD4+ T-cell responses in patients with advanced HCC. J Immunother 2010; 33(2): 211-218 doi: 10.1097/CJI.0b013e3181bb499f pmid:20139774
90
Yoshikawa T, Nakatsugawa M, Suzuki S, Shirakawa H, Nobuoka D, Sakemura N, Motomura Y, Tanaka Y, Hayashi S, Nakatsura T. HLA-A2-restricted glypican-3 peptide-specific CTL clones induced by peptide vaccine show high avidity and antigen-specific killing activity against tumor cells. Cancer Sci 2011; 102(5): 918-925 doi: 10.1111/j.1349-7006.2011.01896.x pmid:21281401
91
Breous E, Thimme R. Potential of immunotherapy for hepatocellular carcinoma. J Hepatol 2011; 54(4): 830-834 doi: 10.1016/j.jhep.2010.10.013 pmid:21145836
92
Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, Xiao YS, Xu Y, Fan J. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009; 15(3): 971-979 doi: 10.1158/1078-0432.CCR-08-1608 pmid:19188168
93
Cai MY, Xu YF, Qiu SJ, Ju MJ, Gao Q, Li YW, Zhang BH, Zhou J, Fan J. Human leukocyte antigen-G protein expression is an unfavorable prognostic predictor of hepatocellular carcinoma following curative resection. Clin Cancer Res 2009; 15(14): 4686-4693 doi: 10.1158/1078-0432.CCR-09-0463 pmid:19584149
94
Eyler CE, Rich JN. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol 2008; 26(17): 2839-2845 doi: 10.1200/JCO.2007.15.1829 pmid:18539962
95
Shi GM, Xu Y, Fan J, Zhou J, Yang XR, Qiu SJ, Liao Y, Wu WZ, Ji Y, Ke AW, Ding ZB, He YZ, Wu B, Yang GH, Qin WZ, Zhang W, Zhu J, Min ZH, Wu ZQ. Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials. J Cancer Res Clin Oncol 2008; 134(11): 1155-1163 doi: 10.1007/s00432-008-0407-1 pmid:18470535
96
Haraguchi N, Ishii H, Mimori K, Tanaka F, Ohkuma M, Kim HM, Akita H, Takiuchi D, Hatano H, Nagano H, Barnard GF, Doki Y, Mori M. CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest 2010; 120(9): 3326-3339 doi: 10.1172/JCI42550 pmid:20697159
97
Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E, Reid LM, Minato H, Honda M, Kaneko S, Tang ZY, Wang XW. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 2009; 136(3): 1012-1024 doi: 10.1053/j.gastro.2008.12.004 pmid:19150350
98
Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, Chu PW, Lam CT, Poon RT, Fan ST. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 2008; 13(2): 153-166 doi: 10.1016/j.ccr.2008.01.013 pmid:18242515
99
Yin S, Li J, Hu C, Chen X, Yao M, Yan M, Jiang G, Ge C, Xie H, Wan D, Yang S, Zheng S, Gu J. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 2007; 120(7): 1444-1450 doi: 10.1002/ijc.22476 pmid:17205516
100
Yamashita T, Honda M, Nio K, Nakamoto Y, Yamashita T, Takamura H, Tani T, Zen Y, Kaneko S. Oncostatin m renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-Fluorouracil by inducing hepatocytic differentiation. Cancer Res 2010; 70(11): 4687-4697 doi: 10.1158/0008-5472.CAN-09-4210 pmid:20484035
101
Mishra L, Banker T, Murray J, Byers S, Thenappan A, He AR, Shetty K, Johnson L, Reddy EP. Liver stem cells and hepatocellular carcinoma. Hepatology 2009; 49(1): 318-329 doi: 10.1002/hep.22704 pmid:19111019
102
Yang XR, Xu Y, Yu B, Zhou J, Qiu SJ, Shi GM, Zhang BH, Wu WZ, Shi YH, Wu B, Yang GH, Ji Y, Fan J. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut 2010; 59(7): 953-962 doi: 10.1136/gut.2008.176271 pmid:20442200
