Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2012, Vol. 6 Issue (2) : 122-133     DOI: 10.1007/s11684-012-0193-7
Translational medicine in hepatocellular carcinoma
Qiang Gao1,2, Yinghong Shi1,2, Xiaoying Wang1,2, Jian Zhou1,2,3, Shuangjian Qiu1,2, Jia Fan1,2,3()
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
Download: PDF(230 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

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.

Keywords hepatocellular carcinoma      molecular classification      molecular targeted therapies      tumor microenvironment      immunotherapy     
Corresponding Authors: Fan Jia,   
Issue Date: 05 June 2012
URL:     OR
DrugsPhasesTrials, nTargets
1Sorafenib1, 1–2, 2, 3, 467BRAF, VEGFR, PDGFR
2Brivanib1, 2, 36FGFR, VEGFR, PDGFR
3Sunitinib2, 36VEGFR, PDGFR, CKIT
4Linifanib2, 32VEGF, PDGFR
6Bevacizumab1, 1–2, 220VEGF
7Cediranib1, 23VEGFR
8AZD62441–2, 24MEK
9Bortezomib1, 24Proteasome
10TAC-1011–2, 24RAR-a
11Everolimus1, 1–2, 2, 37MTORC1
12Rapamycin1, 2–3, 36MTORC1
13Temsirolimus1, 24MTORC1
14AZD80551–21MTORC1, MTORC2
15ARQ1971, 22MET
17Erlotinib1, 1–2, 2, 313EGFR
18Cetuximab1, 23EGFR
20Lapatinib22EGFR, HER2/neu
22Pazopanib22VEGFR, PDGFR, CKIT
23Licartin2, 42HAb18G/CD147
24Alvocidib1, 22Cyclin-dependent kinase
25Cixutumumab1, 23IGF-1R
26OSI-90622IGF-1R, IR
28AVE16421, 21IGF-1R
30PI-882, 33Endo-β-D-glucuronidase heparinase
36Regorafenib21VEGFR, TIE-2
37E70801–21VEGFR, FGFR, SCFR
40Axitinib21VEGFR, PDGFR, CKIT
41Vandetanib21EGFR, VEGFR, RET
49Ispinesib21Kinesin spindel protein
50MLN823721Aurora kinase
52Belinostat1–21Histone deacetylase
53LBH58911Histone deacetylase
54Panobinostat11Histone deacetylase
55Resminostat21Histone deacetylase
56Vorinostat11Histone deacetylase
57Talabostat11Dipeptidyl peptidases
Tab.1  Molecular therapies currently under evaluation in HCC
YearStrategiesPatients, nResponsesReferences
2000Adjuvant: activated autologous lymphocytes vs. no treatment75/75Longer RFS after transfer of activated lymphocytes[63]
Advanced HCC: IFN-α2b vs. no treatment28/30No survival difference[65]
Adjuvant: IFN-β vs. no treatment10/10Recurrence rate after 24 months: 0 vs. 100% without treatment[66]
2001Adjuvant: IFN-α vs. no treatment15/15Recurrence rate: 5/15 vs. 12/15 without treatment[67]
2002Advanced HCC: GM-CSF+ IFN-α15OS after 26 weeks: 40%[68]
Advanced HCC: low dose IL-2182/18 CR, 1/18 PR[69]
2003Advanced HCC: DC pulsed with autologous tumor10Feasibility[70]
Advanced HCC: 5-FU IFN-α2b431/36 CR, 8/36 PR[71]
Advanced HCC: doxorubicin+ 5-FU IFN-α2b302/30 PR[72]
2004Adjuvant: formalin-fixed tumor vaccine vs. no treatment9/13Recurrence rate: 3/18 vs. 13/21 without treatment[73]
Advanced HCC: CIK13Feasibility[74]
Advanced HCC: 131I-Hepama-1 mAb32Median survival: 3 months[75]
2005Advanced HCC: tumor lysate-pulsed DC314/31 PR[76]
Advanced HCC: cisplatin+ doxorubicin+ 5-FU+ IFN-2α264/26 PR[77]
Advanced HCC: local radiation+ intratumoral DC injection142/12 PR[78]
2006Advanced HCC: DC pulsed with AFP peptides10AFP-specific T cells in 6/10 patients[79]
Advanced HCC: 131I-labeled Hab18G/CD147- specific mAb1066/73 PR, 14/73 minor response, 43/73 stable disease; 21-month survival rate: 44.54%[80]
Adjuvant: IFN-α vs. no treatment150No difference in RFS; a benefit on late recurrences in HCV-pure patients (HR: 0.3; 95% CI: 0.09-0.9; P = 0.04)[81]
Adjuvant: IFN-α vs. no treatment236Median OS 63.8 months vs. 38.8 months in control group; Median RFS 31.2 vs. 17.7 months in control group[82]
2007Adjuvant: IFN-α vs. no treatment40No survival benefit for TNM stage I/II tumors; 5-year survival of stage III/IVA tumors 68% vs. 24% without treatment[83]
Adjuvant: IFN-α vs. no treatment1275-year survival rate 83% vs. 66% without treatment[84]
2008Advanced HCC: TACE+ autologous CIK85The 1-year and 18-month recurrence rates: 8.9% and 15.6% vs. 30.0% and 40.0% of the control group[85]
Advanced HCC: thymostimulin442/39 CR (one after RF), 5/39 PR, 24/39 disease[86]
2009Adjuvant: CIK vs. no treatment127Disease-free survival rates significantly higher in CIK-I (P = 0.001) and CIK-II groups (P = 0.004) than in control group[87]
Advanced HCC: DC pulsed with tumor lysate351/35 PR, 28% PR or stable disease[88]
2010Advanced HCC: low-dose cyclophosphamide13Decrease in frequency and function of regulatory T cells; unmask of AFP-specific T cell responses in 6/13[89]
2011Advanced HCC: HLA-A2-restricted GPC3 peptide vaccine14Increase in specific CTL frequency and function in 12/14[90]
Tab.2  Immunotherapy trials in HCC since 2000 (modified according to Greten [])
Fig.1  The immunosuppressive microenvironment of HCC. Antitumor response at the tumor microenvironment is rerouted in a tumor-promoting direction. Tumor suppression mediated by regulatory T cells (Tregs), tumor-associated macrophages (TAM) /neutrophils (TAN), myeloid-derived suppressor cells (MDSC) and various immuno-inhibitory molecules, such as B7-H1, B7-H3, HLA-G and soluble factors, counterbalances the antitumor effect of cytotoxic T cells (CTLs), T helper cells, natural killer cells (NKs), and dendritic cells (DCs). TAM and TAN are distinct M2 and N2 polarized populations, respectively, and promote tumor progression.
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
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
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
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
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
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
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
[1] Xinsen Xu,Yanyan Zhou,Runchen Miao,Wei Chen,Kai Qu,Qing Pang,Chang Liu. Transcriptional modules related to hepatocellular carcinoma survival: coexpression network analysis[J]. Front. Med., 2016, 10(2): 183-190.
[2] Zhi Xu,Chunxiang Cao,Haiyan Xia,Shujing Shi,Lingzhi Hong,Xiaowei Wei,Dongying Gu,Jianmin Bian,Zijun Liu,Wenbin Huang,Yixin Zhang,Song He,Nikki Pui-Yue Lee,Jinfei Chen. Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma[J]. Front. Med., 2016, 10(1): 52-60.
[3] Felice Ho-Ching Tsang,Sandy Leung-Kuen Au,Lai Wei,Dorothy Ngo-Yin Fan,Joyce Man-Fong Lee,Carmen Chak-Lui Wong,Irene Oi-Lin Ng,Chun-Ming Wong. MicroRNA-142-3p and microRNA-142-5p are downregulated in hepatocellular carcinoma and exhibit synergistic effects on cell motility[J]. Front. Med., 2015, 9(3): 331-343.
[4] Farhad Sahebjam,John M. Vierling. Autoimmune hepatitis[J]. Front. Med., 2015, 9(2): 187-219.
[5] Guanghua Rong,Wenlin Bai,Zheng Dong,Chunping Wang,Yinying Lu,Zhen Zeng,Jianhui Qu,Min Lou,Hong Wang,Xudong Gao,Xiujuan Chang,Linjing An,Yan Chen,Yongping Yang. Cryotherapy for cirrhosis-based hepatocellular carcinoma: a single center experience from 1595 treated cases[J]. Front. Med., 2015, 9(1): 63-71.
[6] Marielle Reataza,David K. Imagawa. Advances in managing hepatocellular carcinoma[J]. Front. Med., 2014, 8(2): 175-189.
[7] Kai Qu,Ting Lin,Zhixin Wang,Sinan Liu,Hulin Chang,Xinsen Xu,Fandi Meng,Lei Zhou,Jichao Wei,Minghui Tai,Yafeng Dong,Chang Liu. Reactive oxygen species generation is essential for cisplatin-induced accelerated senescence in hepatocellular carcinoma[J]. Front. Med., 2014, 8(2): 227-235.
[8] Du Yan, Han Xue, Pu Rui, Xie Jiaxin, Zhang Yuwei, Cao Guangwen. Association of miRNA-122-binding site polymorphism at the interleukin-1 α gene and its interaction with hepatitis B virus mutations with hepatocellular carcinoma risk[J]. Front. Med., 2014, 8(2): 217-226.
[9] Carmen Chak-Lui Wong, Alan Ka-Lun Kai, Irene Oi-Lin Ng. The impact of hypoxia in hepatocellular carcinoma metastasis[J]. Front Med, 2014, 8(1): 33-41.
[10] Lunxiu Qin. Osteopontin is a promoter for hepatocellular carcinoma metastasis: a summary of 10 years of studies[J]. Front Med, 2014, 8(1): 24-32.
[11] Li Shang, Mingrong Wang. Molecular alterations and clinical relevance in esophageal squamous cell carcinoma[J]. Front Med, 2013, 7(4): 401-410.
[12] Beicheng Sun, Michael Karin. Inflammation and liver tumorigenesis[J]. Front Med, 2013, 7(2): 242-254.
[13] Chuanbao Zhang, Zhaoshi Bao, Wei Zhang, Tao Jiang. Progress on molecular biomarkers and classification of malignant gliomas[J]. Front Med, 2013, 7(2): 150-156.
[14] Shuangwei Li, Diane DiFang Hsu, Hongyang Wang, Gen-Sheng Feng. Dual faces of SH2-containing protein-tyrosine phosphatase Shp2/PTPN11 in tumorigenesis[J]. Front Med, 2012, 6(3): 275-279.
[15] Min Cheng, Jian Zhang, Wen Jiang, Yongyan Chen, Zhigang Tian. Natural killer cell lines in tumor immunotherapy[J]. Front Med, 2012, 6(1): 56-66.
Full text