Molecular diagnosis of hepatocellular carcinoma: trends in biomarkers combination to enhance early cancer detection

Abstract

Despite of the advances in clinical imaging and applied research in proteomic biomarkers, liver cancer, especially hepatocellular carcinoma remains detected at the very late and advanced stages when curable treatments are unavailable and ineffective. In this regard, there are still huge unmet medical needs in developing and clinically validating those high-potential protein biomarkers preferably in liquid biopsy samples. This review provides a glimpse of emerging biomarkers together with detection tools and techniques which are potentially commercially available to the markets. We also discuss several diagnostic biomarkers having therapeutic potential for developing first-in-class medicines.

Keywords

Hepatocellular carcinoma / biomarkers / targets / α-fetoprotein / cadherin-17 / Yes-associated protein / AXL / Trop2

References

[1] Torre LA,Siegel RL,Lortet-Tieulent J.Global cancer statistics, 2012..CA Cancer J Clin2015;65:87-108

[2] Siegel R,Jemal A.Cancer statistics, 2013..CA Cancer J Clin2013;63:11-30

[3] Bruix J,Sherman M.Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma..Gastroenterology2016;150:835-53

[4] Colli A,Casazza G,Colucci A.Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review..Am J Gastroenterol2006;101:513-23

[5] Bruix J,Sherman M.Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma..Gastroenterology2016;150:835-53

[6] Tsuchiya N,Endo I,Uemura Y.Biomarkers for the early diagnosis of hepatocellular carcinoma..World J Gastroenterol2015;21:10573-83 PMCID:PMC4588079

[7] Mizejewski GJ.Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants..Exp Biol Med2001;226:377-408

[8] Gitlin D,Gitlin JD.The presence of serum alphafetoprotein in sharks and its synthesis by fetal gastrointestinal tract and liver..Comp BiochemPhysiol B1973;46:207-15

[9] Debruyne EN.Diagnosing and monitoring hepatocellular carcinoma with alpha-fetoprotein: new aspects and applications..Clin Chim Acta2008;395:19-26

[10] Chayvialle JA.Radioimmunoassay of alpha-fetoprotein in human plasma..Lancet1973;1:1355-7

[11] Waldmann TA.The use of a radioimmunoassay for alpha-fetoprotein in the diagnosis of malignancy..Cancer1974;34:1510-5

[12] Chayvialle JA.Radioimmunoassay of alpha-fetoprotein in human plasma..Lancet1973;1:1355-7

[13] Lederle FA.Screening for liver cancer: the rush to judgment..Ann Intern Med2012;156:387-9

[14] Chen JG,Chen QG,Shen QJ.Screening for liver cancer: results of a randomized controlled trial in Qidong, China..J Med Screen2003;10:204-9

[15] Zhang BH,Tang ZY.Randomized controlled trial of screening for hepatocellular carcinoma..J Cancer Res Clin Oncol2004;130:417-22

[16] Muguti G,Richardson A.Alpha-fetoprotein expression in hepatocellular carcinoma: a clinical study..J Gastroenterol Hepatol1992;7:374-8

[17] Chu CW,Luo JC,Tsay SH.Clinical, virologic, and pathologic significance of elevated serum alpha-fetoprotein levels in patients with chronic hepatitis C..J Clin Gastroenterol2001;32:240-4

[18] Talerman A,Baggerman L.Serum alphafetoprotein (AFP) in patients with germ cell tumors of the gonads and extragonadal sites: correlation between endodermal sinus (yolk sac) tumor and raised serum AFP..Cancer1980;46:380-5

[19] Ucar E,Ustun H,Huzmeli C.Prognostic value of preoperative CEA, CA 19-9, CA 72-4, and AFP levels in gastric cancer..Adv Ther2008;25:1075-84

[20] Li D,Satomura S.AFP-L3: a new generation of tumor marker for hepatocellular carcinoma..Clin Chim Acta2001;313:15-9

[21] Sterling RK,Gordon F,Reddy KR.Utility of Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gammacarboxy prothrombin, alone or in combination, as biomarkers for hepatocellular carcinoma..Clin Gastroenterol Hepatol2009;7:104-13

[22] Marrero JA,Wang Y,Befeler AS.Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectinbound alpha-fetoprotein in early hepatocellular carcinoma..Gastroenterology2009;137:110-8 PMCID:PMC2704256

[23] Kagebayashi C,Akinaga A,Yokoyama K.Automated immunoassay system for AFP-L3% using on-chip electrokinetic reaction and separation by affinity electrophoresis..Anal Biochem2009;388:306-11

[24] Reichl P,Starlinger P,Nenutil R.Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma..Int J Cancer2015;137:385-94 PMCID:PMC4450342

[25] Zhang Z,Lin L,Au V.Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer..Nat Genet2012;44:852-60 PMCID:PMC3408577

[26] Rankin EB,Taylor TE,Musser M.AXL is an essential factor and therapeutic target for metastatic ovarian cancer..Cancer Res2010;70:7570-9 PMCID:PMC3408227

[27] Dunne PD,Blayney JK,Greer S.AXL is a key regulator of inherent and chemotherapy-induced invasion and predicts a poor clinical outcome in early-stage colon cancer..Clin Cancer Res2014;20:164-75 PMCID:PMC3885388

[28] D’Alfonso TM,Chen Z,Zhou P.Axl receptor tyrosine kinase expression in breast cancer..J Clin Pathol2014;67:690-6 PMCID:PMC4549806

[29] Song X,Logsdon CD,Fleming JB.Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma..Cancer2011;117:734-43 PMCID:PMC4403266

[30] Varnum BC,Elliott G,Bartley TD.Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6..Nature1995;373:623-6

[31] Fridell YW,Quilliam LA,McCloskey P.Differential activation of the Ras/extracellularsignal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase..Mol Cell Biol1996;16:135-45 PMCID:PMC230987

[32] Tai KY,Lee CS,Wu CW.Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-kappaB and Brg-1..Oncogene2008;27:4044-55

[33] Ruan GX.Axl is essential for VEGF-A-dependent activation of PI3K/Akt..EMBO J2012;31:1692-703 PMCID:PMC3321201

[34] Paccez JD,Correa RG,Duncan K.The receptor tyrosine kinase Axl is an essential regulator of prostate cancer proliferation and tumor growth and represents a new therapeutic target..Oncogene2013;32:689-98 PMCID:PMC4078100

[35] Hong CC1,Huang JS,Tang JL.Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia..Cancer Lett2008;268:314-24

[36] Neubauer A,Graham DK,Schmidt CA.Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis..Blood1994;84:1931-41

[37] Shieh YS,Kao YR,Chu YW.Expression of axl in lung adenocarcinoma and correlation with tumor progression..Neoplasia2005;7:1058-64 PMCID:PMC1501169

[38] Li N,Zhang Y,Liu P.Mice lacking Axl and Mer tyrosine kinase receptors are susceptible to experimental autoimmune orchitis induction..Immunol Cell Biol2015;93:311-20 PMCID:PMC5800791

[39] Weinger JG,Loudig O,Macian F.Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during experimental autoimmune encephalomyelitis..J Neuroinflammation2011;8:49 PMCID:PMC3121615

[40] Xu MZ,Liu AM,Fan ST.AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma..Oncogene2011;30:1229-40 PMCID:PMC3330262

[41] Gay CM,Byers LA.Giving AXL the axe: targeting AXL in human malignancy..Br J Cancer2017;116:415-23 PMCID:PMC5318970

[42] Pinato DJ,Lloyd T,Casadio C.The expression of Axl receptor tyrosine kinase influences the tumour phenotype and clinical outcome of patients with malignant pleural mesothelioma..Br J Cancer2013;108:621-8 PMCID:PMC3593571

[43] Reichl P,Starlinger P,Nenutil R.Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma..Int J Cancer2015;137:385-94 PMCID:PMC4450342

[44] Nordberg J.Reactive oxygen species, antioxidants, and the mammalian thioredoxin system..Free Radic Biol Med2001;31:1287-312

[45] Kakolyris S,Koukourakis M,Souglakos J.Thioredoxin expression is associated with lymph node status and prognosis in early operable non-small cell lung cancer..Clin Cancer Res2001;7:3087-91

[46] Raffel J,Gallegos A,Einspahr JG.Increased expression of thioredoxin-1 in human colorectal cancer is associated with decreased patient survival..J Lab Clin Med2003;142:46-51

[47] Li J,Liu Y,Wang K.Serum thioredoxin is a diagnostic marker for hepatocellular carcinoma..Oncotarget2015;6:9551-63 PMCID:PMC4496238

[48] Yang J,Dai W,Shen M.Golgi protein 73 as a biomarker for hepatocellular carcinoma: a diagnostic meta-analysis..Exp Ther Med2015;9:1413-20 PMCID:PMC4353736

[49] Jin D,Li D,Li L.Golgi protein 73 activation of MMP-13 promotes hepatocellular carcinoma cell invasion..Oncotarget2015;6:33523-33 PMCID:PMC4741783

[50] Bachert C,Linstedt AD.Endosomal trafficking and proprotein convertase cleavage of cis Golgi Protein GP73 produces marker for hepatocellular carcinoma..Traffic2007;8:1415-24

[51] Kladney RD,Bulla GA,Fimmel CJ.Expression of GP73, a resident Golgi membrane protein, in viral and nonviral liver disease..Hepatology2002;35:1431-40

[52] Mao Y,Xu H,Sang X.Golgi protein 73 (GOLPH2) is a valuable serum marker for hepatocellular carcinoma..Gut2010;59:1687-93

[53] El-Abd N,Elbaz T.Evaluation of annexin A2 and as potential biomarkers for hepatocellular carcinoma..Tumor Biol2016;37:211-6

[54] Attallah AM,Malak CA,Shiha GE.HCC-DETECT: a combination of nuclear, cytoplasmic, and oncofetal proteins as biomarkers for hepatocellular carcinoma..Tumor Biol2015;36:7667-74

[55] Attallah AM,Abdel Malak CA,Omran MM.A simple diagnostic index comprising epithelial membrane antigen and fibronectin for hepatocellular carcinoma..Ann Hepatol2015;14:869-80

[56] Mao L,Wang D,Fu S.TEMs but not DKK1 could serve as complementary biomarkers for AFP in diagnosing AFP-negative hepatocellular carcinoma..PLoS One2017;12:e0183880 PMCID:PMC5597119

[57] Filmus J.The contribution of in vivo manipulation of gene expression to the understanding of the function of glypicans..Glycoconj J2002;19:319-23

[58] Veugelers M,Ceulemans H,Coomans C.Glypican-6, a new member of the glypican family of cell surface proteoglycans..J Biol Chem1999;274:26968-77

[59] Traister A,Filmus J.Mammalian Notum induces the release of glypicans and other GPI anchored proteins from the cell surface..Biochem J2008;410:503-11

[60] Nakatsura T1,Ito S,Monji M.Identification of glypican-3 as a novel tumor marker for melanoma..Clin Cancer Res2004;10:6612-21

[61] Hsu HC,Lai PL.Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution..Cancer Res1997;57:5179-84

[62] Zhu ZW,Wang L,Zimmermann A.Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders..Gut2001;48:558-64 PMCID:PMC1728256

[63] Nakatsura T,Senju S,Komori H.Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker..Biochem Biophys Res Commun2003;306:16-25

[64] Hippo Y,Watanabe A,Yamamoto S.Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma..Cancer Res2004;64:2418-23

[65] Capurro MI,Lobe C.Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling..Cancer Res2005;65:6245-54

[66] Filmus J,Rast J.Glypicans..Genome Biol2008;9:224 PMCID:PMC2441458

[67] Filmus J.The role of glypican-3 in the regulation of body size and cancer..Cell Cycle2008;7:2787-90

[68] Feitelson MA,Tufan NLS,Pan J.Genetic mechanisms of hepatocarcinogenesis..Oncogene2002;21:2593-604

[69] Kern MA,Schirmacher P.Molecular pathogenesis of human hepatocellular carcinoma..Adv Cancer Res2002;67:112

[70] Xiang YY,Filmus J.Glypican-3 expression is silenced in human breast cancer..Oncogene2001;20:7408-12

[71] Lin H,Schlessinger D.Frequent silencing of the GPC3 gene in ovarian cancer cell lines..Cancer Res1999;59:807-10

[72] Kim H,Borczuk AC,Filmus J.The heparan sulfate proteoglycan GPC3 is a potential lung tumor suppressor..Am J Resp Cell Mol Biol2003;29:694-701

[73] Capurro MI,Shi W,Jia A.Glypican-3 inhibits hedgehog signaling during development by competing with Patched for Hedgehog binding..Dev Cell2008;14:700-11

[74] Tangkijvanich P,Komtong S,Wisedopas N.Diagnostic role of serum glypican-3 in differentiating hepatocellular carcinoma from non-malignant chronic liver disease and other liver cancers..J Gastroenterol Hepatol2010;25:129-37

[75] Jia X,Gao Y,Du Z.Diagnosis accuracy of serum glypican-3 in patients with hepatocellular carcinoma: a systematic review with meta-analysis..Arch Med Res2014;45:580-8

[76] Nakatsura T,Kubo T,Senju S.Mouse homologue of a novel human oncofetal antigen, glypican-3, evokes T-cell-mediated tumor rejection without autoimmune reactions in mice..Clin Cancer Res2004;10:8630-40

[77] Motomura Y,Nakatsura T,Hirata S.Embryonic stem cell-derived dendritic cells expressing glypican-3, a recently identified oncofetal antigen, induce protective immunity against highly metastatic mouse melanoma, B16-F10..Cancer Res2006;66:2414-22

[78] Sawada Y,Nobuoka D,Kuronuma T.Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival..Clin Cancer Res2012;18:3686-96

[79] Gao H,Tu H,Jiang H.Development of T Cells Redirected to Glypican-3 for the Treatment of Hepatocellular Carcinoma..Clin Cancer Res2014;20:6418

[80] Zhai B,Gao H,Jiang H.A phase I study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3+ hepatocellular carcinoma (r/r GPC3+ HCC)..J Clin Oncol2017;35:3049

[81] Ishiguro T,Komatsu SI,Kaneko A.An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors..Sci Transl Med2017;9:eaal4291

[82] Gessner R.Intestinal cell adhesion molecules. Liver-intestine cadherin..Ann N Y Acad Sci2000;915:136-43

[83] Berndorff D,Kreft B,Lajous-Petter AM.Liver-intestine cadherin: molecular cloning and characterization of a novel Ca2+-dependent cell adhesion molecule expressed in liver and intestine..J Cell Biol1994;125:1353-69

[84] Dantzig AH,Tabas LB,Shepard RL.Association of intestinal peptide transport with a protein related to the cadherin superfamily..Science1994;264:430-3

[85] Wong BW,Ng IO,Liu KD.Identification of liver-intestine cadherin in hepatocellular carcinoma--a potential disease marker..Biochem Biophys Res Commun2003;311:618-24

[86] Grotzinger C,Patschan D,Anagnostopoulos I.LI-cadherin: a marker of gastric metaplasia and neoplasia..Gut2001;49:73-81 PMCID:PMC1728355

[87] Takamura M,Ino Y,Ichida T.Expression of liverintestine cadherin and its possible interaction with galectin-3 in ductal adenocarcinoma of the pancreas..Cancer Sci2003;94:425-30

[88] Wang XQ,Leung PP,Stanbridge EJ.Alternative mRNA splicing of liver intestine-cadherin in hepatocellular carcinoma..Clin Cancer Res2005;11:483-9

[89] Takamura M,Matsuda Y,Yamagiwa S.Reduced expression of liver-intestine cadherin is associated with progression and lymph node metastasis of human colorectal carcinoma..Cancer Lett2004;212:253-9

[90] Wong BW,Ng IO,Liu KD.Identification of liver intestine cadherin in hepatocellular carcinoma - a potential disease marker..Biochem Biophys Res Commun2003;311:618-24

[91] Hinoi T,Kuick R,Cho KR.CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia..Gastroenterology2002;123:1565-77

[92] Park JH,Choi HJ,Choi PJ.Comparison of cadherin-17 expression between primary colorectal adenocarcinomas and their corresponding metastases: the possibility of a diagnostic marker for detecting the primary site of metastatic tumour..Histopathology2011;58:315-8

[93] Bartolome RA,Torres S,Mendes M.Cadherin-17 interacts with a2b1 integrin to regulate cell proliferation and adhesion in colorectal cancer cells causing liver metastasis..Oncogene2014;33:1658-69

[94] Liu LX,Chan VW,Zender L.Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma..Hepatology2009;50:1453-63 PMCID:PMC3328302

[95] Su MC,Lin CY.Cadherin-17 is a useful diagnostic marker for adenocarcinomas of the digestive system..Mod Pathol2008;21:1379-86

[96] Okada T,Akimitsu N.Expression of cadherin-17 promotes metastasis in a highly bone marrow metastatic murine breast cancer model..Biomed Res Int2017;2017:8494286 PMCID:PMC5288516

[97] Bartolomé RA,Jaén M,Calviño E.Monoclonal antibodies directed against cadherin RGD exhibit therapeutic activity against melanoma and colorectal cancer metastasis..Clin Cancer Res2018;24:433-44

[98] Zender L,Xue W,Cordon-Cardo C.Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach..Cell2006;125:1253-67 PMCID:PMC3026384

[99] Overholtzer M,Smolen GA,Li W.Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon..Proc Natl Acad Sci USA2006;103:12405-10 PMCID:PMC1533802

[100] Morin-Kensicki EM,Howell M,Teed J.Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65..Mol Cell Biol2006;26:77-87 PMCID:PMC1317614

[101] Zhao B,Yu J,Li W.TEAD mediates YAP-dependent gene induction and growth control..Genes Dev2008;22:1962-71 PMCID:PMC2492741

[102] Dong J,Huang J,Zhang N.Elucidation of a universal size-control mechanism in Drosophila and mammals..Cell2007;130:1120-33 PMCID:PMC2666353

[103] Wu H,Jiang XW,Guo G.Clinicopathological and prognostic significance of Yes-associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma..Tumour Biol2016;37:13499-508

[104] Xu MZ,Lee NP,Chan YT.Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma..Cancer2009;115:4576-85 PMCID:PMC2811690

[105] Wang Y,Zhang Q,Wang E.Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer..Cancer Sci2010;101:1279-85

[106] Hayashi H,Yokoyama N,Sakamoto K.An imbalance in TAZ and YAP expression in hepatocellular carcinoma confers cancer stem cell-like behaviors contributing to disease progression..Cancer Res2015;75:4985-97

[107] Lamar JM,Liu H,Jiang ZG.The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain..Proc Natl Acad Sci U S A2012;109:E2441-50 PMCID:PMC3443162

[108] Zhou Z,Xu Z,Zhang Z.Targeting Hippo pathway by specific interruption of YAP-TEAD interaction using cyclic YAP-like peptides..FASEB J2015;29:724-32

[109] Gibault F,Sturbaut M,Renault N.Toward the discovery of a novel class of YAP-TEAD interaction inhibitors by virtual screening approach targeting YAP-TEAD protein-protein interface..Cancers (Basel)2018;10:E140 PMCID:PMC5977113

[110] Guerra E,Aloisi AL,Vacca G.The Trop-2 signalling network in cancer growth..Oncogene2013;32:1594-600

[111] Fong D,Krammel C,Margreiter R.High expression of TROP2 correlates with poor prognosis in pancreatic cancer..Br J Cancer2008;99:1290-5 PMCID:PMC2570520

[112] Fong D,Gostner JM,Moser P.TROP2: a novel prognostic marker in squamous cell carcinoma of the oral cavity..Mod Pathol2008;21:186-91

[113] Mühlmann G,Gostner J,Maier H.TROP2 expression as prognostic marker for gastric carcinoma..J Clin Pathol2009;62:152-8

[114] Ning S,Xie J,Lu X.TROP2 correlates with microvessel density and poor prognosis in hilar cholangiocarcinoma..J Gastrointest Surg2013;17:360-8

[115] Ohmachi T,Mimori K,Yanaga K.Clinical significance of TROP2 expression in colorectal cancer..Clin Cancer Res2006;12:3057-63

[116] Liu T,Bao X,Liu Y.Overexpression of TROP2 predicts poor prognosis of patients with cervical cancer and promotes the proliferation and invasion of cervical cancer cells by regulating ERK signaling pathway..PLoS One2013;8:e75864 PMCID:PMC3785439

[117] Bignotti E,Calza S,Ravanini M.Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients..Eur J Cancer2010;46:944-53

[118] Chen MB,Zhan Y,Wang AK.Prognostic value of TROP2 expression in patients with gallbladder cancer..Tumour Biol2014;35:11565-9

[119] Lin H,Qiu JR,Tang XJ.Significantly upregulated TACSTD2 and Cyclin D1 correlate with poor prognosis of invasive ductal breast cancer..Exp Mol Pathol2013;94:73-8

[120] Gui T,Li R,Wang Z.Identification of hepatocellular carcinoma-related genes with a machine learning and network analysis..J Comput Biol2015;22:63-71

[121] Ikeda Y,Kumagai H,Morikawa Y.Vasorin, a transforming growth factor beta-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo..Proc Natl Acad Sci USA2004;101:10732-7 PMCID:PMC490003

[122] Chen L,Zhang SH,Song HD.Slit-like 2, a novel zebrafish slit homologue that might involve in zebrafish central neural and vascular morphogenesis..Biochem Biophys Res Commun2005;336:364-71

[123] Li S,Yang X,Huang A.Vasorin is a potential serum biomarker and drug target of hepatocarcinoma screened by subtractive-EMSA-SELEX to clinic patient serum..Oncotarget2015;6:10045-59 PMCID:PMC4496339

[124] Cao DX,Jiang XO,Khin E.Osteopontin as potential biomarker and therapeutic target in gastric and liver cancers..World J Gastroenterol2012;18:3923-30 PMCID:PMC3419986

[125] Kim J,Lee SD,Kim YC.Elevated plasma osteopontin levels in patients with hepatocellular carcinoma..Am J Gastroenterol2006;101:2051-9

[126] Shang S,Ge S,Rosen HR.Identification of osteopontin as a novel marker for early hepatocellular carcinoma..Hepatology2012;55:483-90 PMCID:PMC3914762

[127] Sun T,Sun D,Li P.Osteopontin versus alpha-fetoprotein as a diagnostic marker for hepatocellular carcinoma: a meta-analysis..Onco Targets Ther2018;11:8925-35 PMCID:PMC6292395

[128] Fouad SA,Fawzy MW.Plasma osteopontin level in chronic liver disease and hepatocellular carcinoma..Hepat Mon2015;15:e30753 PMCID:PMC4612688

[129] Sun T,Sun D,Li G.Prognostic value of osteopontin in patients with hepatocellular carcinoma: A systematic review and meta-analysis..Medicine (Baltimore)2018;97:e12954 PMCID:PMC6221565

[130] Liu K,Liu H,Yang J.Precancer antiviral treatment reduces microvascular invasion of early-stage Hepatitis B-related hepatocellular carcinoma..Sci Rep2019;9:2220 PMCID:PMC6379412

[131] Sun BS1,Ye QH,Jia HL.Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma..Hepatology2008;48:1834-42

[132] Shojaei F,Kang X,Fitzgerald AA.Osteopontin induces growth of metastatic tumors in a preclinical model of non-small lung cancer..J Exp Clin Cancer Res2012;31:26 PMCID:PMC3325875

[133] Dai J,Shi J,Zhang D.A humanized anti-osteopontin antibody inhibits breast cancer growth and metastasis in vivo..Cancer Immunol Immunother2010;59:355-66

[134] Lim WA.The principles of engineering immune cells to treat cancer..Cell2017;168:724-40 PMCID:PMC5553442

[135] Kershaw MH,Parker LL,Eshhar Z.A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer..Clin Cancer Res2006;12:6106-15 PMCID:PMC2154351

[136] Lamers CH,van Steenbergen S,van Krimpen B.Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity..Mol Ther2013;21:904-12 PMCID:PMC5189272

[137] Morgan RA,Kitano M,Laurencot CM.Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2..Mol Ther2010;18:843-51 PMCID:PMC2862534

[138] van den Berg JH,van de Wiel B,van den Broek D.Case report of a fatal serious adverse event upon administration of T cells transduced with a MART-1-specific T-cell receptor..Mol Ther2015;23:1541-50 PMCID:PMC4817886

[139] Gupta S,Kohlwes J.Test characteristics of α-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C: A systematic review and critical analysis..Ann Intern Med2003;139:46-50

[140] Shaheen KY,Safwat E.The value of serum midkine level in diagnosis of hepatocellular carcinoma..Int J Hepatol2015;2015:146389 PMCID:PMC4337261

[141] Giannelli G,Trerotoli P,Marinosci F.Clinical validation of combined serological biomarkers for improved hepatocellular carcinoma diagnosis in 961 patients..Clin Chim Acta2007;383:147-52

[142] Sun Y,Cai J,Qu X.Annexin A2 is a discriminative serological candidate in early hepatocellular carcinoma..Carcinogenesis2013;34:595-604 PMCID:PMC3581600

[143] Chounta A,Tzanetakou V,Mplani V.Serum soluble urokinase plasminogen activator receptor as a screening test for the early diagnosis of hepatocellular carcinoma..Liver Int2015;35:601-7