Abstract
Liquid biopsies in cancer have received considerable attention as new biomarkers and subjects of clinical translational research. Liquid biopsy-derived biomarkers, including circulating tumor cells, cell-free nucleic acids, exosomes, tumor-educated platelets, proteins, and metabolites, have shown enormous potential to improve the sensitivity and specificity in early diagnosis of multiple cancer types, including hepatocellular carcinoma (HCC). Several analytes are already used in HCC clinical trials and are currently under investigation with encouraging preliminary results. This article will review the latest studies on liquid biopsy for early diagnosis and screening of HCC and discuss the current advantages and challenges of liquid biopsies in tumor biomarkers and clinical applications. In the future, the validation of large prospective clinical studies, the development of standardized operating procedures, and the integration of other diagnostic tools will open new avenues for applying liquid biopsy in early cancer detection.
Graphical Abstract
[http://dx.doi.org/10.1097/MD.0000000000005904] [PMID: 28248853]
[http://dx.doi.org/10.1002/hep.29913] [PMID: 29624699]
[http://dx.doi.org/10.1053/j.gastro.2018.01.064] [PMID: 29425931]
[http://dx.doi.org/10.4254/wjh.v7.i12.1632] [PMID: 26140083]
[http://dx.doi.org/10.1016/j.gendis.2020.01.014] [PMID: 32884985]
[http://dx.doi.org/10.1002/ijc.33217] [PMID: 32683679]
[http://dx.doi.org/10.1634/theoncologist.2019-0147] [PMID: 31036768]
[http://dx.doi.org/10.1038/s41416-020-01047-5] [PMID: 32968207]
[http://dx.doi.org/10.1016/j.ijid.2017.12.002] [PMID: 29229500]
[http://dx.doi.org/10.1073/pnas.1500076112] [PMID: 25646427]
[http://dx.doi.org/10.1002/hep.32308] [PMID: 34954829]
[http://dx.doi.org/10.1007/s10238-018-0502-9] [PMID: 29749584]
[http://dx.doi.org/10.1159/000510366] [PMID: 32998139]
[http://dx.doi.org/10.1158/1078-0432.CCR-18-3341] [PMID: 31363003]
[http://dx.doi.org/10.1155/2021/3637436] [PMID: 34899905]
[http://dx.doi.org/10.1158/1078-0432.CCR-21-0002] [PMID: 33947693]
[http://dx.doi.org/10.1073/pnas.1819799116] [PMID: 30858324]
[http://dx.doi.org/10.1073/pnas.1814616115] [PMID: 30373822]
[http://dx.doi.org/10.1002/1878-0261.13041] [PMID: 34133846]
[http://dx.doi.org/10.1016/j.ebiom.2020.102811] [PMID: 32512514]
[http://dx.doi.org/10.1016/j.jmoldx.2021.06.003] [PMID: 34182124]
[http://dx.doi.org/10.1126/science.aar3247] [PMID: 29348365]
[http://dx.doi.org/10.1126/science.abb9601] [PMID: 32345712]
[http://dx.doi.org/10.1016/j.ebiom.2018.03.029] [PMID: 29627389]
[http://dx.doi.org/10.1155/2020/6289063] [PMID: 33178361]
[http://dx.doi.org/10.1093/carcin/bgx078] [PMID: 28981677]
[http://dx.doi.org/10.1002/hep.25569.] [PMID: 22234943] [http://dx.doi.org/10.3892/or.2016.4619] [PMID: 26883180]
[http://dx.doi.org/10.1371/journal.pone.0174265] [PMID: 28333958]
[http://dx.doi.org/10.1038/nmat4997] [PMID: 29035356]
[http://dx.doi.org/10.1002/hep.30244] [PMID: 30168613]
[http://dx.doi.org/10.1016/j.cgh.2020.08.065] [PMID: 32889146]
[http://dx.doi.org/10.1038/s41467-020-17316-z] [PMID: 32694610]
[http://dx.doi.org/10.1016/j.annonc.2020.02.011] [PMID: 33506766]
[http://dx.doi.org/10.1136/gutjnl-2019-318882] [PMID: 31358576]
[http://dx.doi.org/10.1016/j.esmoop.2020.100021] [PMID: 33508734]
[http://dx.doi.org/10.1038/s41422-020-00457-7] [PMID: 33589745]
[http://dx.doi.org/10.1038/onc.2015.192] [PMID: 26050619]
[http://dx.doi.org/10.1016/j.bbcan.2017.12.005] [PMID: 29360544]
[http://dx.doi.org/10.3390/cancers11010019] [PMID: 30586936]
[http://dx.doi.org/10.1158/0008-5472.CAN-12-4140] [PMID: 23471846]
[http://dx.doi.org/10.1200/JCO.2012.47.7737] [PMID: 23630207]
[http://dx.doi.org/10.1038/s41575-019-0186-y] [PMID: 31439937]
[http://dx.doi.org/10.1038/nrdp.2016.18] [PMID: 27158749]
[http://dx.doi.org/10.1158/1078-0432.CCR-14-0251] [PMID: 25009297]
[http://dx.doi.org/10.1002/(SICI)1096-9896(199906)188:2<201::AID-PATH339>3.0.CO;2-8] [PMID: 10398165]
[http://dx.doi.org/10.1073/pnas.1617032114] [PMID: 28096363]
[http://dx.doi.org/10.1002/lt.25062] [PMID: 29624843]
[http://dx.doi.org/10.1158/1078-0432.CCR-17-1753] [PMID: 29374055]
[http://dx.doi.org/10.1007/s11605-018-04067-y] [PMID: 30805878]
[http://dx.doi.org/10.1002/hep4.1577] [PMID: 33024921]
[http://dx.doi.org/10.1371/journal.pone.0217586] [PMID: 31141571]
[http://dx.doi.org/10.1097/MD.0000000000011130] [PMID: 29901640]
[http://dx.doi.org/10.1186/s13046-018-0777-4] [PMID: 29843754]
[http://dx.doi.org/10.1016/j.jhep.2020.06.004] [PMID: 32534107]
[http://dx.doi.org/10.1016/j.actbio.2021.03.002] [PMID: 33711526]
[http://dx.doi.org/10.1016/j.jaci.2017.08.034] [PMID: 29074454]
[http://dx.doi.org/10.1038/nrd.2016.246] [PMID: 28209991]
[http://dx.doi.org/10.1534/genetics.112.146704] [PMID: 23463798]
[http://dx.doi.org/10.1016/j.jmb.2012.11.024] [PMID: 23178169]
[http://dx.doi.org/10.1158/0008-5472.CAN-16-2634] [PMID: 28701486]
[http://dx.doi.org/10.1016/j.molcel.2018.06.034] [PMID: 30057200]
[http://dx.doi.org/10.1155/2020/2712310] [PMID: 33150169]
[http://dx.doi.org/10.3389/fonc.2020.01526] [PMID: 33072546]
[http://dx.doi.org/10.1371/journal.pone.0013515] [PMID: 20976003]
[http://dx.doi.org/10.1016/j.jhep.2011.04.026] [PMID: 21749846]
[http://dx.doi.org/10.1002/iub.2096] [PMID: 31190421]
[http://dx.doi.org/10.1038/s41598-019-46872-8] [PMID: 31320713]
[http://dx.doi.org/10.1016/j.ygeno.2020.06.020] [PMID: 32544548]
[http://dx.doi.org/10.1016/j.clinre.2018.12.008] [PMID: 30824368]
[http://dx.doi.org/10.1007/s10238-020-00646-z] [PMID: 32712720]
[http://dx.doi.org/10.1080/21691401.2019.1703723] [PMID: 32088997]
[PMID: 32366560]
[http://dx.doi.org/10.1016/j.ejso.2021.06.015] [PMID: 34175168]
[http://dx.doi.org/10.1080/21691401.2019.1640228] [PMID: 31349749]
[http://dx.doi.org/10.1002/cam4.3204] [PMID: 32558350]
[http://dx.doi.org/10.1155/2020/5417598] [PMID: 32733618]
[http://dx.doi.org/10.1186/s12885-022-09530-3] [PMID: 35443674]
[http://dx.doi.org/10.3748/wjg.v25.i48.6902] [PMID: 31908394]
[http://dx.doi.org/10.1038/s41419-018-1132-6] [PMID: 30361504]
[http://dx.doi.org/10.1155/2018/3073467] [PMID: 29785229]
[PMID: 30426540]
[http://dx.doi.org/10.1016/j.cca.2019.02.001] [PMID: 30716279]
[http://dx.doi.org/10.1016/j.biopha.2019.109517] [PMID: 31698267]
[http://dx.doi.org/10.1093/carcin/bgz154] [PMID: 31535687]
[http://dx.doi.org/10.3389/fphar.2021.639963] [PMID: 33679420]
[http://dx.doi.org/10.1002/jcla.24009] [PMID: 34523755]
[http://dx.doi.org/10.1200/JCO.2011.38.2697] [PMID: 22105822]
[http://dx.doi.org/10.1002/mgg3.1012] [PMID: 31660696]
[http://dx.doi.org/10.1016/S1470-2045(15)00048-0] [PMID: 26088272]
[http://dx.doi.org/10.1111/liv.13356] [PMID: 28061012]
[http://dx.doi.org/10.3748/wjg.v24.i24.2596] [PMID: 29962816]
[http://dx.doi.org/10.3389/fgene.2021.666306] [PMID: 34163524]
[http://dx.doi.org/10.1002/hep4.1451] [PMID: 32025611]
[http://dx.doi.org/10.1096/fj.202101564R] [PMID: 35224785]
[http://dx.doi.org/10.1111/jcmm.15635] [PMID: 32692470]
[http://dx.doi.org/10.1186/s12935-020-01302-y] [PMID: 32536814]
[http://dx.doi.org/10.1002/ijc.32647] [PMID: 31456215]
[http://dx.doi.org/10.1007/s11033-019-04810-x] [PMID: 31004302]
[http://dx.doi.org/10.1016/j.ajg.2020.08.004] [PMID: 33268243]
[http://dx.doi.org/10.2147/IJGM.S354842] [PMID: 35264879]
[http://dx.doi.org/10.1016/j.trsl.2015.10.002] [PMID: 26551349]
[http://dx.doi.org/10.1002/jcla.23071] [PMID: 31693242]
[http://dx.doi.org/10.2217/epi-2018-0218] [PMID: 31339046]
[http://dx.doi.org/10.1126/science.aau6977] [PMID: 32029601]
[http://dx.doi.org/10.1038/s41551-021-00705-0] [PMID: 33820981]
[http://dx.doi.org/10.7150/thno.48206] [PMID: 33391469]
[http://dx.doi.org/10.1002/cam4.1390] [PMID: 29573235]
[http://dx.doi.org/10.1111/cas.14516] [PMID: 32506598]
[http://dx.doi.org/10.1111/jcmm.14783] [PMID: 31811749]
[http://dx.doi.org/10.1515/cclm-2017-0327] [PMID: 29252188]
[http://dx.doi.org/10.3390/jcm9010281] [PMID: 31968558]
[http://dx.doi.org/10.1177/0300060519896144] [PMID: 32339037]
[http://dx.doi.org/10.1038/s41467-020-18311-0] [PMID: 32895384]
[http://dx.doi.org/10.1373/clinchem.2018.301150] [PMID: 30996051]
[http://dx.doi.org/10.18632/aging.103879] [PMID: 33035196]
[http://dx.doi.org/10.1371/journal.pone.0198552] [PMID: 29879168]
[http://dx.doi.org/10.3389/fgene.2020.00712] [PMID: 32793278]
[http://dx.doi.org/10.1002/hep.29291] [PMID: 28555885]
[http://dx.doi.org/10.1016/j.jhep.2017.02.024] [PMID: 28267620]
[http://dx.doi.org/10.1038/emm.2015.68] [PMID: 26380927]
[http://dx.doi.org/10.1002/cam4.3230] [PMID: 32537885]
[http://dx.doi.org/10.1002/ijc.33111] [PMID: 32441313]
[http://dx.doi.org/10.3389/fphys.2018.00930] [PMID: 30065664]
[http://dx.doi.org/10.2174/1389200220666191011120434] [PMID: 31608838]
[http://dx.doi.org/10.1002/jcla.23959] [PMID: 34612554]
[http://dx.doi.org/10.1002/1878-0261.12745] [PMID: 32525601]
[http://dx.doi.org/10.1158/1055-9965.EPI-17-0770] [PMID: 29650788]
[http://dx.doi.org/10.1002/jcb.27109] [PMID: 30015383]
[http://dx.doi.org/10.1016/j.ccell.2015.09.018] [PMID: 26525104]
[http://dx.doi.org/10.1007/s00432-020-03502-5] [PMID: 33792796]
[http://dx.doi.org/10.1016/j.cca.2019.03.1634] [PMID: 30946815]
[http://dx.doi.org/10.1042/BSR20211420] [PMID: 34806748]
[http://dx.doi.org/10.1016/j.clinre.2020.03.023] [PMID: 32312598]
[http://dx.doi.org/10.1371/journal.pone.0256739] [PMID: 34469466]
[http://dx.doi.org/10.1053/j.seminoncol.2012.05.009] [PMID: 22846860]
[http://dx.doi.org/10.3390/cancers13133109] [PMID: 34206321]
[http://dx.doi.org/10.1186/s13045-020-00918-x] [PMID: 32616055]
[http://dx.doi.org/10.1002/ijc.32599] [PMID: 31361910]
[http://dx.doi.org/10.1158/0008-5472.CAN-15-3199] [PMID: 26976432]
[http://dx.doi.org/10.3390/cancers11101497] [PMID: 31590436]
[http://dx.doi.org/10.1021/pr500390y] [PMID: 24853826]
[http://dx.doi.org/10.1002/hep.27264] [PMID: 24923488]
[http://dx.doi.org/10.1002/hep.30319] [PMID: 30325540]
[http://dx.doi.org/10.1080/004982599238047] [PMID: 10598751]
[http://dx.doi.org/10.3390/metabo10020050] [PMID: 32012846]
[http://dx.doi.org/10.1016/j.jchromb.2008.05.001] [PMID: 18502700]
[http://dx.doi.org/10.1371/journal.pone.0016957] [PMID: 21359215]
[http://dx.doi.org/10.1371/journal.pone.0073076] [PMID: 24023812]
[http://dx.doi.org/10.1016/j.aca.2018.05.031] [PMID: 30032758]
[http://dx.doi.org/10.1158/0008-5472.CAN-13-0308] [PMID: 23824744]
[http://dx.doi.org/10.1002/ijc.28706] [PMID: 24382646]
[http://dx.doi.org/10.1186/s12916-015-0462-9] [PMID: 26399231]
[http://dx.doi.org/10.1002/hep.29561] [PMID: 28960374]
[http://dx.doi.org/10.1016/j.cca.2018.10.039] [PMID: 30389456]
[http://dx.doi.org/10.3748/wjg.v26.i31.4607] [PMID: 32884220]
[http://dx.doi.org/10.1021/acsomega.0c04259] [PMID: 33490775]