Clinical Applications of Liquid Biopsy in Hepatocellular Carcinoma

Jin-Cui Yang, Jun-Jie Hu, Yi-Xin Li, Wei Luo, Jin-Zhou Liu, Da-Wei Ye, Jin-Cui Yang, Jun-Jie Hu, Yi-Xin Li, Wei Luo, Jin-Zhou Liu, Da-Wei Ye

Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognosis in the world. The low rate of early diagnosis, as well as the high risk of postoperative metastasis and recurrence, led to the poor clinical prognosis of HCC patients. Currently, it mainly depends on serum markers, imaging examination, and tissue biopsy to diagnose and determine the recurrence and metastasis of HCC after treatments. Nevertheless, the accuracy and sensitivity of serum markers and imaging for early HCC diagnosis are suboptimal. Tissue biopsy, containing limited tissue samples, is insufficient to reveal comprehensive tumor biology information and is inappropriate to monitor dynamic tumor progression due to its invasiveness. Thus, low invasive diagnostic methods and novel biomarkers with high sensitivity and reliability must be found to improve HCC detection and prediction. As a non-invasive, dynamic, and repeatable detection method, "liquid biopsy", has attracted much attention to early diagnosis and monitoring of treatment response, which promotes the progress of precision medicine. This review summarizes the clinical applications of liquid biopsy in HCC, including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosome in early diagnosis, prognostic evaluation, disease monitoring, and guiding personalized treatment.

Keywords: circulating tumor DNA; circulating tumor cells; clinical application; exosome; hepatocellular carcinoma; liquid biopsy.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Yang, Hu, Li, Luo, Liu and Ye.

Figures

Figure 1
Figure 1
Clinical application pattern of liquid biopsy in patients with hepatocellular carcinoma. Tumor composition analyses, such as circulating tumor cells, circulating tumor DNA, and exosomes, are released by tumors to the bloodstream. During the various treatments such as surgery, transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), and targeting molecular treatment, liquid biopsy can be used for diagnosis, prognosis, and progress monitoring of HCC patients. NGS, next-generation sequencing; MRD, minimal/molecular residual disease. Figure 1 created in BioRender (https://biorender.com/).

References

    1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2020. CA Cancer J Clin (2020) 70:7–30. doi: 10.3322/caac.21590
    1. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A Global View of Hepatocellular Carcinoma: Trends, Risk, Prevention and Management. Nat Rev Gastroenterol Hepatol (2019) 16:589–604. doi: 10.1038/s41575-019-0186-y
    1. von Felden J, Garcia-Lezana T, Schulze K, Losic B, Villanueva A. Liquid Biopsy in the Clinical Management of Hepatocellular Carcinoma. Gut (2020) 69:2025–34. doi: 10.1136/gutjnl-2019-320282
    1. European Association for the Study of the Liver . Electronic Address E E E and L European Association for the Study of the, EASL Clinical Practice Guidelines: Management of Hepatocellular Carcinoma. J Hepatol (2018) 69:182–236. doi: 10.1016/j.jhep.2018.03.019
    1. Bruix J, Sherman M, D American Association for the Study of Liver . Management of Hepatocellular Carcinoma: An Update. Hepatology (2011) 53:1020–2. doi: 10.1002/hep.24199
    1. Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, et al. . Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-Analysis. Gastroenterology (2018) 154:1706–18.e1701. doi: 10.1053/j.gastro.2018.01.064
    1. Zamcheck N, Pusztaszeri G. CEA, AFP and Other Potential Tumor Markers. CA Cancer J Clin (1975) 25:204–14. doi: 10.3322/canjclin.25.4.204
    1. Mann J, Reeves HL, Feldstein AE. Liquid Biopsy for Liver Diseases. Gut (2018) 67:2204–12. doi: 10.1136/gutjnl-2017-315846
    1. Zhang Q, Rong Y, Yi K, Huang L, Chen M, Wang F. Circulating Tumor Cells in Hepatocellular Carcinoma: Single-Cell Based Analysis, Preclinical Models, and Clinical Applications. Theranostics (2020) 10:12060–71. doi: 10.7150/thno.48918
    1. Issa IA, Noureddine M. Colorectal Cancer Screening: An Updated Review of the Available Options. World J Gastroenterol (2017) 23:5086–96. doi: 10.3748/wjg.v23.i28.5086
    1. Morrison GJ, Goldkorn A. Development and Application of Liquid Biopsies in Metastatic Prostate Cancer. Curr Oncol Rep (2018) 20:35. doi: 10.1007/s11912-018-0683-0
    1. Hench IB, Hench J, Tolnay M. Liquid Biopsy in Clinical Management of Breast, Lung, and Colorectal Cancer. Front Med (Lausanne) (2018) 5:9. doi: 10.3389/fmed.2018.00009
    1. Ahn JC, Teng PC, Chen PJ, Posadas E, Tseng HR, Lu SC, et al. . Detection of Circulating Tumor Cells and Their Implications as a Novel Biomarker for Diagnosis, Prognostication, and Therapeutic Monitoring in Hepatocellular Carcinoma. Hepatology (2020) 73:422–36. doi: 10.1002/hep.31165
    1. Ye Q, Ling S, Zheng S, Xu X. Liquid Biopsy in Hepatocellular Carcinoma: Circulating Tumor Cells and Circulating Tumor DNA. Mol Cancer (2019) 18:114. doi: 10.1186/s12943-019-1043-x
    1. Li X, Li C, Zhang L, Wu M, Cao K, Jiang F, et al. . The Significance of Exosomes in the Development and Treatment of Hepatocellular Carcinoma. Mol Cancer (2020) 19:1. doi: 10.1186/s12943-019-1085-0
    1. Li J, Han X, Yu X, Xu Z, Yang G, Liu B, et al. . Clinical Applications of Liquid Biopsy as Prognostic and Predictive Biomarkers in Hepatocellular Carcinoma: Circulating Tumor Cells and Circulating Tumor DNA. J Exp Clin Cancer Res (2018) 37:213. doi: 10.1186/s13046-018-0893-1
    1. Pantel K, Speicher MR. The Biology of Circulating Tumor Cells. Oncogene (2016) 35:1216–24. doi: 10.1038/onc.2015.192
    1. Kleiner DE, Stetler-Stevenson WG. Matrix Metalloproteinases and Metastasis. Cancer Chemother Pharmacol (1999) 43(Suppl):S42–51. doi: 10.1007/s002800051097
    1. Miller MC, Doyle GV, Terstappen LW. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients With Metastatic Breast Colorectal and Prostate Cancer. J Oncol (2010) 2010:617421. doi: 10.1155/2010/617421
    1. Massague J, Obenauf AC. Metastatic Colonization by Circulating Tumour Cells. Nature (2016) 529:298–306. doi: 10.1038/nature17038
    1. Mohme M, Riethdorf S, Pantel K. Circulating and Disseminated Tumour Cells - Mechanisms of Immune Surveillance and Escape. Nat Rev Clin Oncol (2017) 14:155–67. doi: 10.1038/nrclinonc.2016.144
    1. Thompson EW, Haviv I. The Social Aspects of EMT-MET Plasticity. Nat Med (2011) 17:1048–9. doi: 10.1038/nm.2437
    1. Liu X, Li J, Cadilha BL, Markota A, Voigt C, Huang Z, et al. . Epithelial-Type Systemic Breast Carcinoma Cells With a Restricted Mesenchymal Transition are a Major Source of Metastasis. Sci Adv (2019) 5:eaav4275. doi: 10.1126/sciadv.aav4275
    1. Pantel K, Alix-Panabieres C. Circulating Tumour Cells in Cancer Patients: Challenges and Perspectives. Trends Mol Med (2010) 16:398–406. doi: 10.1016/j.molmed.2010.07.001
    1. Li YM, Xu SC, Li J, Han KQ, Pi HF, Zheng L, et al. . Epithelial-Mesenchymal Transition Markers Expressed in Circulating Tumor Cells in Hepatocellular Carcinoma Patients With Different Stages of Disease. Cell Death Dis (2013) 4:e831. doi: 10.1038/cddis.2013.347
    1. Cheung KJ, Ewald AJ. A Collective Route to Metastasis: Seeding by Tumor Cell Clusters. Science (2016) 352:167–9. doi: 10.1126/science.aaf6546
    1. Sun YF, Xu Y, Yang XR, Guo W, Zhang X, Qiu SJ, et al. . Circulating Stem Cell-Like Epithelial Cell Adhesion Molecule-Positive Tumor Cells Indicate Poor Prognosis of Hepatocellular Carcinoma After Curative Resection. Hepatology (2013) 57:1458–68. doi: 10.1002/hep.26151
    1. Zhou Y, Wang B, Wu J, Zhang C, Zhou Y, Yang X, et al. . Association of Preoperative EpCAM Circulating Tumor Cells and Peripheral Treg Cell Levels With Early Recurrence of Hepatocellular Carcinoma Following Radical Hepatic Resection. BMC Cancer (2016) 16:506. doi: 10.1186/s12885-016-2526-4
    1. Ogle LF, Orr JG, Willoughby CE, Hutton C, McPherson S, Plummer R, et al. . Imagestream Detection and Characterisation of Circulating Tumour Cells - A Liquid Biopsy for Hepatocellular Carcinoma? J Hepatol (2016) 65:305–13. doi: 10.1016/j.jhep.2016.04.014
    1. Shi J, Li Y, Liang S, Zeng J, Liu G, Mu F, et al. . Circulating Tumour Cells as Biomarkers for Evaluating Cryosurgery on Unresectable Hepatocellular Carcinoma. Oncol Rep (2016) 36:1845–51. doi: 10.3892/or.2016.5050
    1. Yu JJ, Xiao W, Dong SL, Liang HF, Zhang ZW, Zhang BX, et al. . Effect of Surgical Liver Resection on Circulating Tumor Cells in Patients With Hepatocellular Carcinoma. BMC Cancer (2018) 18:835. doi: 10.1186/s12885-018-4744-4
    1. Qi LN, Xiang BD, Wu FX, Ye JZ, Zhong JH, Wang YY, et al. . Circulating Tumor Cells Undergoing EMT Provide a Metric for Diagnosis and Prognosis of Patients With Hepatocellular Carcinoma. Cancer Res (2018) 78:4731–44. doi: 10.1158/0008-5472.CAN-17-2459
    1. von Felden J, Schulze K, Krech T, Ewald F, Nashan B, Pantel K, et al. . Circulating Tumor Cells as Liquid Biomarker for High HCC Recurrence Risk After Curative Liver Resection. Oncotarget (2017) 8:89978–87. doi: 10.18632/oncotarget.21208
    1. Shen J, Wang WS, Zhu XL, Ni CF. High Epithelial Cell Adhesion Molecule-Positive Circulating Tumor Cell Count Predicts Poor Survival of Patients With Unresectable Hepatocellular Carcinoma Treated With Transcatheter Arterial Chemoembolization. J Vasc Interv Radiol (2018) 29:1678–84. doi: 10.1016/j.jvir.2018.07.030
    1. Kelley RK, Magbanua MJ, Butler TM, Collisson EA, Hwang J, Sidiropoulos N, et al. . Circulating Tumor Cells in Hepatocellular Carcinoma: A Pilot Study of Detection, Enumeration, and Next-Generation Sequencing in Cases and Controls. BMC Cancer (2015) 15:206. doi: 10.1186/s12885-015-1195-z
    1. Wang S, Zhang C, Wang G, Cheng B, Wang Y, Chen F, et al. . Aptamer-Mediated Transparent-Biocompatible Nanostructured Surfaces for Hepotocellular Circulating Tumor Cells Enrichment. Theranostics (2016) 6:1877–86. doi: 10.7150/thno.15284
    1. Chen J, Cao SW, Cai Z, Zheng L, Wang Q. Epithelial-Mesenchymal Transition Phenotypes of Circulating Tumor Cells Correlate With the Clinical Stages and Cancer Metastasis in Hepatocellular Carcinoma Patients. Cancer Biomark (2017) 20:487–98. doi: 10.3233/CBM-170315
    1. Schulze K, Gasch C, Staufer K, Nashan B, Lohse AW, Pantel K, et al. . Presence of EpCAM-Positive Circulating Tumor Cells as Biomarker for Systemic Disease Strongly Correlates to Survival in Patients With Hepatocellular Carcinoma. Int J Cancer (2013) 133:2165–71. doi: 10.1002/ijc.28230
    1. Guo W, Yang XR, Sun YF, Shen MN, Ma XL, Wu J, et al. . Clinical Significance of EpCAM mRNA-Positive Circulating Tumor Cells in Hepatocellular Carcinoma by an Optimized Negative Enrichment and qRT-PCR-Based Platform. Clin Cancer Res (2014) 20:4794–805. doi: 10.1158/1078-0432.CCR-14-0251
    1. Sun YF, Guo W, Xu Y, Shi YH, Gong ZJ, Ji Y, et al. . Circulating Tumor Cells From Different Vascular Sites Exhibit Spatial Heterogeneity in Epithelial and Mesenchymal Composition and Distinct Clinical Significance in Hepatocellular Carcinoma. Clin Cancer Res (2018) 24:547–59. doi: 10.1158/1078-0432.CCR-17-1063
    1. Wang L, Li Y, Xu J, Zhang A, Wang X, Tang R, et al. . Quantified Postsurgical Small Cell Size CTCs and EpCAM(+) Circulating Tumor Stem Cells With Cytogenetic Abnormalities in Hepatocellular Carcinoma Patients Determine Cancer Relapse. Cancer Lett (2018) 412:99–107. doi: 10.1016/j.canlet.2017.10.004
    1. Ha Y, Kim TH, Shim JE, Yoon S, Jun MJ, Cho YH, et al. . Circulating Tumor Cells are Associated With Poor Outcomes in Early-Stage Hepatocellular Carcinoma: A Prospective Study. Hepatol Int (2019) 13:726–35. doi: 10.1007/s12072-019-09994-9
    1. Zhou J, Zhang Z, Zhou H, Leng C, Hou B, Zhou C, et al. . Preoperative Circulating Tumor Cells to Predict Microvascular Invasion and Dynamical Detection Indicate the Prognosis of Hepatocellular Carcinoma. BMC Cancer (2020) 20:1047. doi: 10.1186/s12885-020-07488-8
    1. Luo Q, Wang C, Peng B, Pu X, Cai L, Liao H, et al. . Circulating Tumor-Cell-Associated White Blood Cell Clusters in Peripheral Blood Indicate Poor Prognosis in Patients With Hepatocellular Carcinoma. Front Oncol (2020) 10:1758. doi: 10.3389/fonc.2020.01758
    1. Qi LN, Ma L, Chen YY, Chen ZS, Zhong JH, Gong WF, et al. . Outcomes of Anatomical Versus non-Anatomical Resection for Hepatocellular Carcinoma According to Circulating Tumour-Cell Status. Ann Med (2020) 52:21–31. doi: 10.1080/07853890.2019.1709655
    1. Rau K-M, Liu C-T, Hsiao Y-C, Hsiao K-Y, Wang T-M, Hung W-S, et al. . Sequential Circulating Tumor Cell Counts in Patients With Locally Advanced or Metastatic Hepatocellular Carcinoma: Monitoring the Treatment Response. J Clin Med (2020) 9:188. doi: 10.3390/jcm9010188
    1. Li J, Shi L, Zhang X, Sun B, Yang Y, Ge N, et al. . pERK/Pakt Phenotyping in Circulating Tumor Cells as a Biomarker for Sorafenib Efficacy in Patients With Advanced Hepatocellular Carcinoma. Oncotarget (2016) 7:2646–59. doi: 10.18632/oncotarget.6104
    1. D’Avola D, Villacorta-Martin C, Martins-Filho SN, Craig A, Labgaa I, von Felden J, et al. . High-Density Single Cell mRNA Sequencing to Characterize Circulating Tumor Cells in Hepatocellular Carcinoma. Sci Rep (2018) 8:11570. doi: 10.1038/s41598-018-30047-y
    1. Sun C, Liao W, Deng Z, Li E, Feng Q, Lei J, et al. . The Diagnostic Value of Assays for Circulating Tumor Cells in Hepatocellular Carcinoma: A Meta-Analysis. Med (Baltimore) (2017) 96:e7513. doi: 10.1097/MD.0000000000007513
    1. Went PT, Lugli A, Meier S, Bundi M, Mirlacher M, Sauter G, et al. . Frequent EpCam Protein Expression in Human Carcinomas. Hum Pathol (2004) 35:122–8. doi: 10.1016/j.humpath.2003.08.026
    1. Wang Z, Luo L, Cheng Y, He G, Peng B, Gao Y, et al. . Correlation Between Postoperative Early Recurrence of Hepatocellular Carcinoma and Mesenchymal Circulating Tumor Cells in Peripheral Blood. J Gastrointest Surg (2018) 22:633–9. doi: 10.1007/s11605-017-3619-3
    1. Hamaoka M, Kobayashi T, Tanaka Y, Mashima H, Ohdan H. Clinical Significance of Glypican-3-Positive Circulating Tumor Cells of Hepatocellular Carcinoma Patients: A Prospective Study. PloS One (2019) 14.e0217586. doi: 10.1371/journal.pone.0217586
    1. Bai T, Mai R, Ye J, Chen J, Qi L, Tang J, et al. . Circulating Tumor Cells and CXCR4 in the Prognosis of Hepatocellular Carcinoma. Trans Cancer Res (2020) 9:1384–94. doi: 10.21037/tcr.2020.01.14
    1. Gkountela S, Castro-Giner F, Szczerba BM, Vetter M, Landin J, Scherrer R, et al. . Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding. Cell (2019) 176:98–112.e114. doi: 10.1016/j.cell.2018.11.046
    1. Wu X, Yang C, Yu H, Cao F, Shan Y, Zhao W. The Predictive Values of Serum Dickkopf-1 and Circulating Tumor Cells in Evaluating the Efficacy of Transcatheter Arterial Chemoembolization Treatment on Hepatocellular Carcinoma. Med (Baltimore) (2019) 98:e16579. doi: 10.1097/MD.0000000000016579
    1. Li Y, Huang N, Wang C, Ma H, Zhou M, Lin L, et al. . Impact of Liver Tumor Percutaneous Radiofrequency Ablation on Circulating Tumor Cells. Oncol Lett (2018) 16:2839–50. doi: 10.3892/ol.2018.9019
    1. Guo W, Sun YF, Shen MN, Ma XL, Wu J, Zhang CY, et al. . Circulating Tumor Cells With Stem-Like Phenotypes for Diagnosis, Prognosis, and Therapeutic Response Evaluation in Hepatocellular Carcinoma. Clin Cancer Res (2018) 24:2203–13. doi: 10.1158/1078-0432.CCR-17-1753
    1. Fan ZC, Yan J, Liu GD, Tan XY, Weng XF, Wu WZ, et al. . Real-Time Monitoring of Rare Circulating Hepatocellular Carcinoma Cells in an Orthotopic Model by In Vivo Flow Cytometry Assesses Resection on Metastasis. Cancer Res (2012) 72:2683–91. doi: 10.1158/0008-5472.CAN-11-3733
    1. Zhang Y, Zhang X, Zhang J, Sun B, Zheng L, Li J, et al. . Microfluidic Chip for Isolation of Viable Circulating Tumor Cells of Hepatocellular Carcinoma for Their Culture and Drug Sensitivity Assay. Cancer Biol Ther (2016) 17:1177–87. doi: 10.1080/15384047.2016.1235665
    1. Xu F, Jin T, Zhu Y, Dai C. Immune Checkpoint Therapy in Liver Cancer. J Exp Clin Cancer Res (2018) 37:110. doi: 10.1186/s13046-018-0777-4
    1. Winograd P, Hou S, Court CM, Sadeghi S, Finn RS, DiPardo B, et al. . Evaluation of Hepatocellular Carcinoma Circulating Tumor Cells Expressing Programmed Death-Ligand 1. Hpb (2018) 20:S2–3. doi: 10.1016/j.hpb.2018.02.004
    1. Winograd P, Hou S, Court CM, Lee YT, Chen PJ, Zhu Y, et al. . Hepatocellular Carcinoma-Circulating Tumor Cells Expressing PD-L1 Are Prognostic and Potentially Associated With Response to Checkpoint Inhibitors. Hepatol Commun (2020) 4:1527–40. doi: 10.1002/hep4.1577
    1. van der Vaart M, Pretorius PJ. The Origin of Circulating Free DNA. Clin Chem (2007) 53:2215. doi: 10.1373/clinchem.2007.092734
    1. Alix-Panabieres C, Schwarzenbach H, Pantel K. Circulating Tumor Cells and Circulating Tumor DNA. Annu Rev Med (2012) 63:199–215. doi: 10.1146/annurev-med-062310-094219
    1. Thierry AR, El Messaoudi S, Gahan PB, Anker P, Stroun M. Origins, Structures, and Functions of Circulating DNA in Oncology. Cancer Metastasis Rev (2016) 35:347–76. doi: 10.1007/s10555-016-9629-x
    1. Cortese R, Almendros I, Wang Y, Gozal D. Tumor Circulating DNA Profiling in Xenografted Mice Exposed to Intermittent Hypoxia. Oncotarget (2015) 6:556–69. doi: 10.18632/oncotarget.2785
    1. Xu RH, Wei W, Krawczyk M, Wang W, Luo H, Flagg K, et al. . Circulating Tumour DNA Methylation Markers for Diagnosis and Prognosis of Hepatocellular Carcinoma. Nat Mater (2017) 16:1155–61. doi: 10.1038/nmat4997
    1. Oussalah A, Rischer S, Bensenane M, Conroy G, Filhine-Tresarrieu P, Debard R, et al. . Plasma Msept9: A Novel Circulating Cell-Free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma. EBioMedicine (2018) 30:138–47. doi: 10.1016/j.ebiom.2018.03.029
    1. Kisiel JB, Dukek BA, R VSRK, Ghoz HM, Yab TC, Berger CK, et al. . Hepatocellular Carcinoma Detection by Plasma Methylated DNA: Discovery, Phase I Pilot, and Phase II Clinical Validation. Hepatology (2019) 69:1180–92. doi: 10.1002/hep.30244
    1. Yong E. Cancer Biomarkers: Written in Blood. Nature (2014) 511:524–6. doi: 10.1038/511524a
    1. Mouliere F, Chandrananda D, Piskorz AM, Moore EK, Morris J, Ahlborn LB, et al. . Enhanced Detection of Circulating Tumor DNA by Fragment Size Analysis. Sci Transl Med (2018) 10. doi: 10.1126/scitranslmed.aat4921
    1. Bergman Y, Cedar H. DNA Methylation Dynamics in Health and Disease. Nat Struct Mol Biol (2013) 20:274–81. doi: 10.1038/nsmb.2518
    1. Zhang P, Wen X, Gu F, Deng X, Li J, Dong J, et al. . Methylation Profiling of Serum DNA From Hepatocellular Carcinoma Patients Using an Infinium Human Methylation 450 BeadChip. Hepatol Int (2013) 7:893–900. doi: 10.1007/s12072-013-9437-0
    1. Chan KC, Jiang P, Chan CW, Sun K, Wong J, Hui EP, et al. . Noninvasive Detection of Cancer-Associated Genome-Wide Hypomethylation and Copy Number Aberrations by Plasma DNA Bisulfite Sequencing. Proc Natl Acad Sci USA (2013) 110:18761–8. doi: 10.1073/pnas.1313995110
    1. Huang G, Krocker JD, Kirk JL, Merwat SN, Ju H, Soloway RD, et al. . Evaluation of INK4A Promoter Methylation Using Pyrosequencing and Circulating Cell-Free DNA From Patients With Hepatocellular Carcinoma. Clin Chem Lab Med (2014) 52:899–909. doi: 10.1515/cclm-2013-0885
    1. Ji XF, Fan YC, Gao S, Yang Y, Zhang JJ, Wang K. MT1M and MT1G Promoter Methylation as Biomarkers for Hepatocellular Carcinoma. World J Gastroenterol (2014) 20:4723–9. doi: 10.3748/wjg.v20.i16.4723
    1. Kuo CC, Lin CY, Shih YL, Hsieh CB, Lin PY, Guan SB, et al. . Frequent Methylation of HOXA9 Gene in Tumor Tissues and Plasma Samples From Human Hepatocellular Carcinomas. Clin Chem Lab Med (2014) 52:1235–45. doi: 10.1515/cclm-2013-0780
    1. Lu CY, Chen SY, Peng HL, Kan PY, Chang WC, Yen CJ. Cell-Free Methylation Markers With Diagnostic and Prognostic Potential in Hepatocellular Carcinoma. Oncotarget (2017) 8:6406–18. doi: 10.18632/oncotarget.14115
    1. Wu HC, Yang HI, Wang Q, Chen CJ, Santella RM. Plasma DNA Methylation Marker and Hepatocellular Carcinoma Risk Prediction Model for the General Population. Carcinogenesis (2017) 38:1021–8. doi: 10.1093/carcin/bgx078
    1. Cai J, Chen L, Zhang Z, Zhang X, Lu X, Liu W, et al. . Genome-Wide Mapping of 5-Hydroxymethylcytosines in Circulating Cell-Free DNA as a non-Invasive Approach for Early Detection of Hepatocellular Carcinoma. Gut (2019) 68:2195–205. doi: 10.1136/gutjnl-2019-318882
    1. Chen L, Abou-Alfa GK, Zheng B, Liu JF, Bai J, Du LT, et al. . Genome-Scale Profiling of Circulating Cell-Free DNA Signatures for Early Detection of Hepatocellular Carcinoma in Cirrhotic Patients. Cell Res (2021) 31:589–92. doi: 10.1038/s41422-020-00457-7
    1. Piciocchi M, Cardin R, Vitale A, Vanin V, Giacomin A, Pozzan C, et al. . Circulating Free DNA in the Progression of Liver Damage to Hepatocellular Carcinoma. Hepatol Int (2013) 7:1050–7. doi: 10.1007/s12072-013-9481-9
    1. Huang A, Zhang X, Zhou SL, Cao Y, Huang XW, Fan J, et al. . Detecting Circulating Tumor DNA in Hepatocellular Carcinoma Patients Using Droplet Digital PCR Is Feasible and Reflects Intratumoral Heterogeneity. J Cancer (2016) 7:1907–14. doi: 10.7150/jca.15823
    1. Liao W, Yang H, Xu H, Wang Y, Ge P, Ren J, et al. . Noninvasive Detection of Tumor-Associated Mutations From Circulating Cell-Free DNA in Hepatocellular Carcinoma Patients by Targeted Deep Sequencing. Oncotarget (2016) 7:40481–90. doi: 10.18632/oncotarget.9629
    1. Qu C, Wang Y, Wang P, Chen K, Wang M, Zeng H, et al. . Detection of Early-Stage Hepatocellular Carcinoma in Asymptomatic HBsAg-Seropositive Individuals by Liquid Biopsy. Proc Natl Acad Sci USA (2019) 116:6308–12. doi: 10.1073/pnas.1819799116
    1. Tao K, Bian Z, Zhang Q, Guo X, Yin C, Wang Y, et al. . Machine Learning-Based Genome-Wide Interrogation of Somatic Copy Number Aberrations in Circulating Tumor DNA for Early Detection of Hepatocellular Carcinoma. EBioMedicine (2020) 56:102811. doi: 10.1016/j.ebiom.2020.102811
    1. Cai Z, Chen G, Zeng Y, Dong X, Li Z, Huang Y, et al. . Comprehensive Liquid Profiling of Circulating Tumor DNA and Protein Biomarkers in Long-Term Follow-Up Patients With Hepatocellular Carcinoma. Clin Cancer Res (2019) 25:5284–94. doi: 10.1158/1078-0432.CCR-18-3477
    1. Wang Y, Balaji V, Kaniyappan S, Kruger L, Irsen S, Tepper K, et al. . The Release and Trans-Synaptic Transmission of Tau via Exosomes. Mol Neurodegener (2017) 12:5. doi: 10.1186/s13024-016-0143-y
    1. Ikeda S, Lim JS, Kurzrock R. Analysis of Tissue and Circulating Tumor DNA by Next-Generation Sequencing of Hepatocellular Carcinoma: Implications for Targeted Therapeutics. Mol Cancer Ther (2018) 17:1114–22. doi: 10.1158/1535-7163.MCT-17-0604
    1. Liu A, Wu Q, Peng D, Ares I, Anadon A, Lopez-Torres B, et al. . A Novel Strategy for the Diagnosis, Prognosis, Treatment, and Chemoresistance of Hepatocellular Carcinoma: DNA Methylation. Med Res Rev (2020) 40:1973–2018. doi: 10.1002/med.21696
    1. Kotoh Y, Suehiro Y, Saeki I, Hoshida T, Maeda M, Iwamoto T, et al. . Novel Liquid Biopsy Test Based on a Sensitive Methylated SEPT9 Assay for Diagnosing Hepatocellular Carcinoma. Hepatol Commun (2020) 4:461–70. doi: 10.1002/hep4.1469
    1. Yan L, Chen Y, Zhou J, Zhao H, Zhang H, Wang G. Diagnostic Value of Circulating Cell-Free DNA Levels for Hepatocellular Carcinoma. Int J Infect Dis (2018) 67:92–7. doi: 10.1016/j.ijid.2017.12.002
    1. Li F, Qiao CY, Gao S, Fan YC, Chen LY, Wang K. Circulating Cell-Free DNA of Methylated Insulin-Like Growth Factor-Binding Protein 7 Predicts a Poor Prognosis in Hepatitis B Virus-Associated Hepatocellular Carcinoma After Hepatectomy. Free Radic Res (2018) 52:455–64. doi: 10.1080/10715762.2018.1443448
    1. Ren N, Qin LX, Tu H, Liu YK, Zhang BH, Tang ZY. The Prognostic Value of Circulating Plasma DNA Level and Its Allelic Imbalance on Chromosome 8p in Patients With Hepatocellular Carcinoma. J Cancer Res Clin Oncol (2006) 132:399–407. doi: 10.1007/s00432-005-0049-5
    1. Kim SS, Eun JW, Choi JH, Woo HG, Cho HJ, Ahn HR, et al. . MLH1 Single-Nucleotide Variant in Circulating Tumor DNA Predicts Overall Survival of Patients With Hepatocellular Carcinoma. Sci Rep (2020) 10:17862. doi: 10.1038/s41598-020-74494-y
    1. Park S, Lee EJ, Rim CH, Seong J. Plasma Cell-Free DNA as a Predictive Marker After Radiotherapy for Hepatocellular Carcinoma. Yonsei Med J (2018) 59:470–9. doi: 10.3349/ymj.2018.59.4.470
    1. Zhao W, Qiu L, Liu H, Xu Y, Zhan M, Zhang W, et al. . Circulating Tumor DNA as a Potential Prognostic and Predictive Biomarker During Interventional Therapy of Unresectable Primary Liver Cancer. J Gastrointest Oncol (2020) 11:1065–77. doi: 10.21037/jgo-20-409
    1. Ikeda S, Tsigelny IF, Skjevik AA, Kono Y, Mendler M, Kuo A, et al. . Next-Generation Sequencing of Circulating Tumor DNA Reveals Frequent Alterations in Advanced Hepatocellular Carcinoma. Oncologist (2018) 23:586–93. doi: 10.1634/theoncologist.2017-0479
    1. Parikh AR, Leshchiner I, Elagina L, Goyal L, Levovitz C, Siravegna G, et al. . Liquid Versus Tissue Biopsy for Detecting Acquired Resistance and Tumor Heterogeneity in Gastrointestinal Cancers. Nat Med (2019) 25:1415–21. doi: 10.1038/s41591-019-0561-9
    1. von Felden J, Craig AJ, Garcia-Lezana T, Labgaa I, Haber PK, D’Avola D, et al. . Mutations in Circulating Tumor DNA Predict Primary Resistance to Systemic Therapies in Advanced Hepatocellular Carcinoma. Oncogene (2021) 40:140–51. doi: 10.1038/s41388-020-01519-1
    1. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle Formation During Reticulocyte Maturation. Association of Plasma Membrane Activities With Released Vesicles (Exosomes). J Biol Chem (1987) 262:9412–20. doi: 10.1016/S0021-9258(18)48095-7
    1. Yanez-Mo M, Siljander PR, Andreu Z, Zavec AB, Borras FE, Buzas EI, et al. . Biological Properties of Extracellular Vesicles and Their Physiological Functions. J Extracell Vesicles (2015) 4.27066. doi: 10.3402/jev.v4.27066
    1. Raab-Traub N, Dittmer DP. Viral Effects on the Content and Function of Extracellular Vesicles. Nat Rev Microbiol (2017) 15:559–72. doi: 10.1038/nrmicro.2017.60
    1. Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, et al. . Proteomic Comparison Defines Novel Markers to Characterize Heterogeneous Populations of Extracellular Vesicle Subtypes. Proc Natl Acad Sci USA (2016) 113:E968–77. doi: 10.1073/pnas.1521230113
    1. Wang M, Wang Y, Ye F, Yu K, Wei W, Liu M, et al. . Exosome Encapsulated ncRNAs in the Development of HCC: Potential Circulatory Biomarkers and Clinical Therapeutic Targets. Am J Cancer Res (2021) 11:3794–812.
    1. Wang B, Zhang Y, Ye M, Wu J, Ma L, Chen H. Cisplatin-Resistant MDA-MB-231 Cell-Derived Exosomes Increase the Resistance of Recipient Cells in an Exosomal miR-423-5p-Dependent Manner. Curr Drug Metab (2019) 20:804–14. doi: 10.2174/1389200220666190819151946
    1. Pan JH, Zhou H, Zhao XX, Ding H, Li W, Qin L, et al. . Role of Exosomes and Exosomal microRNAs in Hepatocellular Carcinoma: Potential in Diagnosis and Antitumour Treatments (Review). Int J Mol Med (2018) 41:1809–16. doi: 10.3892/ijmm.2018.3383
    1. Zhou Y, Ren H, Dai B, Li J, Shang L, Huang J, et al. . Hepatocellular Carcinoma-Derived Exosomal miRNA-21 Contributes to Tumor Progression by Converting Hepatocyte Stellate Cells to Cancer-Associated Fibroblasts. J Exp Clin Cancer Res (2018) 37:324. doi: 10.1186/s13046-018-0965-2
    1. Zhou B, Xu K, Zheng X, Chen T, Wang J, Song Y, et al. . Application of Exosomes as Liquid Biopsy in Clinical Diagnosis. Signal Transduct Target Ther (2020) 5:144. doi: 10.1038/s41392-020-00258-9
    1. Cai X, Janku F, Zhan Q, Fan JB. Accessing Genetic Information With Liquid Biopsies. Trends Genet (2015) 31:564–75. doi: 10.1016/j.tig.2015.06.001
    1. Lin XJ, Fang JH, Yang XJ, Zhang C, Yuan Y, Zheng L, et al. . Hepatocellular Carcinoma Cell-Secreted Exosomal MicroRNA-210 Promotes Angiogenesis In Vitro and In Vivo . Mol Ther Nucleic Acids (2018) 11:243–52. doi: 10.1016/j.omtn.2018.02.014
    1. Rao Q, Zuo B, Lu Z, Gao X, You A, Wu C, et al. . Tumor-Derived Exosomes Elicit Tumor Suppression in Murine Hepatocellular Carcinoma Models and Humans In Vitro. Hepatology (2016) 64:456–72. doi: 10.1002/hep.28549
    1. Kalluri R, LeBleu VS. The Biology, Function, and Biomedical Applications of Exosomes. Science (2020) 367. doi: 10.1126/science.aau6977
    1. Wang H, Lu Z, Zhao X. Tumorigenesis, Diagnosis, and Therapeutic Potential of Exosomes in Liver Cancer. J Hematol Oncol (2019) 12:133. doi: 10.1186/s13045-019-0806-6
    1. Sohn W, Kim J, Kang SH, Yang SR, Cho JY, Cho HC, et al. . Serum Exosomal microRNAs as Novel Biomarkers for Hepatocellular Carcinoma. Exp Mol Med (2015) 47:e184. doi: 10.1038/emm.2015.68
    1. Cho HJ, Baek GO, Seo CW, Ahn HR, Sung S, Son JA, et al. . Exosomal microRNA-4661-5p-Based Serum Panel as a Potential Diagnostic Biomarker for Early-Stage Hepatocellular Carcinoma. Cancer Med (2020) 9:5459–72. doi: 10.1002/cam4.3230
    1. Ma F, Liu X, Li D, Wang P, Li N, Lu L, et al. . MicroRNA-466l Upregulates IL-10 Expression in TLR-Triggered Macrophages by Antagonizing RNA-Binding Protein Tristetraprolin-Mediated IL-10 mRNA Degradation. J Immunol (2010) 184:6053–9. doi: 10.4049/jimmunol.0902308
    1. Cho HJ, Eun JW, Baek GO, Seo CW, Ahn HR, Kim SS, et al. . Serum Exosomal MicroRNA, miR-10b-5p, as a Potential Diagnostic Biomarker for Early-Stage Hepatocellular Carcinoma. J Clin Med (2020) 9:281. doi: 10.3390/jcm9010281
    1. Arbelaiz A, Azkargorta M, Krawczyk M, Santos-Laso A, Lapitz A, Perugorria MJ, et al. . Serum Extracellular Vesicles Contain Protein Biomarkers for Primary Sclerosing Cholangitis and Cholangiocarcinoma. Hepatology (2017) 66:1125–43. doi: 10.1002/hep.29291
    1. Ma X, Yuan T, Yang C, Wang Z, Zang Y, Wu L, et al. . X-Inactive-Specific Transcript of Peripheral Blood Cells is Regulated by Exosomal Jpx and Acts as a Biomarker for Female Patients With Hepatocellular Carcinoma. Ther Adv Med Oncol (2017) 9:665–77. doi: 10.1177/1758834017731052
    1. Xu H, Chen Y, Dong X, Wang X. Serum Exosomal Long Noncoding RNAs ENSG00000258332.1 and LINC00635 for the Diagnosis and Prognosis of Hepatocellular Carcinoma. Cancer Epidemiol Biomarkers Prev (2018) 27:710–6. doi: 10.1158/1055-9965.EPI-17-0770
    1. Fu Q, Zhang Q, Lou Y, Yang J, Nie G, Chen Q, et al. . Primary Tumor-Derived Exosomes Facilitate Metastasis by Regulating Adhesion of Circulating Tumor Cells via SMAD3 in Liver Cancer. Oncogene (2018) 37:6105–18. doi: 10.1038/s41388-018-0391-0
    1. Wang Y, Zhang C, Zhang P, Guo G, Jiang T, Zhao X, et al. . Serum Exosomal microRNAs Combined With Alpha-Fetoprotein as Diagnostic Markers of Hepatocellular Carcinoma. Cancer Med (2018) 7:1670–9. doi: 10.1002/cam4.1390
    1. Lee YR, Kim G, Tak WY, Jang SY, Kweon YO, Park JG, et al. . Circulating Exosomal Noncoding RNAs as Prognostic Biomarkers in Human Hepatocellular Carcinoma. Int J Cancer (2019) 144:1444–52. doi: 10.1002/ijc.31931
    1. Wang G, Liu W, Zou Y, Wang G, Deng Y, Luo J, et al. . Three Isoforms of Exosomal Circptgr1 Promote Hepatocellular Carcinoma Metastasis via the Mir449a-MET Pathway. EBioMedicine (2019) 40:432–45. doi: 10.1016/j.ebiom.2018.12.062
    1. Zhang PF, Gao C, Huang XY, Lu JC, Guo XJ, Shi GM, et al. . Cancer Cell-Derived Exosomal Circuhrf1 Induces Natural Killer Cell Exhaustion and may Cause Resistance to Anti-PD1 Therapy in Hepatocellular Carcinoma. Mol Cancer (2020) 19:110. doi: 10.1186/s12943-020-01222-5
    1. Sun XH, Wang YT, Li GF, Zhang N, Fan L. Serum-Derived three-circRNA Signature as a Diagnostic Biomarker for Hepatocellular Carcinoma. Cancer Cell Int (2020) 20:226. doi: 10.1186/s12935-020-01302-y
    1. Kim SS, Baek GO, Ahn HR, Sung S, Seo CW, Cho HJ, et al. . Serum Small Extracellular Vesicle-Derived LINC00853 as a Novel Diagnostic Marker for Early Hepatocellular Carcinoma. Mol Oncol (2020) 14:2646–59. doi: 10.1002/1878-0261.12745
    1. Huang X, Sun L, Wen S, Deng D, Wan F, He X, et al. . RNA Sequencing of Plasma Exosomes Revealed Novel Functional Long Noncoding RNAs in Hepatocellular Carcinoma. Cancer Sci (2020) 111:3338–49. doi: 10.1111/cas.14516
    1. Ghosh S, Bhowmik S, Majumdar S, Goswami A, Chakraborty J, Gupta S, et al. . The Exosome Encapsulated microRNAs as Circulating Diagnostic Marker for Hepatocellular Carcinoma With Low Alpha-Fetoprotein. Int J Cancer (2020) 147:2934–47. doi: 10.1002/ijc.33111
    1. Zhang YC, Xu Z, Zhang TF, Wang YL. Circulating microRNAs as Diagnostic and Prognostic Tools for Hepatocellular Carcinoma. World J Gastroenterol (2015) 21:9853–62. doi: 10.3748/wjg.v21.i34.9853
    1. Wang H, Hou L, Li A, Duan Y, Gao H, Song X. Expression of Serum Exosomal microRNA-21 in Human Hepatocellular Carcinoma. BioMed Res Int (2014) 2014:864894. doi: 10.1155/2014/864894
    1. Lu Y, Duan Y, Xu Q, Zhang L, Chen W, Qu Z, et al. . Circulating Exosome-Derived Bona Fide Long non-Coding RNAs Predicting the Occurrence and Metastasis of Hepatocellular Carcinoma. J Cell Mol Med (2020) 24:1311–8. doi: 10.1111/jcmm.14783
    1. Zhu L, Li J, Gong Y, Wu Q, Tan S, Sun D, et al. . Exosomal tRNA-Derived Small RNA as a Promising Biomarker for Cancer Diagnosis. Mol Cancer (2019) 18:74. doi: 10.1186/s12943-019-1000-8
    1. Taleb RSZ, Moez P, Younan D, Eisenacher M, Tenbusch M, Sitek B, et al. . Quantitative Proteome Analysis of Plasma Microparticles for the Characterization of HCV-Induced Hepatic Cirrhosis and Hepatocellular Carcinoma. Proteomics Clin Appl (2017) 11. doi: 10.1002/prca.201700014
    1. Jiang SS, Weng DS, Wang QJ, Pan K, Zhang YJ, Li YQ, et al. . Galectin-3 Is Associated With a Poor Prognosis in Primary Hepatocellular Carcinoma. J Transl Med (2014) 12:273. doi: 10.1186/s12967-014-0273-3
    1. Liu W, Hu J, Zhou K, Chen F, Wang Z, Liao B, et al. . Serum Exosomal miR-125b Is a Novel Prognostic Marker for Hepatocellular Carcinoma. Onco Targets Ther (2017) 10:3843–51. doi: 10.2147/OTT.S140062
    1. Shi M, Jiang Y, Yang L, Yan S, Wang YG, Lu XJ. Decreased Levels of Serum Exosomal miR-638 Predict Poor Prognosis in Hepatocellular Carcinoma. J Cell Biochem (2018) 119:4711–6. doi: 10.1002/jcb.26650
    1. Luo Y, Liu F, Gui R. High Expression of Circulating Exosomal Circakt3 is Associated With Higher Recurrence in HCC Patients Undergoing Surgical Treatment. Surg Oncol (2020) 33:276–81. doi: 10.1016/j.suronc.2020.04.021
    1. Macias M, Alegre E, Diaz-Lagares A, Patino A, Perez-Gracia JL, Sanmamed M, et al. . Liquid Biopsy: From Basic Research to Clinical Practice. Adv Clin Chem (2018) 83:73–119. doi: 10.1016/bs.acc.2017.10.003

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit