Skip to main content
SpringerLink
Log in

HCC and Tumor Biomarkers: Does One Size Fits All?

  • Review Article
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Hepatocellular carcinoma (HCC) is a highly malignant disease and early diagnosis rates remain to be unsatisfactory. Owing to this limitation, advances in treatment options including liver transplantation (LT) are limited to improve survival. Recent HCC guidelines no longer recommend alpha-fetoprotein (AFP) as a surveillance and diagnostic tool for HCC. Hence, utilization of novel biomarkers has become imperative to improve disease management strategies. Noninvasive, serum-based biomarkers are potential options to aid early diagnosis as well as prompting treatment. However, further studies are required to find out the accuracy and potential of these approaches and introduce into clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Availability of Data and Material

Not applicable.

Abbreviations

AFP:

Alpha-fetoprotein

AGP:

Alpha-1 acid glycoprotein

CTDNA:

Circulating tumor DNA

CTRNA:

Circulating tumor RNA

DCP:

des-gamma-carboxy prothrombin

Gly:

Glycan

GP73:

Golgi protein 73

HCC:

Hepatocellular carcinoma

LT:

Liver transplantation

lnRNA:

Long coding RNA

NAFLD:

Non-alcoholic fatty liver disease

OPN:

Osteopontin

DKK1:

Dickkopf 1

PIVKA II:

Prothrombin induced by vitamin K absence II

TAAbs:

Tumor-associated antibodies

TAAGs:

Tumor-associated antigens

References

  1. World Health Organisation (WHO) International agency for research on cancer, The Global Cancer Observatory,Globocan. 2018. https://gco.iarc.fr/today/online-analysis-pie

  2. Kim SU, Park JH, Kim HS, Lee JM, Lee HG, Kim H, et al. Serum Dickkopf-1 as a biomarker for the diagnosis of hepatocellular carcinoma. Yonsei Med J. 2015;56(5):1296–306.

    Article  CAS  Google Scholar 

  3. Zhang L, Chen J, Gao C. An efficient model for auxiliary diagnosis of hepatocellular carcinoma based on gene expression programming. Med Biol Eng Comput. 2018;56:1771–9.

    Article  Google Scholar 

  4. Wu M, Liu Z, Li X, Zhang A, Li N. Dynamic changes in serum markers and their utility in the early diagnosis of all stages of hepatitis B-associated hepatocellular carcinoma. Onco Targets Ther. 2020;13:827–40.

    Article  CAS  Google Scholar 

  5. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.

    Article  Google Scholar 

  6. Jiao C, Cui L, Piao J, et al. Clinical significance and expression of serum Golgi protein 73 in primary hepatocellular carcinoma. J Can Res Ther. 2018;14:1239–44.

    CAS  Google Scholar 

  7. Hiroaki T, Tadashi N, Mitsuteru K, et al. Acylcarnitine: useful biomarker for early diagnosis of hepatocellular carcinoma in non-steatohepatitis patients. World J Gastrointest Oncol. 2019;11(10):887–97.

    Article  Google Scholar 

  8. Song PP, Xia JF, Inagaki Y, Hasegawa K, Sakamoto Y, Kokudo N, et al. Controversies regarding and perspectives on clinical utility of biomarkers in hepatocellular carcinoma. World J Gastroenterol. 2016;22(1):262–74.

    Article  CAS  Google Scholar 

  9. Zhou L, Liu J, Luo F. Serum tumor markers for detection of hepatocellular carcinoma. World J Gastroenterol. 2006;12(8):1175–81.

    Article  CAS  Google Scholar 

  10. Kagan, Zhu J, Wang M, et al. Evaluation of AGP fucosylation as a marker for hepatocellular carcinoma of three different etiologies. Sci Rep. 2019;9(1):11580. https://doi.org/10.1038/s41598-019-48043-1.

  11. Seino S, Tsuchiya A, Watanabe Y, Kawata Y, Kojima Y, Ikarashi S, et al. Clinical outcome of hepatocellular carcinoma can be predicted by the expression of hepatic progenitor cell markers and serum tumour markers. Oncotarget. 2018;9(31):21844–60.

    Article  Google Scholar 

  12. Park SJ, Jang JY, Jeong SW, et al. Usefulness of AFP, AFP-L3, and PIVKA-II, and their combinations in diagnosing hepatocellular carcinoma. Medicine. 2017;96:11.

    Google Scholar 

  13. Toyoda H, Kumada T, Tada T, Sone Y, Kaneoka Y, Maeda A. Tumor markers for hepatocellular carcinoma: simple and significant predictors of outcome in patients with HCC. Liver Cancer. 2015;4(2):126–36. https://doi.org/10.1159/000367735.

  14. Janf ES, Jeong SH, Kim JW, et al. Diagnostic performance of alpha-fetoprotein, protein induced by vitamin K absence, osteopontin, Dickkopf-1 and its combinations for hepatocellular carcinoma. PLoS One. 2016;11(3):e0151069. https://doi.org/10.1371/journal.pone.0151069.

    Article  CAS  Google Scholar 

  15. Rich N, Singal A. Hepatocellular carcinoma tumour markers: current role and expectations. Best Pract Res Clin Gastroenterol. 2014;28:843–53.

    Article  CAS  Google Scholar 

  16. Wang H, Guo D, Li J, Wei B, Zheng H. Increased expression of osteopontin indicates poor prognosis in hepatocellular carcinoma. Int J Clin Exp Pathol. 2018;11(12):5916–22.

    CAS  Google Scholar 

  17. Sun T, Li P, Sun D, et al. Prognostic value of osteopontin in patients with hepatocellular carcinoma: a systematic review and meta-analysis. Medicine. 2018;97:43.

    Google Scholar 

  18. Sun T, Tang Y, Sun D, Bu Q, Li P. Osteopontin versus alpha-fetoprotein as a diagnostic marker for hepatocellular carcinoma: a meta-analysis. Onco Targets Therapy. 2018;11:8925–35.

    Article  CAS  Google Scholar 

  19. Lu Y, Li N, Gao L, et al. Acetylcarnitine is a candidate diagnostic and prognostic biomarker of hepatocellular carcinoma. Cancer Res. 2016;76(10):2912–20. https://doi.org/10.1158/0008-5472.CAN-15-3199.

  20. Higai K, Aoki Y, Azuma Y, Matsumoto K. Glycosylation of site-specific glycans of α1-acid glycoprotein and alterations in acute and chronic inflammation. Biochim Biophys Acta. 2005;1725:128–35.

    Article  CAS  Google Scholar 

  21. Åstrom E, Stål P, Zenlander R, et al. Reverse lectin ELISA for detecting fucosylated forms of α1- acid glycoprotein associated with hepatocellular carcinoma. PLoS One. 2017;12(3):e0173897.

    Article  Google Scholar 

  22. Fujiwara N, Nakagawa H, Enooku K, Kudo Y, Hayata Y, Nakatsuka T, et al. CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity. Gut. 2018;67:1–12. https://doi.org/10.1136/gutjnl-2017-315193.

    Article  CAS  Google Scholar 

  23. Lin M, Lv D, Zheng Y, Wu M, Xu C, Zhang Q, et al. Downregulation of cPT2 promotes tumorigenesis and chemoresistance to cisplatin in hepatocellular carcinoma. Onco Targets Ther. 2018;11:3101–10.

    Article  Google Scholar 

  24. de Oliveira RM, Ornelas Ricart CA, Araujo Martins AM. Use of mass spectrometry to screen glycan early markers in hepatocellular carcinoma. Front Oncol. 2018;7:328. https://doi.org/10.3389/fonc.2017.00328.

    Article  Google Scholar 

  25. Yoshida Y, Furukawa Jİ, Naito S, Higashino K, Numata Y, Shinohara Y. Identification of unique glycoisoforms of vitamin D-binding protein and haptoglobin as biomarker candidates in hepatocarcinogenesis of STAM mice. Glycoconj J. 2018;35:467–76.

    Article  CAS  Google Scholar 

  26. Klein A, Michalski JC, Morelle W. Modifications of human total serum N-glycome during liver fibrosis–cirrhosis, is it all about immunoglobulins? Proteomics Clin Appl. 2010;4:372–8.

    Article  CAS  Google Scholar 

  27. El-Derany MO. Polymorphisms in interleukin 13 signaling and interacting genes predict advanced fibrosis and hepatocellular carcinoma development in non-alcoholic steatohepatitis. Biology. 2020;9:75. https://doi.org/10.3390/biology9040075.

    Article  Google Scholar 

  28. Citores MJ, Lucena JL, de la Fuente S, et al. Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation. World J Hepatol. 2019;11(1):50–64.

    Article  Google Scholar 

  29. Tang S, Kim PS. A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery. PNAS. 2019;116:49–24506. www.pnas.org/cgi/doi/10.1073/pnas.1916916116.

    Google Scholar 

  30. Oldenhove G, Boucquey E, Tauqin A, et al. PD-1 is involved in the dysregulation of type 2 innate lymphoid cells in a murine model of obesity. Cell Rep. 2018;25:2053–60.

    Article  CAS  Google Scholar 

  31. Zhou JW, Li Y, Yue LX, Luo CL, Chen Y, Zhang JY. Autoantibody response to Sui1 and its tissue-specific expression in hepatocellular carcinoma. Tumor Biol. 2016;37:2547–53.

    Article  CAS  Google Scholar 

  32. Hwang HM, Heo CK, Lee HJ, Kwak SS, Lim WH, Yoo JS, et al. Identification of anti-SF3B1 autoantibody as a diagnostic marker in patients with hepatocellular carcinoma. J Transl Med. 2018;16:177.

    Article  CAS  Google Scholar 

  33. Heo CK, Hwang HM, Lee HJ, et al. Serum anti-EIF3A autoantibody as a potential diagnostic marker for hepatocellular carcinoma. 2019;9:11059. https://doi.org/10.1038/s41598-019-47365-4www.nature.com/scientificreports.

  34. Mocan T, Simao AL, Castro RE, et al. Liquid biopsies in hepatocellular carcinoma: are we winning? J Clin Med. 2020;9:1541. https://doi.org/10.3390/jcm9051541.

    Article  CAS  Google Scholar 

  35. Okajima W, Komatsu S, Ichikawa D, Miyamae M, Kawaguchi T, Hirajima S, et al. Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function. Oncotarget. 2016;7(33):53820–36.

    Article  Google Scholar 

  36. Li J, Han X, Yu X, 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.

    Article  Google Scholar 

  37. Court CM, Hou S, Winograd P, Segel NH, Li QW, Zhu Y, et al. A novel multimarker assay for the phenotypic profiling of circulating tumor cells in hepatocellular carcinoma. Liver Transpl. 2018;24(7):946–60. https://doi.org/10.1002/lt.25062.

    Article  Google Scholar 

  38. Zhang N, Hu Z, Qiang Y, et al. Circulating miR-130b- and miR-21-based diagnostic markers and therapeutic targets for hepatocellular carcinoma. Mol Genet Genomic Med. 2019;7:e1012.

    CAS  Google Scholar 

  39. Chen R, Xu X, Tao Y, et al. Exosomes in hepatocellular carcinoma: a new horizon. Cell Commun Signal. 2019;17:1. https://doi.org/10.1186/s12964-018-0315-1.

    Article  Google Scholar 

  40. 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. https://doi.org/10.1186/s12943-019-1085-0.

    Article  Google Scholar 

  41. Chen L, Guo P, He Y, et al. HCC-derived exosomes elicit HCC progression and recurrence by epithelial- mesenchymal transition through MAPK/ ERK signalling pathway. Cell Death Dis. 2018;9:513. https://doi.org/10.1038/s41419-018-0534-9.

    Article  CAS  Google Scholar 

  42. Kayaalp C, Ince V, Ersan V, Karakas S, Kahraman AS, Yilmaz S. Liver transplantation for hepatocellular carcinoma at inonu university. J Gastrointest Cancer. 2017;48:268–71. https://doi.org/10.1007/s12029-017-9965-2.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, 244280, Malatya, Turkey

    Dincer Ozgor & Emrah Otan

  2. Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Elazig Yolu 10. Km, 44280, Malatya, Turkey

    Dincer Ozgor

Authors
  1. Dincer Ozgor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emrah Otan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to the manuscript.

Corresponding author

Correspondence to Dincer Ozgor.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Code Availability

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ozgor, D., Otan, E. HCC and Tumor Biomarkers: Does One Size Fits All?. J Gastrointest Canc 51, 1122–1126 (2020). https://doi.org/10.1007/s12029-020-00485-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-020-00485-x

Keywords

Search

Navigation