Serum Markers of Hepatocellular Carcinoma

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with increasing incidence worldwide. Most of patients with HCC are diagnosed at a late stage. Therefore, the prognosis of HCC patients is generally very poor with a 5-year survival rate of less than 5%. Screening strategies including α-fetoprotein (AFP) and ultrasound every 6 months in patients with liver cirrhosis, the major risk factor for HCC development, have been recommended to detect HCC at earlier stages amenable to effective treatment strategies. AFP, however, is a marker with poor sensitivity and specificity and the ultrasound is highly dependent on the operator's experience. Apart from AFP, lens culinaris agglutinin-reactive AFP and des-gamma carboxyprothrombin and several other biomarkers (e.g., glypican-3, human hepatocyte growth factor, and insulin-like growth factor) have been proposed as markers for HCC detection. In addition, with recently employed techniques, such as gene-expressing microarrays and proteomics, it is to be expected that new HCC-specific markers will become available in the near future. For all such proposed markers, however, the clinical usefulness has to be carefully evaluated and validated.

KEYWORDS

Tumor markers - α-fetoprotein - lens culinaris agglutinin-reactive AFP - des-gamma carboxyprothrombin

REFERENCES

• 1 Bruix J, Sherman M. Management of hepatocellular carcinoma.  Hepatology. 2005;  42 1208-1236
• 2 Bruix J, Sherman M, Llovet J M et al.. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver.  J Hepatol. 2001;  35 421-430
• 3 Srinivas P R, Kramer B S, Srivastava S. Trends in biomarker research for cancer detection.  Lancet Oncol. 2001;  2 698-704
• 4 Srivastava S, Gopal-Srivastava R. Biomarkers in cancer screening: a public health perspective.  J Nutr. 2002;  132 2471S-2475S
• 5 Pepe M S, Etzioni R, Feng Z et al.. Phases of biomarker development for early detection of cancer.  J Natl Cancer Inst. 2001;  93 1054-1061
• 6 Collier J, Sherman M. Screening for hepatocellular carcinoma.  Hepatology. 1998;  27 273-278
• 7 Sherman M, Peltekian K M, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population.  Hepatology. 1995;  22 432-438
• 8 Trevisani F, D'Intino P E, Morselli-Labate A M et al.. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status.  J Hepatol. 2001;  34 570-575
• 9 Peng Y C, Chan C S, Chen G H. The effectiveness of serum alpha-fetoprotein level in anti-HCV positive patients for screening hepatocellular carcinoma.  Hepatogastroenterology. 1999;  46 3208-3211
• 10 Cedrone A, Covino M, Caturelli E et al.. Utility of alpha-fetoprotein (AFP) in the screening of patients with virus-related chronic liver disease: does different viral etiology influence AFP levels in HCC? A study in 350 western patients.  Hepatogastroenterology. 2000;  47 1654-1658
• 11 Gambarin-Gelwan M, Wolf D C, Shapiro R et al.. Sensitivity of commonly available screening tests in detecting hepatocellular carcinoma in cirrhotic patients undergoing liver transplantation.  Am J Gastroenterol. 2000;  95 1535-1538
• 12 Nguyen M H, Garcia R T, Simpson P W et al.. Racial differences in effectiveness of alpha-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosis.  Hepatology. 2002;  36 410-417
• 13 Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C: a systematic review and critical analysis.  Ann Intern Med. 2003;  139 46-50
• 14 Taketa K, Sekiya C, Namiki M et al.. Lectin-reactive profiles of alpha-fetoprotein characterizing hepatocellular carcinoma and related conditions.  Gastroenterology. 1990;  99 508-518
• 15 Johnson P J, Poon T C, Hjelm N M et al.. Structures of disease-specific serum alpha-fetoprotein isoforms.  Br J Cancer. 2000;  83 1330-1337
• 16 Taketa K, Okada S, Win N et al.. Evaluation of tumor markers for the detection of hepatocellular carcinoma in Yangon General Hospital, Myanmar.  Acta Med Okayama. 2002;  56 317-320
• 17 Khien V V, Mao H V, Chinh T T et al.. Clinical evaluation of lentil lectin-reactive alpha-fetoprotein-L3 in histology-proven hepatocellular carcinoma.  Int J Biol Markers. 2001;  16 105-111
• 18 Yoshida S, Kurokohchi K, Arima K et al.. Clinical significance of lens culinaris agglutinin-reactive fraction of serum alpha-fetoprotein in patients with hepatocellular carcinoma.  Int J Oncol. 2002;  20 305-309
• 19 Wang S S, Lu R H, Lee F Y et al.. Utility of lentil lectin affinity of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma.  J Hepatol. 1996;  25 166-171
• 20 Taketa K, Endo Y, Sekiya C et al.. A collaborative study for the evaluation of lectin-reactive alpha-fetoproteins in early detection of hepatocellular carcinoma.  Cancer Res. 1993;  53 5419-5423
• 21 Oka H, Saito A, Ito K et al.. Multicenter prospective analysis of newly diagnosed hepatocellular carcinoma with respect to the percentage of Lens culinaris agglutinin-reactive alpha-fetoprotein.  J Gastroenterol Hepatol. 2001;  16 1378-1383
• 22 Shiraki K, Takase K, Tameda Y et al.. A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients.  Hepatology. 1995;  22 802-807
• 23 Sato Y, Nakata K, Kato Y et al.. Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein.  N Engl J Med. 1993;  328 1802-1806
• 24 Liebman H A, Furie B C, Tong M J et al.. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma.  N Engl J Med. 1984;  310 1427-1431
• 25 Liebman H A. Isolation and characterization of a hepatoma-associated abnormal (des-gamma-carboxy) prothrombin.  Cancer Res. 1989;  49 6493-6497
• 26 Ono M, Ohta H, Ohhira M et al.. Measurement of immunoreactive prothrombin precursor and vitamin-K-dependent gamma-carboxylation in human hepatocellular carcinoma tissues: decreased carboxylation of prothrombin precursor as a cause of des-gamma-carboxyprothrombin synthesis.  Tumour Biol. 1990;  11 319-326
• 27 Aoyagi Y, Oguro M, Yanagi M et al.. Clinical significance of simultaneous determinations of alpha-fetoprotein and des-gamma-carboxy prothrombin in monitoring recurrence in patients with hepatocellular carcinoma.  Cancer. 1996;  77 1781-1786
• 28 Mita Y, Aoyagi Y, Yanagi M et al.. The usefulness of determining des-gamma-carboxy prothrombin by sensitive enzyme immunoassay in the early diagnosis of patients with hepatocellular carcinoma.  Cancer. 1998;  82 1643-1648
• 29 Nomura F, Ishijima M, Kuwa K et al.. Serum des-gamma-carboxy prothrombin levels determined by a new generation of sensitive immunoassays in patients with small-sized hepatocellular carcinoma.  Am J Gastroenterol. 1999;  94 650-654
• 30 Lamerz R, Runge M, Stieber P et al.. Use of serum PIVKA-II (DCP) determination for differentiation between benign and malignant liver diseases.  Anticancer Res. 1999;  19 2489-2493
• 31 Grazi G L, Mazziotti A, Legnani C et al.. The role of tumor markers in the diagnosis of hepatocellular carcinoma, with special reference to the des-gamma-carboxy prothrombin.  Liver Transpl Surg. 1995;  1 249-255
• 32 Marrero J A, Su G L, Wei W et al.. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in American patients.  Hepatology. 2003;  37 1114-1121
• 33 Izuno K, Fujiyama S, Yamasaki K et al.. Early detection of hepatocellular carcinoma associated with cirrhosis by combined assay of des-gamma-carboxy prothrombin and alpha-fetoprotein: a prospective study.  Hepatogastroenterology. 1995;  42 387-393
• 34 Ikoma J, Kaito M, Ishihara T et al.. Early diagnosis of hepatocellular carcinoma using a sensitive assay for serum des-gamma-carboxy prothrombin: a prospective study.  Hepatogastroenterology. 2002;  49 235-238
• 35 Ishii M, Gama H, Chida N et al.. Simultaneous measurements of serum alpha-fetoprotein and protein induced by vitamin K absence for detecting hepatocellular carcinoma. South Tohoku District Study Group.  Am J Gastroenterol. 2000;  95 1036-1040
• 36 Shimauchi Y, Tanaka M, Kuromatsu R et al.. A simultaneous monitoring of Lens culinaris agglutinin A-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin as an early diagnosis of hepatocellular carcinoma in the follow-up of cirrhotic patients.  Oncol Rep. 2000;  7 249-256
• 37 Okuda H, Nakanishi T, Takatsu K et al.. Comparison of clinicopathological features of patients with hepatocellular carcinoma seropositive for alpha-fetoprotein alone and those seropositive for des-gamma-carboxy prothrombin alone.  J Gastroenterol Hepatol. 2001;  16 1290-1296
• 38 Hamamura K, Shiratori Y, Shiina S et al.. Unique clinical characteristics of patients with hepatocellular carcinoma who present with high plasma des-gamma-carboxy prothrombin and low serum alpha-fetoprotein.  Cancer. 2000;  88 1557-1564
• 39 Weitz I C, Liebman H A. Des-gamma-carboxy (abnormal) prothrombin and hepatocellular carcinoma: a critical review.  Hepatology. 1993;  18 990-997
• 40 Fujiyama S, Tanaka M, Maeda S et al.. Tumor markers in early diagnosis, follow-up and management of patients with hepatocellular carcinoma.  Oncology. 2002;  62(suppl 1) 57-63
• 41 Filmus J, Church J G, Buick R N. Isolation of a cDNA corresponding to a developmentally regulated transcript in rat intestine.  Mol Cell Biol. 1988;  8 4243-4249
• 42 Bernfield M, Gotte M, Park P W et al.. Functions of cell surface heparan sulfate proteoglycans.  Annu Rev Biochem. 1999;  68 729-777
• 43 Zhu Z W, Friess H, Wang L et al.. Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders.  Gut. 2001;  48 558-564
• 44 Hsu H C, Cheng W, Lai P L. Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution.  Cancer Res. 1997;  57 5179-5184
• 45 Nakatsura T, Yoshitake Y, Senju S et al.. Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker.  Biochem Biophys Res Commun. 2003;  306 16-25
• 46 Capurro M, Wanless I R, Sherman M et al.. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma.  Gastroenterology. 2003;  125 89-97
• 47 Hippo Y, Watanabe K, Watanabe A et al.. Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma.  Cancer Res. 2004;  64 2418-2423
• 48 Kladney R D, Bulla G A, Guo L et al.. GP73, a novel Golgi-localized protein upregulated by viral infection.  Gene. 2000;  249 53-65
• 49 Marrero J A, Romano P R, Nikolaeva O et al.. GP73, a resident Golgi glycoprotein, is a novel serum marker for hepatocellular carcinoma.  J Hepatol. 2005;  43 1007-1012
• 50 Nakamura T. Structure and function of hepatocyte growth factor.  Prog Growth Factor Res. 1991;  3 67-85
• 51 Tomiya T, Tani M, Yamada S et al.. Serum hepatocyte growth factor levels in hepatectomized and nonhepatectomized surgical patients.  Gastroenterology. 1992;  103 1621-1624
• 52 Tomiya T, Nagoshi S, Fujiwara K. Significance of serum human hepatocyte growth factor levels in patients with hepatic failure.  Hepatology. 1992;  15 1-4
• 53 Shiota G, Okano J, Kawasaki H et al.. Serum hepatocyte growth factor levels in liver diseases: clinical implications.  Hepatology. 1995;  21 106-112
• 54 Yanagawa K, Yamashita T, Yada K et al.. The antiproliferative effect of HGF on hepatoma cells involves induction of apoptosis with increase in intracellular polyamine concentration levels.  Oncol Rep. 1998;  5 185-190
• 55 Yamagamim H, Moriyama M, Matsumura H et al.. Serum concentrations of human hepatocyte growth factor is a useful indicator for predicting the occurrence of hepatocellular carcinomas in C-viral chronic liver diseases.  Cancer. 2002;  95 824-834
• 56 Baserga R. The insulin-like growth factor I receptor: a key to tumor growth?.  Cancer Res. 1995;  55 249-252
• 57 Baserga R, Hongo A, Rubini M et al.. The IGF-I receptor in cell growth, transformation and apoptosis.  Biochim Biophys Acta. 1997;  1332 F105-F126
• 58 Resnicoff M, Abraham D, Yutanawiboonchai W et al.. The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo.  Cancer Res. 1995;  55 2463-2469
• 59 Mazziotti G, Sorvillo F, Morisco F et al.. Serum insulin-like growth factor I evaluation as a useful tool for predicting the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a prospective study.  Cancer. 2002;  95 2539-2545
• 60 Moon W S, Rhyu K H, Kang M J et al.. Overexpression of VEGF and angiopoietin 2: a key to high vascularity of hepatocellular carcinoma?.  Mod Pathol. 2003;  16 552-557
• 61 Poon R T, Ho J W, Tong C S et al.. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma.  Br J Surg. 2004;  91 1354-1360
• 62 Sacco R, Leuci D, Tortorella C et al.. Transforming growth factor beta1 and soluble Fas serum levels in hepatocellular carcinoma.  Cytokine. 2000;  12 811-814
• 63 Song B C, Chung Y H, Kim J A et al.. Transforming growth factor-beta1 as a useful serologic marker of small hepatocellular carcinoma.  Cancer. 2002;  94 175-180
• 64 Tangkijvanich P, Tosukhowong P, Bunyongyod P et al.. Alpha-L-fucosidase as a serum marker of hepatocellular carcinoma in Thailand.  Southeast Asian J Trop Med Public Health. 1999;  30 110-114
• 65 Ishizuka H, Nakayama T, Matsuoka S et al.. Prediction of the development of hepato-cellular-carcinoma in patients with liver cirrhosis by the serial determinations of serum alpha-L-fucosidase activity.  Intern Med. 1999;  38 927-931