Molecular Diagnosis

, Volume 8, Issue 4, pp 207–212 | Cite as

Glypican-3 and Alphafetoprotein as Diagnostic Tests for Hepatocellular Carcinoma

  • Jorge Filmus
  • Mariana Capurro
Review Article


Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumor. It is usually asymptomatic in the early stages and tends to be intravascularly and intrabiliary invasive. Therefore, most patients present with incurable disease at the time of detection and early diagnosis of HCC is critical for a good prognosis.

The imaging-based diagnosis of small tumors is relatively inaccurate, as cirrhotic and dysplastic nodules mimic HCC radiologically. The availability of a suitable serological marker to distinguish between HCC and benign liver lesions would, therefore, be very useful for early diagnosis. The only serological marker currently widely used for the diagnosis of HCC is alphafetoprotein (AFP). However, the sensitivity of this marker is limited (41–65%). Given the high heterogeneity of HCC, it is currently thought that an optimal serological test for HCC will be based on the simultaneous measurement of two or three highly specific serological markers.

Several laboratories have recently reported that glypican-3 (GPC3), a membrane-bound proteoglycan, is expressed by a large proportion of HCCs, but is undetectable in normal hepatocytes and non-malignant liver disease. Furthermore, various studies demonstrated that GPC3 could be used as a serological test for the diagnosis of patients with HCC. Although the specificity of the test was very high in the context of a population with chronic liver disease, the sensitivity was limited (within the same range as AFP). Interestingly, in most cases, elevated GPC3 values did not correlate with elevated AFP values. As a consequence, the serological level of at least one of the two markers was elevated in a large majority of HCC patients. These results suggest that the sensitivity of the diagnostic test can be significantly improved without compromising specificity with the simultaneous measurement of both GPC3 and AFP.


Focal Nodular Hyperplasia Serological Marker Biliary Tract Cancer Dysplastic Nodule Benign Liver Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Heather Bird for her help in the preparation of this review.

Funding for work described in this review was provided by the NIH. Dr Filmus does consulting work for Biomosaics.


  1. 1.
    Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999; 49(1): 33–64PubMedCrossRefGoogle Scholar
  2. 2.
    Okuda K, Kojiro M. Neoplasms of the liver. In: Schiff L, Schiff ER, editors. Diseases of the liver. 7th ed. Philadelphia (PA): JB Lippincott Co., 1993Google Scholar
  3. 3.
    Bruix J, Boix L, Sala M, et al. Focus on hepatocellular carcinoma. Cancer Cell 2004; 5: 215–9PubMedCrossRefGoogle Scholar
  4. 4.
    Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2004; 362: 1907–17CrossRefGoogle Scholar
  5. 5.
    Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 2002; 122: 1609–19PubMedCrossRefGoogle Scholar
  6. 6.
    El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 2004; 127 (5 Suppl. 1): S27–34PubMedCrossRefGoogle Scholar
  7. 7.
    Tanaka Y, Hanada K, Mizokami M, et al. A comparison of the molecular clock of hepatitis C virus in the United States and Japan predicts that hepatocellular carcinoma incidence in the United States will increase over the next two decades. Proc Natl Acad Sci U S A 2002; 99: 15584–9PubMedCrossRefGoogle Scholar
  8. 8.
    Fong Y, Kemeny N, Lawrence T. Cancer of the liver and biliary tree. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 6th ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2001Google Scholar
  9. 9.
    Rustgi VK. Epidemiology of hepatocellular carcinoma. Gastroenterol Clin North Am 1987; 16: 545–51PubMedGoogle Scholar
  10. 10.
    Wands JR. Prevention of hepatocellular carcinoma. N Engl J Med 2004; 351: 1567–70PubMedCrossRefGoogle Scholar
  11. 11.
    Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Semin Liver Dis 1995; 15: 64–9PubMedCrossRefGoogle Scholar
  12. 12.
    Hasan F, Jeffers LJ, De Medina M, et al. Hepatitis C-associated hepatocellular carcinoma. Hepatology 1990; 12: 589–91PubMedCrossRefGoogle Scholar
  13. 13.
    El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340: 745–50PubMedCrossRefGoogle Scholar
  14. 14.
    Murakami T, Kim T, Oi H, et al. Detectability of hypervascular hepatocellular carcinoma by arterial phase images of MR and spiral CT. Acta Radiol 1995; 36: 372–6PubMedGoogle Scholar
  15. 15.
    Levy I, Greig PD, Gallinger S, et al. Resection of hepatocellular carcinoma without preoperative tumor biopsy. Ann Surg 2001; 34: 206–9CrossRefGoogle Scholar
  16. 16.
    Bosch FX, Ribes J, Diaz M, et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004; 127: S5–S16PubMedCrossRefGoogle Scholar
  17. 17.
    Di Bisceglie AM. Issues in screening and surveillance for hepatocellular carcinoma. Gastroenterology 2004; 127: S104–7PubMedCrossRefGoogle Scholar
  18. 18.
    Collier J, Sherman M. Screening for hepatocellular carcinoma. Hepatology 1998; 27: 273–8PubMedCrossRefGoogle Scholar
  19. 19.
    Collier J, Sherman M. Elevated alphafetoprotein in benign liver diseases. Viral Hepatitis Rev 1998; 4: 31–41Google Scholar
  20. 20.
    Daniele B, Bencivenga A, Megna AS, et al. α-Fetoprotein and ultrasonography screening for hepatocellular carcinoma. Gastroenterology 2004; 127: S108–12PubMedCrossRefGoogle Scholar
  21. 21.
    Chan D, Sell S. Tumor markers. In: Burtis CA, Ashwood A, Tietz NW, editors. Tietz textbook of clinical chemistry. 3rd ed. Philadelphia (PA): WB Saunders, 1999: 722–49Google Scholar
  22. 22.
    Taketa K. α-Fetoprotein: reevaluation in hepatology. Hepatology 1990; 12: 1420–32PubMedCrossRefGoogle Scholar
  23. 23.
    Gupta S, Bent S, Kohlwes J. Test characteristics of α-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. Ann Intern Med 2003; 139: 46–50PubMedGoogle Scholar
  24. 24.
    Levy I, Greig PD, Gallinger S, et al. Resection of hepatocellular carcinoma without preoperative tumor biopsy. Ann Surg 2001; 234: 206–9PubMedCrossRefGoogle Scholar
  25. 25.
    Johnson PJ. The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis 2001; 5: 145–59PubMedCrossRefGoogle Scholar
  26. 26.
    Trevisani F, D’Intino PE, Morselli-Labate AM, 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: 570–5PubMedCrossRefGoogle Scholar
  27. 27.
    Sherman M. Alphafetoprotein: an obituary. J Hepatol 2001; 34: 603–5PubMedCrossRefGoogle Scholar
  28. 28.
    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: 650–4PubMedCrossRefGoogle Scholar
  29. 29.
    Grazi GL, 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: 249–55PubMedCrossRefGoogle Scholar
  30. 30.
    Kasahara A, Hayashi N, Fusamoto H, et al. Clinical evaluation of plasma des-gamma-carboxy prothrombin as a marker protein of hepatocellular carcinoma in patients with tumors of various sizes. Dig Dis Sci 1993; 38: 2170–6PubMedCrossRefGoogle Scholar
  31. 31.
    Ishii M, Gama H, Chida N, et al. Simultaneous measurements of serum alphafetoprotein and protein induced by vitamin K absence for detecting hepatocellular carcinoma: South Tohoku District Study Group. Am J Gastroenterol 2000; 95: 1036–40PubMedGoogle Scholar
  32. 32.
    Li D, Mallory T, Satomura S. AFP-L3: a new generation of tumor marker for hepatocellular carcinoma. Clin Chim Acta 2001; 313: 15–9PubMedCrossRefGoogle Scholar
  33. 33.
    Marrero JA, Lok ASF. Newer markers for hepatocellular carcinoma. Gastroenterology 2004; 127 (5 Suppl. 1): S1 13–9CrossRefGoogle Scholar
  34. 34.
    Bruix J, Sherman M, Llovet JM, 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: 421–30Google Scholar
  35. 35.
    Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002; 31: 339–46PubMedCrossRefGoogle Scholar
  36. 36.
    Lander AD, Stipp CS, Ivins JK. The glypican family of heparan sulfate proteoglycans: major cell-surface proteoglycans: major cell-surface proteoglycans of the developing nervous system. Perspect Dev Neurobiol 1998; 1: 1–7Google Scholar
  37. 37.
    Veugelers M, David G. The glypicans: a family of GPI-anchored heparan sulfate proteoglycans with a potential role in the control of cell division. Trends Glycosci Glycotechnol 1998; 10: 145–52CrossRefGoogle Scholar
  38. 38.
    Filmus J, Selleck SB. Glypicans: proteoglycans with a surprise. J Clin Invest 2001; 108: 497–501PubMedGoogle Scholar
  39. 39.
    Filmus J, Song HH. Glypicans. In: Iozzo RV, editor. Proteoglycans. New York: Marcel Dekker, 2000Google Scholar
  40. 40.
    Veugelers M, De Cat B, Ceulemans H, et al. Glypican-6, a new member of the glypican family of cell surface proteoglycans. J Biol Chem 1999; 274: 26968–77PubMedCrossRefGoogle Scholar
  41. 41.
    Jackson SM, Nakato H, Sugiura M, et al. Dally, a Drosophila glypican, controls cellular responses to the TGF-beta-related morphogen Dpp. Development 1997; 124: 4113–20PubMedGoogle Scholar
  42. 42.
    Baeg GH, Perrimon N. Functional binding of secreted molecules to heparan sulfate proteoglycans in Drosophila. Curr Opin Cell Biol 2000; 12: 575–80PubMedCrossRefGoogle Scholar
  43. 43.
    Perrimon N, Bernfield M. Specificities of heparan sulphate proteoglycans in developmental processes. Nature 2000; 404: 725–8PubMedCrossRefGoogle Scholar
  44. 44.
    Paine-Saunders S, Viviano BL, Zupicich J, et al. Glypican-3 controls cellular responses to Bmp4 in limb patterning and skeletal development. Dev Biol 2000; 225: 179–87PubMedCrossRefGoogle Scholar
  45. 45.
    Lum L, Yao S, Mozer B, et al. Identification of hedgehog pathway components by RNAi in Drosophila cultured cells. Science 2003; 299: 2039–45PubMedCrossRefGoogle Scholar
  46. 46.
    Desbordes SC, Sanson B. The glypican dally-like is required for hedgehog signalling in the embryonic epidermis of Drosophila. Development 2003; 130: 6245–55PubMedCrossRefGoogle Scholar
  47. 47.
    Topczewsky J, Sepich DS, Myers DC, et al. The zebrafish glypican knypek controls cell polarity during gastrulation movements of convergent extension. Dev Cell 2001; 1: 251–64CrossRefGoogle Scholar
  48. 48.
    Ohkarawa B, Yamamoto TS, Tada M, et al. Role of glypican 4 in the regulation of convergent extension movements during gastrulation in Xenopus laevis. Development 2003; 130: 2129–38CrossRefGoogle Scholar
  49. 49.
    De Cat B, Muyldermans SY, Coomans C, et al. Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements. J Cell Biol 2003; 163: 625–35PubMedCrossRefGoogle Scholar
  50. 50.
    Kramer KL, Yost HJ. Heparan sulfate core proteins in cell-cell signaling. Annu Rev Genet 2003; 37: 461–84PubMedCrossRefGoogle Scholar
  51. 51.
    Baeg GH, Lin X, Khare N, et al. Heparan sulfate proteoglycans are critical for the organization of the extracellular distribution of Wingless. Development 2001; 128: 87–94PubMedGoogle Scholar
  52. 52.
    Han C, Belenkaya TY, Wang B, et al. Drosophila glypicans control the cell-to-cell movement of hedgehog by a dynamin-independent process. Development 2004; 131: 601–11PubMedCrossRefGoogle Scholar
  53. 53.
    Cumberledge S, Reichsman F. Glycosaminoglycans and WNTs: just a spoonful of sugar helps the signal go down. Trends Genet 1997; 13: 421–3PubMedCrossRefGoogle Scholar
  54. 54.
    Ai X, Do AT, Lozynska O, et al. QSulf1 remodels the 6-O sulfation states of cell surface proteoglycans to promote Wnt signaling. J Cell Biol 2003; 162: 341–51PubMedCrossRefGoogle Scholar
  55. 55.
    Fujise M, Takeo S, Kamimura K, et al. Dally regulates Dpp morphogen gradient formation in the Drosophila wing. Development 2003; 130: 1515–22PubMedCrossRefGoogle Scholar
  56. 56.
    Hsu HC, Cheng W, Lai PL. Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution. Cancer Res 1997; 57: 5179–84PubMedGoogle Scholar
  57. 57.
    Lage H, Dietel M. Cloning and characterization of human cDNAs encoding a protein with high homology to rat intestinal development protein OCI-5. Gene 1997; 188: 151–6PubMedCrossRefGoogle Scholar
  58. 58.
    Pilia G, Hughes-Benzie RM, MacKenzie A, et al. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet 1996; 12: 241–7PubMedCrossRefGoogle Scholar
  59. 59.
    Zhu ZW, Friess H, Wang L, et al. Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders. Gut 2001; 48: 558–64PubMedCrossRefGoogle Scholar
  60. 60.
    Zhou XP, Wang HY, Yang GS, et al. Cloning and expression of MXR7 in human HCC tissue. World J Gastroenterol 2000; 6: 57–60PubMedGoogle Scholar
  61. 61.
    Huang JS, Chao CC, Su TL, et al. Diverse cellular transformation capability of overexpressed genes in human hepatocellular carcinoma. Biochem Biophys Res Commun 2004; 315: 950–8PubMedCrossRefGoogle Scholar
  62. 62.
    Capurro M, Wanless IR, Sherman M, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology 2003; 125: 81–90CrossRefGoogle Scholar
  63. 63.
    Sung YK, Hwang SY, Park MK, et al. Glypican-3 is overexpressed in human hepatocellular carcinoma. Cancer Sci 2003; 94: 259–62PubMedCrossRefGoogle Scholar
  64. 64.
    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: 16–25PubMedCrossRefGoogle Scholar
  65. 65.
    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: 2418–23PubMedCrossRefGoogle Scholar
  66. 66.
    Filmus J, Capurro M. Glypican-3 as a serum marker for hepatocellular carcinoma [letter]. Cancer Res 2005 Jan 1; 65(1): 372PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Division of Molecular and Cell BiologySunnybrook & Women’s College Health Sciences CentreTorontoCanada

Personalised recommendations