Skip to main content
SpringerLink
Log in

Glypican 3 overexpression in primary and metastatic Wilms tumors

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Glypican 3 (GPC3), a heparan sulfate proteoglycan, plays a role in cell growth and differentiation. Mutations of the GPC3 gene are responsible for Simpson-Golabi-Behmel syndrome, which is characterized by anomalies of postnatal overgrowth and an increased risk of developing pediatric malignancies, mostly Wilms tumor and liver cancer. In order to understand the possible role of GPC3 in renal development and Wilms tumor formation, we analyzed messenger RNA (mRNA) and protein levels of GPC3 in sporadic Wilms tumors and compared it to normal kidneys and other common renal epithelial tumors. By using Affymetrix HGU133 oligonucleotide gene expression microarray data from 191 renal tumors and 12 normal kidneys, we found significant overexpression of GPC3 in Wilms tumors (p < 0.01), with 3.5-fold higher expression in comparison to normal kidneys and 6.5-fold higher than any type of renal tumors. The GPC3 gene product in Wilms tumor was further evaluated by immunohistochemistry and quantified by an automated image analysis. Cytoplasmic and membranous GPC3 immunoreactivity was present in 77 % of primary Wilms tumors (23/30), 93 % of metastatic Wilms tumors (13/14), 50 % of metanephric adenomas (4/8), 33 % of congenital mesoblastic nephromas (2/6), 100 % of nephrogenic rests (11/11), and 100 % of fetal kidneys (5/5). GPC3 staining was predominantly identified in blastemal and epithelial components of Wilms tumors, similar to that of fetal non-neoplastic kidney. All adult renal tumors (n = 60) and normal kidneys (n = 15) were GPC3 negative. These findings suggest the utility of GPC3 in differential diagnosis and follow-up of Wilms tumors. Our data also indicate that GPC3 is an oncofetal protein with a potential therapeutic value.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hartwig S, Hu MC, Cella C, Piscione T, Filmus J, Rosenblum ND (2005) Glypican-3 modulates inhibitory BMP2-Smad signaling to control renal development in vivo. Mech Dev 122(7–8):928–938

    Article  CAS  PubMed  Google Scholar 

  2. White GR, Kelsey AM, Varley JM, Birch JM (2002) Somatic glypican 3 (GPC3) mutations in Wilms’ tumour. Br J Cancer 86(12):1920–1922

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Hughes-Benzie RM, Hunter AG, Allanson JE, Mackenzie AE (1992) Simpson-Golabi-Behmel syndrome associated with renal dysplasia and embryonal tumor: localization of the gene to Xqcen-q21. Am J Med Genet 43(1–2):428–435

    Article  CAS  PubMed  Google Scholar 

  4. Iglesias BV, Centeno G, Pascuccelli H, Ward F, Peters MG, Filmus J et al (2008) Expression pattern of glypican-3 (GPC3) during human embryonic and fetal development. Histol Histopathol 23(11):1333–1340

    CAS  PubMed  Google Scholar 

  5. Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R et al (1996) Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet 12(3):241–247

    Article  CAS  PubMed  Google Scholar 

  6. Saikali Z, Sinnett D (2000) Expression of glypican 3 (GPC3) in embryonal tumors. Int J Cancer 89(5):418–422

    Article  CAS  PubMed  Google Scholar 

  7. Toretsky JA, Zitomersky NL, Eskenazi AE, Voigt RW, Strauch ED, Sun CC et al (2001) Glypican-3 expression in Wilms tumor and hepatoblastoma. J Pediatr Hematol Oncol 23(8):496–499

    Article  CAS  PubMed  Google Scholar 

  8. Gillan TL, Hughes R, Godbout R, Grundy PE (2003) The Simpson-Golabi-Behmel gene, GPC3, is not involved in sporadic Wilms tumorigenesis. Am J Med Genet A 122A(1):30–36

    Article  PubMed  Google Scholar 

  9. Takahashi M, Yang XJ, Sugimura J, Backdahl J, Tretiakova M, Qian CN et al (2003) Molecular subclassification of kidney tumors and the discovery of new diagnostic markers. Oncogene 22(43):6810–6818

    Article  CAS  PubMed  Google Scholar 

  10. Baumhoer D, Tornillo L, Stadlmann S, Roncalli M, Diamantis EK, Terracciano LM (2008) Glypican 3 expression in human nonneoplastic, preneoplastic, and neoplastic tissues: a tissue microarray analysis of 4,387 tissue samples. Am J Clin Pathol 129(6):899–906

    Article  PubMed  Google Scholar 

  11. Neri G, Marini R, Cappa M, Borrelli P, Opitz JM (1988) Simpson-Golabi-Behmel syndrome: an X-linked encephalo-tropho-schisis syndrome. Am J Med Genet 30(1–2):287–299

    Article  CAS  PubMed  Google Scholar 

  12. Opitz JM, Herrmann J, Gilbert EF, Matalon R (1988) Simpson-Golabi-Behmel syndrome: follow-up of the Michigan family. Am J Med Genet 30(1–2):301–308

    Article  CAS  PubMed  Google Scholar 

  13. Veugelers M, Cat BD, Muyldermans SY, Reekmans G, Delande N, Frints S et al (2000) Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene. Hum Mol Genet 9(9):1321–1328

    Article  CAS  PubMed  Google Scholar 

  14. Li M, Shuman C, Fei YL, Cutiongco E, Bender HA, Stevens C et al (2001) GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson-Golabi-Behmel syndrome. Am J Med Genet 102(2):161–168

    Article  CAS  PubMed  Google Scholar 

  15. Filmus J (2001) Glypicans in growth control and cancer. Glycobiology 11(3):19R–23R

    Article  CAS  PubMed  Google Scholar 

  16. De Cat B, David G (2001) Developmental roles of the glypicans. Semin Cell Dev Biol 12(2):117–125

    Article  PubMed  Google Scholar 

  17. Khan S, Blackburn M, Mao DL, Huber R, Schlessinger D, Fant M (2001) Glypican-3 (GPC3) expression in human placenta: localization to the differentiated syncytiotrophoblast. Histol Histopathol 16(1):71–78

    CAS  PubMed  Google Scholar 

  18. Pellegrini M, Pilia G, Pantano S, Lucchini F, Uda M, Fumi M et al (1998) GPC3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome. Dev Dyn 213(4):431–439

    Article  CAS  PubMed  Google Scholar 

  19. Midorikawa Y, Ishikawa S, Iwanari H, Imamura T, Sakamoto H, Miyazono K et al (2003) Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling. Int J Cancer 103(4):455–465

    Article  CAS  PubMed  Google Scholar 

  20. Mast AE, Higuchi DA, Huang ZF, Warshawsky I, Schwartz AL, Broze GJ Jr (1997) Glypican-3 is a binding protein on the HepG2 cell surface for tissue factor pathway inhibitor. Biochem J 327(Pt 2):577–583

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Taguchi A, Emoto M, Okuya S, Fukuda N, Nakamori Y, Miyazaki M et al (2008) Identification of glypican3 as a novel GLUT4-binding protein. Biochem Biophys Res Commun 369(4):1204–1208

    Article  CAS  PubMed  Google Scholar 

  22. Song HH, Shi W, Xiang YY, Filmus J (2005) The loss of glypican-3 induces alterations in Wnt signaling. J Biol Chem 280(3):2116–2125

    Article  CAS  PubMed  Google Scholar 

  23. Grisaru S, Rosenblum ND (2001) Glypicans and the biology of renal malformations. Pediatr Nephrol 16(3):302–306

    Article  CAS  PubMed  Google Scholar 

  24. Cano-Gauci DF, Song HH, Yang H, McKerlie C, Choo B, Shi W et al (1999) Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome. J Cell Biol 146(1):255–264

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Jain S, Suarez AA, McGuire J, Liapis H (2007) Expression profiles of congenital renal dysplasia reveal new insights into renal development and disease. Pediatr Nephrol 22(7):962–974

    Article  PubMed  Google Scholar 

  26. Lapunzina P, Badia I, Galoppo C, De Matteo E, Silberman P, Tello A et al (1998) A patient with Simpson-Golabi-Behmel syndrome and hepatocellular carcinoma. J Med Genet 35(2):153–156

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Nakatsura T, Kageshita T, Ito S, Wakamatsu K, Monji M, Ikuta Y et al (2004) Identification of glypican-3 as a novel tumor marker for melanoma. Clin Cancer Res 10(19):6612–6621

    Article  CAS  PubMed  Google Scholar 

  28. Charles AK, Brown KW, Berry PJ (1998) Microdissecting the genetic events in nephrogenic rests and Wilms’ tumor development. Am J Pathol 153(3):991–1000

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Guertl B, Ratschek M, Harms D, Jaenig U, Leuschner I, Poremba C et al (2003) Clonality and loss of heterozygosity of WT genes are early events in the pathogenesis of nephroblastomas. Hum Pathol 34(3):278–281

    Article  CAS  PubMed  Google Scholar 

  30. Park S, Bernard A, Bove KE, Sens DA, Hazen-Martin DJ, Garvin AJ et al (1993) Inactivation of WT1 in nephrogenic rests, genetic precursors to Wilms’ tumour. Nat Genet 5(4):363–367

    Article  CAS  PubMed  Google Scholar 

  31. Rivera MN, Haber DA (2005) Wilms’ tumour: connecting tumorigenesis and organ development in the kidney. Nat Rev Cancer 5(9):699–712

    Article  CAS  PubMed  Google Scholar 

  32. Rodriguez-Criado G, Magano L, Segovia M, Gurrieri F, Neri G, Gonzalez-Meneses A et al (2005) Clinical and molecular studies on two further families with Simpson-Golabi-Behmel syndrome. Am J Med Genet A 138A(3):272–277

    Article  PubMed  Google Scholar 

  33. Chan ES, Pawel BR, Corao DA, Venneti S, Russo P, Santi M et al (2013) Immunohistochemical expression of glypican-3 in pediatric tumors: an analysis of 414 cases. Pediatr Dev Pathol 16(4):272–277

    Article  PubMed  Google Scholar 

  34. Thway K, Selfe J, Missiaglia E, Fisher C, Shipley J (2011) Glypican-3 is expressed in rhabdomyosarcomas but not adult spindle cell and pleomorphic sarcomas. J Clin Pathol 64(7):587–591

    Article  PubMed  Google Scholar 

  35. Zynger DL, Gupta A, Luan C, Chou PM, Yang GY, Yang XJ (2008) Expression of glypican 3 in hepatoblastoma: an immunohistochemical study of 65 cases. Hum Pathol 39(2):224–230

    Article  CAS  PubMed  Google Scholar 

  36. Kohashi K, Nakatsura T, Kinoshita Y, Yamamoto H, Yamada Y, Tajiri T et al (2013) Glypican 3 expression in tumors with loss of SMARCB1/INI1 protein expression. Hum Pathol 44(4):526–533

    Article  CAS  PubMed  Google Scholar 

  37. Feng M, Gao W, Wang R, Chen W, Man YG, Figg WD et al (2013) Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma. Proc Natl Acad Sci U S A 110(12):E1083–E1091

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Ikeda M, Ohkawa S, Okusaka T, Mitsunaga S, Kobayashi S, Morizane C et al (2014) Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma. Cancer Sci 105(4):455–462

    Article  CAS  PubMed  Google Scholar 

  39. Sawada Y, Yoshikawa T, Fujii S, Mitsunaga S, Nobuoka D, Mizuno S et al (2013) Remarkable tumor lysis in a hepatocellular carcinoma patient immediately following glypican-3-derived peptide vaccination: an autopsy case. Hum Vaccin Immunother 9(6):1228–1233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Sawada Y, Yoshikawa T, Nobuoka D, Shirakawa H, Kuronuma T, Motomura Y et al (2012) Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival. Clin Cancer Res 18(13):3686–3696

    Article  CAS  PubMed  Google Scholar 

  41. Suzuki S, Shibata K, Kikkawa F, Nakatsura T (2014) Significant clinical response of progressive recurrent ovarian clear cell carcinoma to glypican-3-derived peptide vaccine therapy: two case reports. Hum Vaccin Immunother 10(2):338–343

    Article  CAS  PubMed  Google Scholar 

  42. Tada Y, Yoshikawa T, Shimomura M, Sawada Y, Sakai M, Shirakawa H et al (2013) Analysis of cytotoxic T lymphocytes from a patient with hepatocellular carcinoma who showed a clinical response to vaccination with a glypican3 derived peptide. Int J Oncol 43(4):1019–1026

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Zhu AX, Gold PJ, El-Khoueiry AB, Abrams TA, Morikawa H, Ohishi N et al (2013) First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma. Clin Cancer Res 19(4):920–928

    Article  CAS  PubMed  Google Scholar 

  44. Kesik V, Ozcan A, Sari E, Guven A, Kismet E, Koseoglu V (2010) Alpha-fetoprotein producing tumor cells in children with Wilms’ tumor. Fetal Pediatr Pathol 29(3):127–132

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Washington, 325 9th Ave, Seattle, WA, 98104, USA

    Maria Tretiakova

  2. Department of Pathology, University of Washington and Seattle Children’s Hospital, Seattle, WA, USA

    Maria Tretiakova, Nicole K. Andeen & Laura S. Finn

  3. Department of Pathology, The Ohio State University, Columbus, OH, USA

    Debra L. Zynger

  4. Department of Pathology, Feinberg 7-334, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, 251 East Huron Street, Chicago, IL, 60611, USA

    Chunyan Luan & Ximing J. Yang

  5. Department of Health Studies, University of Chicago, Chicago, IL, USA

    Masha Kocherginsky

  6. Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI, USA

    Bin T. Teh

Authors
  1. Maria Tretiakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Debra L. Zynger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chunyan Luan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicole K. Andeen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laura S. Finn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masha Kocherginsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bin T. Teh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ximing J. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Tretiakova.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tretiakova, M., Zynger, D.L., Luan, C. et al. Glypican 3 overexpression in primary and metastatic Wilms tumors. Virchows Arch 466, 67–76 (2015). https://doi.org/10.1007/s00428-014-1669-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-014-1669-4

Keywords

Search

Navigation