Archives of Gynecology and Obstetrics

, Volume 284, Issue 5, pp 1231–1239 | Cite as

Investigation of galectin-3 and heparanase in endometrioid and serous carcinomas of the endometrium and correlation with known predictors of survival

  • Çiğdem Berna Ege
  • Metin Akbulut
  • Osman Zekioğlu
  • Necmettin Özdemir
Gynecologic Oncology



Inhibitors of tumor angiogenesis and metastasis are emerging as important new drug candidates for cancer therapy. Galectin-3 and heparanase have been shown to function in tumor progression and metastatic spread. Both of them exert pleiotropic effects; proliferation, cell migration, differentiation and tissue remodeling. The aim of this study was to investigate heparanase and galectin-3 expression in endometrioid and serous carcinomas of the endometrium and their relation with well-known prognostic factors, in addition to estrogen, progesterone, C-erbB-2, Ki-67 and p53.

Materials and methods

Sixty-four endometrial cancers, which include 24 serous types, were obtained from previously untreated patients. Immunohistochemical analysis of 64 carcinomas, 20 endometrial hyperplasia (ten of simple hyperplasia and ten of complex atypic hyperplasia) and 20 normal endometrium (ten of proliferative and ten of secretory) was performed.


This investigation suggests that the decreased expression of galectin-3 may be involved in the pathogenesis of endometrial carcinomas from normal endometrium to carcinoma. Also down-regulated stromal expression of galectin-3 in endometrial carcinoma may be involved in lymph node metastasis. Further studies on a larger advanced stage (FIGO stage 3–4) endometrial carcinoma group may determine the value of heparanase in the endometrial carcinoma.


Galectin-3 Heparanase Serous endometrial carcinoma Endometrial hyperplasia 



This work is supported by grant of ‘BAP’ comission of Pamukkale University, No 2008TPF009. Some of the findings about galectin-3 were presented orally in the 22nd European Pathology Congress and also this presentation was supported in part by grant of ‘BAP’ comission of Pamukkale University, No 2009KKP073 and 2007KRM001. We thank Dr. Mehmet Zencir and Dr. Özgür Önal for their contributions in statistical analysis and Mr. Emin Ateş for technical assistance.

Conflict of interest



  1. 1.
    Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A et al (2005) Cancer statistics 2005. CA Cancer J Clin 55:10–30PubMedCrossRefGoogle Scholar
  2. 2.
    Sorosky JI (2008) Endometrial cancer. Obstet Gynecol 111:436–447PubMedCrossRefGoogle Scholar
  3. 3.
    Ronnett BM, Zaino RJ, Ellenson LH, Kurman JR (2002) Endometrial carcinoma. In: Kurman RJ (ed) Blaustein’s pathology of female genital tract, 5th edn. Springer Verlag, Berlin, pp 501–559Google Scholar
  4. 4.
    International Federation of Gynecology and Obstetrics: Annual report on the results of treatment in gynecologic cancer: FIGO. Stockholm, Sweden, International Federation of Gynecology and Obstetrics, 1985Google Scholar
  5. 5.
    Gong HC, Honjo Y, Nangia-Makker P, Hogan V, Mazurak N, Bresalier RS, Raz A (1999) The NH2 terminus of galectin-3 governs cellular compartmentalization and functions in cancer cells. Cancer Res 59:6239–6245PubMedGoogle Scholar
  6. 6.
    Califice S, Castronovo V, van den Brule F (2004) Galectin-3 and cancer. Int J Oncol 25:983–992PubMedGoogle Scholar
  7. 7.
    Krzeslak A, Lipinska A (2004) Galectin-3 as a multifunctional protein. Cell Mol Biol Lett 9:305–328PubMedGoogle Scholar
  8. 8.
    Dangue A, Camby I, Kiss R (2002) Galectins and cancer. Biochim Biophys Acta 1572:285–293Google Scholar
  9. 9.
    Von Wolff M, Wang X, Gabius HJ, Strowitzki T (2005) Galectin-3 fingerprinting in human endometrium and decidua during the menstrual cycle and in early gestation. Mol Hum Reprod 11:189–194CrossRefGoogle Scholar
  10. 10.
    Lehr JE, Pienta KJ (1998) Preferential adhesion of prostate cancer cells to a human bone marrow endothelial cell line. J Natl Cancer Inst 90:118–123PubMedCrossRefGoogle Scholar
  11. 11.
    Robert L, Jacob MP, Fülöp T, Timar J, Hornebeck W (1989) Elastonectin and the elastin receptor. Pathol Biol 37:736–741PubMedGoogle Scholar
  12. 12.
    Inufusa H, Nakamura M, Adachi T, Aga M, Kurimoto M, Nakatani Y et al (2001) Role of galectin-3 in adenocarcinoma liver metastasis. Int J Oncol 19:913–919PubMedGoogle Scholar
  13. 13.
    Poirier F (2002) Roles of galectins in vivo. Biochem Soc Symp 69:95–103PubMedGoogle Scholar
  14. 14.
    Cotter F (2008) Interim phase 2 results on prospect therapeutics’ GCS-100 presented at the 10th international conference on malignant lymphoma. Accessed 13 April 2009
  15. 15.
    Grous JJ, Redfern CH, Mahadevan D, Schindler J (2006) GCS-100, a galectin-3 antagonist, in refractory solid tumors: a phase I study. ASCO Annual Meeting Proceedings Accessed 22 March 2009
  16. 16.
    Nakajima M, Irimura T, Nicolson GL (1998) Heparanases and tumor metastasis. J Cell Biochem 36:1–11Google Scholar
  17. 17.
    Vlodavsky I, Eldor A, Haimovitz-Friedman A, Matzner Y, Ihai-Michaeli R, Lider O et al (1992) Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. Invasion Metastasis 12:112–127PubMedGoogle Scholar
  18. 18.
    Kodama J, Shinyo Y, Hasengaowa, Kusumoto T, Seki N, Nakamura K, Hongo A, Hiramatsu Y (2005) Loss of basement membrane heparan sulfate expression is associated with pelvic lymph node metastasis in invasive cervical cancer. Oncol Rep 14(1):89–92Google Scholar
  19. 19.
    Liu CJ, Lee PH, Lin DY, Wu CC, Jeng LB, Lin PW et al (2009) Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety, optimal dosage. J Hepatol 50(5):958–968PubMedCrossRefGoogle Scholar
  20. 20.
    Parish CR, Freeman C, Brown KJ, Francis DJ, Cowden WB (1999) Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Res 59:344–3433Google Scholar
  21. 21.
    Vlodavsky I, Mohsen M, Lider O, Svahn CM, Ekre HP, Vigoda M et al (1994–1995) Inhibition of tumor metastasis by heparanase inhibiting species of heparin. Invasion Metastasis 14:290–302Google Scholar
  22. 22.
    Ferro V, Dredge K, Liu L, Hammond E, Bytheway I, Li C et al (2007) PI-88 and novel heparan sulfate mimetics inhibit angiogenesis. Semin Thromb Hemost 33:557–568PubMedCrossRefGoogle Scholar
  23. 23.
    Merseburger AS, Kramer MW, Hennenlotter J, Simon P, Knapp J, Hartmann JT et al (2008) Involvement of decreased galectin-3 expression in the pathogenesis and progression of prostate cancer. Prostate 68:72–77PubMedCrossRefGoogle Scholar
  24. 24.
    Van den Brule FA, Waltregny D, Liu FT, Castronovo V (2000) Alteration of the cytoplasmic/nuclear expression pattern of galectin-3 correlates with prostate carcinoma progression. Int J Cancer 89:361–367PubMedCrossRefGoogle Scholar
  25. 25.
    Shimonishi T, Miyazaki K, Kono N, Sabit H, Tuneyama K, Harada K et al (2001) Expression of endogenous gal-1 and gal-3 in intrahepatic cholangiocarcinoma. Hum Pathol 32:302–310PubMedCrossRefGoogle Scholar
  26. 26.
    Sanjuan X, Fernandez PL, Castells A, Catronovo V, Van Den Brule F (1997) Differential expression of galectin 3 and galectin 1 in colorectal cancer progression. Gastroenterology 113:1906–1915PubMedCrossRefGoogle Scholar
  27. 27.
    Pacis RA, Pilat MJ, Pienta KJ, Wojno K, Raz A, Hogan V, Cooper CR (2000) Decreased galectin-3 expression in prostate cancer. Prostate 44:118–123PubMedCrossRefGoogle Scholar
  28. 28.
    Idikio H (1998) Galectin-3 expression in human breast carcinoma: correlation with cancer histological grade. Int J Oncol 12:1287–1290PubMedGoogle Scholar
  29. 29.
    Van den Brule FA, Califice S, Castronovo V (2004) Expression of galectins in cancer: a critical review. Glycoconj J 19:537–542PubMedCrossRefGoogle Scholar
  30. 30.
    Brustmann H, Riss D, Naude S (2003) Galectin-3 expression in normal, hyperplastic, and neoplastic endometrial tissues. Pathol Res Pract 199:151–158PubMedCrossRefGoogle Scholar
  31. 31.
    van den Brule FA, Buicu C, Berchuck A, Bast RC, Deprez M, Liu FT et al (1996) Expression of the 67-kD laminin receptor, galectin-1, and galectin-3 in advanced human uterine adenocarcinoma. Human Pathol 27:1185–1191CrossRefGoogle Scholar
  32. 32.
    Lloyd RV (2001) Distinguishing benign from malignant thyroid lesions: galectin-3 as the latest candidate. Endocr Pathol 12:255–257PubMedCrossRefGoogle Scholar
  33. 33.
    Weinberger PM, Adam BL, Gourin CG, Moretz WH, Bollag RJ, Wang BY et al (2007) Association of nuclear, cytoplasmic expression of galectin-3 with beta-catenin/Wnt-pathway activation in thyroid carcinoma. Arch Otolaryngol Head Neck Surg 133:503–510PubMedCrossRefGoogle Scholar
  34. 34.
    Carcangiu ML, Steeper T, Zampi G, Rosai J (1985) Anaplastic thyroid carcinoma. A study of 70 cases. Am J Clin Pathol 83:135–158PubMedGoogle Scholar
  35. 35.
    Langbein S, Brade J, Badawi JK, Hatzinger M, Kaltner H (2007) Gene-expression signature of adhesion/growth-regulatory tissue lectins (galectins) in transitional cell cancer and its prognostic relevance. Histopathology 51:681–690PubMedCrossRefGoogle Scholar
  36. 36.
    Yoshimura A, Gemma A, Hosoya Y, Komaki E, Hosomi Y (2003) Increased expression of the LGALS3 (galectin3) gene in human non-small-cell lung cancer. Genes Chromosomes Cancer 37:159–164PubMedCrossRefGoogle Scholar
  37. 37.
    Lapis K, Timar J (2002) Role of elastin-matrix interactions in tumor progression. Semin Cancer Biol 12:209–217PubMedCrossRefGoogle Scholar
  38. 38.
    Piantelli M, Iacobelli S, Almadori G, Iezzi M, Tinari N, Natoli C et al (2002) Lack of expression of galectin-3 is associated with a poor outcome in node-negative patients with laryngeal squamous-cell carcinoma. J Clin Oncol 20:3850–3856PubMedCrossRefGoogle Scholar
  39. 39.
    Plzak J, Betka J, Smetana KJ, Chovanec M, Kaltner H (2004) Galectin-3-an emerging prognostic indicator in advanced head and neck carcinoma. Eur J Cancer 40:2324–2330PubMedCrossRefGoogle Scholar
  40. 40.
    Gaudin JC, Arar C, Monsigny M, Legrand A (1997) Modulation of the expression of the rabbit galectin-3 gene by p53 and c-Ha-ras proteins and PMA. Glycobiology 7:1089–1098PubMedCrossRefGoogle Scholar
  41. 41.
    Ceehinelli B, Lavra L, Rinaldo C, Iacovelli S, Gurtner A, Gasbarri A et al (2006) Repression of the antiapoptotic molecule galectin-3 by homeodomain-interacting protein kinase 2-activated p53 is required for p53-induced apoptosis. Mol Cell Biol 26:4746–4757CrossRefGoogle Scholar
  42. 42.
    Takenaka Y, Fukumori T, Yoshii T, Oka N, Inohara H, Kim HR, Bresalier RS, Raz A (2004) Nuclear export of phosphorylated galectin-3 regulates its antiapoptotic activity in response to chemotherapeutic drugs. Mol Cell Biol 24:4395–4406PubMedCrossRefGoogle Scholar
  43. 43.
    Kim HR, Lin HM, Bilirian H, Raz A (1999) Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast cells. Cancer Res 59:4148–4154PubMedGoogle Scholar
  44. 44.
    Yang RY, Hsu DK, Liu FT (1996) Expression of galectin-3 modulates T-cell growth and apoptosis. Proc Natl Acad Sci 93:6737–6742PubMedCrossRefGoogle Scholar
  45. 45.
    Moon BK, Lee YJ, Battle P, Jessup JM, Raz A, Kim HRC (2001) Galectin-3 protects human breast carcinoma cells against nitric oxide-induced apoptosis: implication of galectin-3 function during metastasis. Am J Pathol 159:1055–1060PubMedCrossRefGoogle Scholar
  46. 46.
    Zubieta MR, Furman D, Barrio M, Bravo AI, Domenichini E, Mordoh J (2006) Galectin-3 expression correlates with apoptosis of tumor-associated lymphocytes in human melanoma biopsies. Am J Pathol 168:1666–1675PubMedCrossRefGoogle Scholar
  47. 47.
    van den Brule FA, Engel J, Stetler-Stevenson WG et al (1992) Genes involved in tumor invasion and metastasis are differentially modulated by estradiol and progestin in human breast-cancer cells. Int J Cancer 52:653–657PubMedCrossRefGoogle Scholar
  48. 48.
    Le Marer N (2000) Galectin-3 expression in differentiating human myeloid cells. Cell Bio Int 24:245–251CrossRefGoogle Scholar
  49. 49.
    Mackay A, Jones C, Dexter T, Silva RL, Bulmer K, Jones A et al (2003) cDNA microarray analysis of genes associated with ERBB2 (HER2/neu) overexpression in human mammary luminal epithelial cells. Oncogene 22:2680–2688PubMedCrossRefGoogle Scholar
  50. 50.
    Petrov SV, Raskin GA, Khasanov RS (2006) A new hypothesis on the role of c-erbB2 oncogene in the progress of breast cancer. Bull Exp Biol Med 142:94–97PubMedCrossRefGoogle Scholar
  51. 51.
    Yoshii T, Inohara T, Takenaka Y, Honjo Y, Akahani S, Nomura T, Raz A, Kubo T (2001) Galectin-3 maintains the transformed phenotype of thyroid papillary carcinoma cells. Int J Oncol 18:787–792PubMedGoogle Scholar
  52. 52.
    Friedmann Y, Vlodavsky I, Aingorn H, Aviv A, Peretz T, Pecker I et al (2000) Expression of heparanase in normal, dysplastic, and neoplastic human colonic mucosa and stroma: evidence for its role in colonic tumourigenesis. Am J Pathol 157:1167–1175PubMedCrossRefGoogle Scholar
  53. 53.
    Ikuta M, Podyma KA, Maruyama K, Enomoto S, Yanagishita M (2001) Expression of heparanase in oral cancer cell lines and oral cancer tissues. Oral Oncol 37:177–184PubMedCrossRefGoogle Scholar
  54. 54.
    Ueno Y, Yamamoto M, Vlodavsky I, Pecker I, Ohshima K, Fukushima T (2005) Decreased expression of heparanase in glioblastoma multiforme. J Neurosurg 102:513–521PubMedCrossRefGoogle Scholar
  55. 55.
    Ikeguchi M, Hirooka Y, Kaibara N (2003) Heparanase gene expression and its correlation with spontaneous apoptosis in hepatocytes of cirrhotic liver carcinoma. Eur J Cancer 39:86–90PubMedCrossRefGoogle Scholar
  56. 56.
    Stadlmann S, Moser PL, Pollheimer J, Steiner P, Krugman J, Dirnhofer S, Mikuz G, Margreiter R, Amberger A (2003) Heparanase-1 gene expression in normal, hyperplastic and neoplastic prostatic tissue. Eur J Cancer 39:2229–2233PubMedCrossRefGoogle Scholar
  57. 57.
    Watanabe M, Aoki Y, Kase H, Tanaka K (2003) Heparanase expression and angiogenesis in endometrial cancer. Gynecol Obstet Invest 56:77–82PubMedCrossRefGoogle Scholar
  58. 58.
    Inamine M, Nagai Y, Hirakawa M, Mekaru K, Yagi C, Masamoto H et al (2008) Heparanase expression in endometrial cancer: analysis of immunohistochemistry. J Obstet Gynaecol 28:634–637PubMedCrossRefGoogle Scholar
  59. 59.
    Hasengaowa, Kodama J, Kusumoto T, Seki N, Matsuo T, Ojima Y et al (2006) Heparanase expression in both normal endometrium and endometrial cancer. Int J Gynecol Cancer 16(3):1401–1406Google Scholar
  60. 60.
    Canaani J, Ilan N, Back S, Gutman G, Vlodavsky I, Grisaru D (2008) Heparanase expression increases throughout the endometrial hyperplasia-cancer sequence. Int J Gynaecol Obstet 101:166–171PubMedCrossRefGoogle Scholar
  61. 61.
    Xu X, Rao G, Quiros RM, Kim AW, Miao HQ, Brunn GJ, Platt JL, Gattuso P, Prinz RA (2007) In vivo and in vitro degradation of heparan sulfate (HS) proteoglycans by HPR1 in pancreatic adenocarcinomas. Loss of cell surface HS suppresses fibroblast growth factor 2-mediated cell signaling and proliferation. J Biol Chem 282:2363–2373PubMedCrossRefGoogle Scholar
  62. 62.
    El-Assal ON, Yamanoi A, Ono T, Kohno H, Nagasue N (2001) The clinicopathological significance of heparanase and basic fibroblast growth factor expressions in hepatocellular carcinoma. Clin Cancer Res 7:1299–1305PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Çiğdem Berna Ege
    • 1
  • Metin Akbulut
    • 2
  • Osman Zekioğlu
    • 3
  • Necmettin Özdemir
    • 3
  1. 1.Patoloji LaboratuarıSiverek Devlet HastanesiSiverek/SanliurfaTurkey
  2. 2.Pamukkale Üniversitesi HastanesiDenizliTurkey
  3. 3.Patoloji Ana Bilim DalıEge Üniversitesi HastanesiBornova/IzmirTurkey

Personalised recommendations