Top

Published in:

Open Access 01-12-2014 | Research

Wnt/β-catenin pathway as a potential prognostic and predictive marker in patients with advanced ovarian cancer

Authors: Lubomir Bodnar, Aleksandra Stanczak, Szczepan Cierniak, Marta Smoter, Marzena Cichowicz, Wojciech Kozlowski, Cezary Szczylik, Maciej Wieczorek, Monika Lamparska-Przybysz

Published in: Journal of Ovarian Research | Issue 1/2014

Abstract

Background

β-catenin is the key protein in the WNT signalling pathway and it forms adherent junctions together with E-cadherin. In ovarian carcinoma, abnormal expression of β-catenin, E-cadherin and WNT-1 was observed, but their prognostic and predictive role is unclear. The aim of this study was to clarify the prognostic and predictive role of E-cadherin, β-catenin and WNT-1 in advanced epithelial ovarian carcinoma (AEOC).

Methods

The expression of E-cadherin, β-catenin and WNT-1 was determined by immunohistochemistry in AEOC. The correlation between expression of these proteins and progression-free survival (PFS) and overall survival (OS) was evaluated. Statistical analyses included Kaplan-Meier estimation, log-rank test, Spearman correlation and Cox proportional-hazards model.

Results

In ovarian cancer, intense expression of E-cadherin, β-catenin and WNT-1 was found. In multivariate analysis, strong membrane β-catenin expression was an independent unfavourable predictor for PFS (HR 2.19, 95% CI 1.09-4.39; p = 0.028), while in univariate analysis, strong membrane β-catenin expression was a prognostic factor for OS in patients with AOC (p = 0.039). In multivariate analysis, only resistance to first-line chemotherapy was an adverse independent prognostic factor for OS (HR 16.84; 95% CI 5.07-55.98; p < 0.0001). Additionally, strong membranous β-catenin expression was associated with resistance to platinum-based chemotherapy (p = 0.027).

Conclusions

These findings support that WNT/β-catenin pathway and E-cadherin are important factors in advanced epithelial ovarian cancer.

Available only for authorised users

Lee KR, Tavassoli FA, Prat J, Dietel M, Gersell DJ, Karseladze AI, Hauptmann S, Rutgers J, Russell P, Buckley CH, Pisani P, Schwartz P, Goldgar DE, Silva E, Caduf R, Kubik-Huch RA: Surface epithelial-stromal tumours. In World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Edited by: Tavassoli FA, Devilee P. Lyon: IARCPress; 2003:113–202.

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. http://globocan.iarc.fr

Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin 2012, 62: 10–29. 10.3322/caac.20138CrossRefPubMed

Classe JM, Fontanelli R, Bischof-Delaloye A, Chatal JF: Ovarian cancer management. Practice guidelines for nuclear physicians. Q J Nucl Med Mol Imaging 2004, 48: 143–149.PubMed

Aebi S, Castiglione M, ESMO Guidelines Working Group: Newly and relapsed epithelial ovarian carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009,20(Suppl 4):21–23.PubMed

Jacobs I, Bast RC Jr: The CA125 tumour associated antigen: a review of the literature. Hum Reprod 1989, 4: 1–12. 10.1093/humrep/4.suppl_1.1CrossRefPubMed

Hawkins RE, Roberts K, Wiltshaw E, Mundy J, Fryatt IJ, McCready VR: The prognostic significance of the half-life of serum CA 125 in patients responding to chemotherapy for epithelial ovarian carcinoma. Br J Obstet Gynaecol 1989, 6: 1395–1399.CrossRef

Gadducci A, Zola P, Landoni F, Maggino T, Sartori E, Bergamino T, Cristofani R: Serum half-life of CA125 during early chemotherapy as an independent prognostic variable for patients with advanced epithelial ovarian cancer: results of a multicentric Italian study. Gynecol Oncol 1995, 58: 42–47. 10.1006/gyno.1995.1181CrossRefPubMed

Vasudev NS, Trigonis I, Cairns DA, Hall GD, Jackson DP, Broadhead T, Buxton J, Hutson R, Nugent D, Perren TJ: The prognostic and predictive value of CA-125 regression during neoadjuvant chemotherapy for advanced ovarian or primary peritoneal carcinoma. Arch Gynecol Obstet 2011, 284: 221–227. 10.1007/s00404-010-1655-2PubMedCentralCrossRefPubMed

10.

Gadducci A, Cosio S, Fanucchi A, Negri S, Cristofani R, Genazzani AR: The predictive and prognostic value of serum CA 125 halflife during paclitaxel/platinum-based chemotherapy in patients with advanced ovarian carcinoma. Gynecol Oncol 2004, 93: 131–136. 10.1016/j.ygyno.2003.12.043CrossRefPubMed

11.

Riedinger JM, Eche N, Basuyau JP, Dalifard I, Hacene K, Pichon MF: Prognostic value of serum CA 125 bi-exponential decrease during first line paclitaxel/platinum chemotherapy: a French multicentric study. Gynecol Oncol 2008, 109: 194–198. 10.1016/j.ygyno.2008.01.035CrossRefPubMed

12.

Moon RT, Kohn AD, De Ferrari GV, Kaykas A: WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 2004, 5: 691–701. 10.1038/nrg1427CrossRefPubMed

13.

Gadducci A, Cosio S, Tana R, Genazzani AR: Serum and tissue biomarkers as predictive and prognostic variables in epithelial ovarian cancer. Crit Rev Oncol Hematol 2009, 69: 12–27. 10.1016/j.critrevonc.2008.05.001CrossRefPubMed

14.

Gatcliffe TA, Monk BJ, Planutis K, Holcombe RF: Wnt signaling in ovarian tumorigenesis. Int J Gynecol Cancer 2008, 18: 954–962. 10.1111/j.1525-1438.2007.01127.xPubMedCentralCrossRefPubMed

15.

Aberle H, Schwartz H, Kemler R: Cadherin-catenin complex: protein interactions and their implications for cadherin function. J Cell Biochem 1996, 61: 514–523. 10.1002/(SICI)1097-4644(19960616)61:4<514::AID-JCB4>3.0.CO;2-RCrossRefPubMed

16.

Wnt Homepage. Stanford: The Nusse Laboratory, Stanford School of Medicine; [http://www.stanford.edu/group/nusselab/cgi-bin/wnt/target_genes]

17.

Polakis P: The many ways of Wnt in cancer. Curr Opin Genet Dev 2007, 17: 45–51. 10.1016/j.gde.2006.12.007CrossRefPubMed

18.

Berx G, van Roy F: Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb Perspect Biol 2009, 1: a003129.PubMedCentralCrossRefPubMed

19.

Palacios J, Gamallo C: Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Res 1998, 58: 1344–1347.PubMed

20.

Gamallo C, Palacios J, Moreno G, Calvo de Mora J, Suarez A, Armas A: beta-catenin expression pattern in stage I and II ovarian carcinomas: Relationship with beta catenin gene mutations, clinicopathological features, and clinical outcome. Am J Pathol 1999, 155: 527–536. 10.1016/S0002-9440(10)65148-6PubMedCentralCrossRefPubMed

21.

Wright K, Wilson P, Morland S, Campbell I, Walsh M, Hurst T, Ward B, Cummings M, Chenevix-Trench G: beta-catenin mutation and expression analysis in ovarian cancer: Exon 3 mutations and nuclear translocation in 16% of endometrioid tumours. Int J Cancer 1999, 82: 625–629. 10.1002/(SICI)1097-0215(19990827)82:5<625::AID-IJC1>3.0.CO;2-2CrossRefPubMed

22.

Davies BR, Worsley SD, Ponder BA: Expression of E-cadherin, alpha-catenin and beta-catenin in normal ovarian surface epithelium and epithelial ovarian cancers. Histopathology 1998, 32: 69–80. 10.1046/j.1365-2559.1998.00341.xCrossRefPubMed

23.

Imai T, Horiuchi A, Shiozawa T, Osada R, Kikuchi N, Ohira S, Oka K, Konishi I: Elevated expression of E-cadherin and alpha-, beta-, and gamma-catenins in metastatic lesions compared with primary epithelial ovarian carcinomas. Hum Pathol 2004, 35: 1469–1476. 10.1016/j.humpath.2004.09.014CrossRefPubMed

24.

Sarrió D, Moreno-Bueno G, Sánchez-Estévez C, Bañón-Rodríguez I, Hernández-Cortés G, Hardisson D, Palacios J: Expression of cadherins and catenins correlates with distinct histologic types of ovarian carcinomas. Hum Pathol 2006, 37: 1042–1049. 10.1016/j.humpath.2006.03.003CrossRefPubMed

25.

Voutilainen KA, Anttila MA, Sillanpää SM, Ropponen KM, Saarikoski SV, Juhola MT, Kosma VM: Prognostic significance of E-cadherin-catenin complex in epithelial ovarian cancer. J Clin Pathol 2006, 59: 460–467. 10.1136/jcp.2005.029876PubMedCentralCrossRefPubMed

26.

Badiglian Filho L, Oshima CT, De Oliveira LF, De Oliveira CH, De Sousa DR, Gomes TS, Gonçalves WJ: Canonical and noncanonical Wnt pathway: a comparison among normal ovary, benign ovarian tumor and ovarian cancer. Oncol Rep 2009, 21: 313–320.PubMed

27.

Rosen DG, Zhang Z, Chang B, Wang X, Lin E, Liu J: Low membranous expression of beta-catenin and high mitotic count predict poor prognosis in endometrioid carcinoma of the ovary. Mod Pathol 2010, 23: 113–122. 10.1038/modpathol.2009.141CrossRefPubMed

28.

Faleiro-Rodrigues C, Macedo-Pinto I, Pereira D, Lopes CS: Prognostic value of E-cadherin immunoexpression in patients with primary ovarian carcinomas. Ann Oncol 2004, 15: 1535–1542. 10.1093/annonc/mdh387CrossRefPubMed

29.

Peralta-Soler A, Knudsen KA, Tecson-Miguel A, McBrearty FX, Han AC, Salazar H: Expression of E-cadherin and Ncadherin in surface epithelial stromal tumors of the ovary distinguishes mucinous from serous and endometrioid tumors. Human Path 1997, 28: 734–739. 10.1016/S0046-8177(97)90184-2CrossRef

30.

Sundfeldt K, Piontkewitz Y, Ivarsson K, Nilsson O, Hellberg P, Brännström M, Janson PO, Enerback S, Hedin L: E-cadherin expression in human epithelial ovarian cancer and normal ovary. Int J Cancer 1997, 74: 275–280. 10.1002/(SICI)1097-0215(19970620)74:3<275::AID-IJC7>3.0.CO;2-WCrossRefPubMed

31.

Wong AS, Maines-Bandiera SL, Rosen B, Wheelock MJ, Johnson KR, Leung PC, Roskelley CD, Auersperg N: Constitutive and conditional cadherin expression in cultured human ovarian surface epithelium: influence of family history of ovarian cancer. Int J Can 1999, 81: 180–188. 10.1002/(SICI)1097-0215(19990412)81:2<180::AID-IJC3>3.0.CO;2-7CrossRef

32.

Sundfeldt K: Cell-cell adhesion in the normal ovary and ovarian tumors of epithelial origin; an exception to the rule. Mol Cell Endocrinol 2003, 202: 89–96. 10.1016/S0303-7207(03)00068-6CrossRefPubMed

33.

Davidson B, Gotlieb WH, Ben-Baruch G, Nesland JM, Bryne M, Goldberg I, Kopolovic J, Berner A: E-Cadherin complex protein expression and survival in ovarian carcinoma. Gynecol Oncol 2000, 79: 362–371. 10.1006/gyno.2000.5964CrossRefPubMed

34.

Flam F, Einhorn N, Sjövall K: Symptomatology of ovarian cancer. Eur J Obstet Gynecol Reprod Biol 1988, 27: 53–57. 10.1016/S0028-2243(88)80010-8CrossRefPubMed

35.

Davidson B, Berner A, Nesland JM, Risberg B, Berner HS, Tropè CG, Kristensen GB, Bryne M, Ann Florenes V: E-cadherin and alpha-, beta-, and gamma-catenin protein expression is up-regulated in ovarian carcinoma cells in serous effusions. J Pathol 2000, 192: 460–469. 10.1002/1096-9896(2000)9999:9999<::AID-PATH726>3.0.CO;2-MCrossRefPubMed

36.

Naora H, Montell DJ: Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer 2005, 5: 355–366. 10.1038/nrc1611CrossRefPubMed

37.

Pece S, Chiariello M, Murga C, Gutkind JS: Activation of the protein kinase Akt/PKB by the formation of E-cadherin-mediated cell-cell junctions. Evidence for the association of phosphatidylinositol 3-kinase with the E-cadherin adhesion complex. J Biol Chem 1999, 274: 19347–19351. 10.1074/jbc.274.27.19347CrossRefPubMed

38.

Reddy P, Liu L, Ren C, Lindgren P, Boman K, Shen Y, Lundin E, Ottander U, Rytinki M, Liu K: Formation of E-cadherin-mediated cell-cell adhesion activates AKT and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells. Mol Endocrinol 2005, 19: 2564–2578. 10.1210/me.2004-0342CrossRefPubMed

39.

De Santis G, Miotti S, Mazzi M, Canevari S, Tomassetti A: E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells. Oncogene 2009, 28: 1206–1217. 10.1038/onc.2008.470CrossRefPubMed

40.

Wang J, Zhou D, He X, Wang Y, Hu W, Jiang L, Dou J: Effect of downregulated β-catenin on cell proliferative activity, the sensitivity to chemotherapy drug and tumorigenicity of ovarian cancer cells. Cell Mol Biol (Noisy-le-grand) 2011,57(Suppl):OL1606-OL1613.

41.

Stein U, Arlt F, Walther W, Smith J, Waldman T, Harris ED, Mertins SD, Heizmann CW, Allard D, Birchmeier W, Schlag PM, Shoemaker RH: The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor signaling in colon cancer. Gastroenterology 2006, 131: 1486–1500. 10.1053/j.gastro.2006.08.041CrossRefPubMed

42.

Pu P, Zhang Z, Kang C, Jiang R, Jia Z, Wang G, et al.: Downregulation of Wnt2 and beta-catenin by siRNA suppresses malignant glioma cell growth. Cancer Gene Ther 2009, 16: 351–361. 10.1038/cgt.2008.78CrossRefPubMed

43.

Teng Y, Wang X, Wang Y, Ma D: Wnt/beta-catenin signaling regulates cancer stem cells in lung cancer A549 cells. Biochem Biophys Res Commun 2010, 392: 373–379. 10.1016/j.bbrc.2010.01.028CrossRefPubMed

44.

Xiao L, Zhuo-ying H: Expression of Wnt-1, beta-catenin and c-myc in ovarian epithelial tumor and its implication. Chin J Cancer Res 2008, 20: 73–76. 10.1007/s11670-008-0073-5CrossRef

45.

Peng C, Zhang X, Yu H, Wu D, Zheng J: Wnt5a as a predictor in poor clinical outcome of patients and a mediator in chemoresistance of ovarian cancer. Int J Gynecol Cancer 2011, 21: 280–288. 10.1097/IGC.0b013e31820aaadbCrossRefPubMed

46.

Yoshioka S, King ML, Ran S, Okuda H, MacLean JA 2nd, McAsey ME, Sugino N, Brard L, Watabe K, Hayashi K: WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway. Mol Cancer Res 2012, 10: 469–482. 10.1158/1541-7786.MCR-11-0177PubMedCentralCrossRefPubMed

47.

Kohn AD, Moon RT: Wnt and calcium signaling: beta-catenin-independent pathways. Cell Calcium 2012, 38: 439–446.CrossRef

48.

Jenny A, Mlodzik M: Planar cell polarity signaling: a common mechanism for cellular polarization. Mt Sinai J Med 2006, 73: 738–750.PubMed

49.

Kikuchi A, Yamamoto H, Sato A: Selective activation mechanisms of Wnt signaling pathways. Trends Cell Biol 2009, 19: 119–129. 10.1016/j.tcb.2009.01.003CrossRefPubMed

50.

Shridhar V, Lee J, Pandita A, Iturria S, Avula R, Staub J, Morrissey M, Calhoun E, Sen A, Kalli K, Keeney G, Roche P, Cliby W, Lu K, Schmandt R, Mills GB, Bast RC Jr, James CD, Couch FJ, Hartmann LC, Lillie J, Smith DI: Genetic analysis of early- versus late-stage ovarian tumors. Cancer Res 2001, 61: 5895–5904.PubMed

51.

Shridhar V, Sen A, Chien J, Staub J, Avula R, Kovats S, Lee J, Lillie J, Smith DI: Identification of underexpressed genes in early- and late-stage primary ovarian tumors by suppression subtraction hybridization. Cancer Res 2002, 62: 262–270.PubMed

52.

Gritsko TM, Coppola D, Paciga JE, Yang L, Sun M, Shelley SA, Fiorica JV, Nicosia SV, Cheng JQ: Activation and overexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Cancer Res 2003, 9: 1420–1426.

53.

Wiener JR, Windham TC, Estrella VC, Parikh NU, Thall PF, Deavers MT, Bast RC, Mills GB, Gallick GE: Activated SRC protein tyrosine kinase is overexpressed in late-stage human ovarian cancers. Gynecol Oncol 2003, 88: 73–79. 10.1006/gyno.2002.6851CrossRefPubMed

54.

de Graeff P, Crijns AP, Ten Hoor KA, Klip HG, Hollema H, Oien K, Bartlett JM, Wisman GB, de Bock GH, de Vries EG, de Jong S, van der Zee AG: The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer. Br J Cancer 2008, 99: 341–349. 10.1038/sj.bjc.6604471PubMedCentralCrossRefPubMed

55.

Sinnberg T, Menzel M, Ewerth D, Sauer B, Schwarz M, Schaller M, Garbe C, Schittek B: β-Catenin signaling increases during melanoma progression and promotes tumor cell survival and chemoresistance. PLoS One 2011, 6: e23429. 10.1371/journal.pone.0023429PubMedCentralCrossRefPubMed

56.

Cimbora-Zovko T, Ambriović-Ristov A, Loncarek J, Osmak M: Altered cell-cell adhesion in cisplatin-resistant human carcinoma cells: a link between beta-catenin/plakoglobin ratio and cisplatin resistance. Eur J Pharmacol 2007, 558: 27–36. 10.1016/j.ejphar.2006.11.077CrossRefPubMed

57.

Sutherland RM: Cell and environment interactions in tumor microregions: the multicell spheroid model. Science 1988, 240: 177–184. 10.1126/science.2451290CrossRefPubMed

58.

Sherman-Baust CA, Weeraratna AT, Rangel LB, Pizer ES, Cho KR, Schwartz DR, Shock T, Morin: Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells. Cancer Cell PJ 2003, 3: 377–386. 10.1016/S1535-6108(03)00058-8CrossRef

59.

Li J, Wood WH 3rd, Becker KG, Weeraratna AT, Morin PJ: Gene expression response to cisplatin treatment in drug-sensitive and drug-resistant ovarian cancer cells. Oncogene 2007, 26: 2860–2872. 10.1038/sj.onc.1210086CrossRefPubMed

60.

Kim CJ, Lee JW, Choi JJ, Choi HY, Park YA, Jeon HK, Sung CO, Song SY, Lee YY, Choi CH, Kim TJ, Lee JH, Kim BG, Bae DS: High claudin-7 expression is associated with a poor response to platinum-based chemotherapy in epithelial ovarian carcinoma. Eur J Cancer 2011, 47: 918–925. 10.1016/j.ejca.2010.11.007CrossRefPubMed

61.

Pan S, Cheng L, White JT, Lu W, Utleg AG, Yan X, Urban ND, Drescher CW, Hood L, Lin B: Quantitative proteomics analysis integrated with microarray data reveals that extracellular matrix proteins, catenins, and p53 binding protein 1 are important for chemotherapy response in ovarian cancers. OMICS 2009, 13: 345–354. 10.1089/omi.2009.0008CrossRefPubMed

Title: Wnt/β-catenin pathway as a potential prognostic and predictive marker in patients with advanced ovarian cancer
Authors: Lubomir Bodnar
Aleksandra Stanczak
Szczepan Cierniak
Marta Smoter
Marzena Cichowicz
Wojciech Kozlowski
Cezary Szczylik
Maciej Wieczorek
Monika Lamparska-Przybysz
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Journal of Ovarian Research / Issue 1/2014
Electronic ISSN: 1757-2215
DOI: https://doi.org/10.1186/1757-2215-7-16

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Wnt/β-catenin pathway as a potential prognostic and predictive marker in patients with advanced ovarian cancer

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2014

Plasma concentrations of D-dimer and outcome of in vitro fertilization

4-Methylumbelliferone inhibits ovarian cancer growth by suppressing thymidine phosphorylase expression

Lipid index changes in the blood serum of patients with hyperplastic and early neoplastic lesions in the ovaries

RETRACTED ARTICLE: Metastatic ovarian papillary cystadenocarcinoma to the small intestine serous surface: report of a case of high-grade histopathologic malignancy

Ovarian cancer initially presenting with isolated ipsilateral superficial inguinal lymph node metastasis: a case study and review of the literature

Journal of Ovarian Research reviewer acknowledgement 2013