The molecular pathogenesis of thymoma remains largely unknown. It has been recently demonstrated, that activation of Wnt signaling pathway leads to increased incidence of thymoma in murine models. The present study investigated the activation of molecules of the Wnt signaling pathway in human thymoma. A total of 112 thymoma cases with complete clinical and follow-up data and 8 controls were included in the present study. Patients with thymoma and controls were examined immunohistochemically for β-catenin and E-cadherin. The mRNA expression levels of CTNNB1, CCND1, MYC, AXIN2 and CDH1 were analyzed by reverse transcription-quantitative PCR. Immunohistochemically, β-catenin and E-cadherin were overexpressed in neoplastic cells of all thymomas. In type A, B1 and non-invasive type B2 thymoma, both molecules were located in the cytoplasm, in contrast to invasive type B2 and B3 thymoma, where membranous immunopositivities were observed. mRNA expression levels of genes involved in the Wnt pathway and of E-cadherin were significantly increased in both type A and B thymoma compared with controls; increasing gradually from type B1 to B3, and with higher stage of disease. In recurrent type B thymoma, the mRNA expression of the molecules was significantly higher. Despite the activation of Wnt pathway in indolent type A thymoma, the negative feedback of the pathway was preserved by overexpression of inhibitory molecule axin2, which was not overexpressed in type B thymoma. In summary, the Wnt pathway was activated in human thymoma and may contribute to oncogenesis. Detection of molecules of the Wnt pathway may be of diagnostic and prognostic value.

1st Department of Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague 128 08 Czech Republic

3rd Department of Surgery 1st Faculty of Medicine Charles University and Motol University Hospital Prague 150 06 Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and General University Hospital Prague 128 08 Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and Motol University Hospital Prague 150 06 Czech Republic

Zobrazit více v PubMed

Travis W, Brambilla E, Burke A, Marx A, Nicholson A. IARC Press; Lyon: 2015. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. PubMed

Li Q, Su YL, Shen WX. A novel prognostic signature of seven genes for the prediction in patients with thymoma. J Cancer Res Clin Oncol. 2019;145:109–116. doi: 10.1007/s00432-018-2770-x. PubMed DOI PMC

Girard N. Thymic tumors: Relevant molecular data in the clinic. J Thorac Oncol. 2010;5:S291–S295. doi: 10.1097/JTO.0b013e3181f209b9. (10 Suppl 4) PubMed DOI

Inoue M, Starostik P, Zettl A, Ströbel P, Schwarz S, Scaravilli F, Henry K, Willcox N, Müller-Hermelink HK, Marx A. Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas. Cancer Res. 2003;63:3708–3715. PubMed

Liang CC, Lu TL, Yu YR, You LR, Chen CM. β-catenin activation drives thymoma initiation and progression in mice. Oncotarget. 2015;6:13978–13993. doi: 10.18632/oncotarget.4368. PubMed DOI PMC

International Non-Hodgkin's Lymphoma Prognostic Factors Project, corp-author. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. 1993;329:987–994. doi: 10.1056/NEJM199309303291402. PubMed DOI

Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, Klasa R, Savage KJ, Shenkier T, Sutherland J, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109:1857–1861. doi: 10.1182/blood-2006-08-038257. PubMed DOI

Girard N, Ruffini E, Marx A, Faivre-Finn C, Peters S, ESMO Guidelines Committee Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;5(Suppl 26):v40–v55. doi: 10.1093/annonc/mdv277. PubMed DOI

Boehm T, Swann JB. Thymus involution and regeneration: Two sides of the same coin? Nat Rev Immunol. 2013;13:831–838. doi: 10.1038/nri3534. PubMed DOI

Detterbeck FC, Nicholson AG, Kondo K, Van Schil P, Moran C. The Masaoka-Koga stage classification for thymic malignancies: Clarification and definition of terms. Zhongguo Fei Ai Za Zhi. 2014;17:75–81. (In Chinese) PubMed PMC

Bijwaard KE, Aguilera NS, Monczak Y, Trudel M, Taubenberger JK, Lichy JH. Quantitative real-time reverse transcription-PCR assay for cyclin D1 expression: utility in the diagnosis of mantle cell lymphoma. Clin Chem. 2001;47:195–201. doi: 10.1093/clinchem/47.2.195. PubMed DOI

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–408. doi: 10.1006/meth.2001.1262. PubMed DOI

Strobel P, Hohenberger P, Marx A. Thymoma and thymic carcinoma: Molecular pathology and targeted therapy. J Thorac Oncol. 2010;5(10 Suppl 4):S286–290. doi: 10.1097/JTO.0b013e3181f209a8. PubMed DOI

Zhou R, Zettl A, Ströbel P, Wagner K, Müller-Hermelink HK, Zhang S, Marx A, Starostik P. Thymic epithelial tumors can develop along two different pathogenetic pathways. Am J Pathol. 2001;159:1853–1860. doi: 10.1016/S0002-9440(10)63031-3. PubMed DOI PMC

Hankey W, Frankel WL, Groden J. Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: Implications for therapeutic targeting. Cancer Metastasis Rev. 2018;37:159–172. doi: 10.1007/s10555-017-9725-6. PubMed DOI PMC

Stamos JL, Weis WI. The β-catenin destruction complex. Cold Spring Harb Perspect Boil. 2013;5:a007898. doi: 10.1101/cshperspect.a007898. PubMed DOI PMC

Yamulla RJ, Kane EG, Moody AE, Politi KA, Lock NE, Foley AV, Roberts DM. Testing models of the APC tumor suppressor/β-catenin interaction reshapes our view of the destruction complex in Wnt signaling. Genetics. 2014;197:1285–1302. doi: 10.1534/genetics.114.166496. PubMed DOI PMC

Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T. Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level. Genes Cells. 1998;3:395–403. doi: 10.1046/j.1365-2443.1998.00198.x. PubMed DOI

Zhang L, Shay JW. Multiple roles of APC and its therapeutic implications in colorectal cancer. J Natl Cancer Inst. 2017;109 doi: 10.1093/jnci/djw332. PubMed DOI PMC

Hirschman BA, Pollock BH, Tomlinson GE. The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr. 2005;147:263–266. doi: 10.1016/j.jpeds.2005.04.019. PubMed DOI

Huber AH, Stewart DB, Laurents DV, Nelson WJ, Weis WI. The cadherin cytoplasmic domain is unstructured in the absence of beta-catenin. A possible mechanism for regulating cadherin turnover. J Boil Chem. 2001;276:12301–12309. doi: 10.1074/jbc.M010377200. PubMed DOI

Gloushankova NA, Rubtsova SN, Zhitnyak IY. Cadherin-mediated cell-cell interactions in normal and cancer cells. Tissue Barriers. 2017;5:e1356900. doi: 10.1080/21688370.2017.1356900. PubMed DOI PMC

Yoshino I, Kase S, Yano T, Sugio K, Sugimachi K. Expression status of E-cadherin and alpha-, beta-, and gamma-catenins in thymoma. Ann Thorac Surg. 2002;73:933–937. doi: 10.1016/S0003-4975(01)03434-8. PubMed DOI

Wang Y, Li L, Li Q, Xie C, Wang E, Wang E. Expression of P120 catenin, Kaiso, and metastasis tumor antigen-2 in thymomas. Tumour Biol. 2012;33:1871–1879. doi: 10.1007/s13277-012-0447-7. PubMed DOI

Riess JW, West R, Dean M, Klimowicz AC, Neal JW, Hoang C, Wakelee HA. GLI1, CTNNB1 and NOTCH1 protein expression in a thymic epithelial malignancy tissue microarray. Anticancer Res. 2015;35:669–676. PubMed PMC

Pan CC, Ho DM, Chen WY, Chiang H, Fahn HJ, Wang LS. Expression of E-cadherin and alpha- and beta-catenins in thymoma. J Pathol. 1998;184:207–211. doi: 10.1002/(SICI)1096-9896(199802)184:2<207::AID-PATH967>3.0.CO;2-X. PubMed DOI

Kumar R, Bashyam MD. Multiple oncogenic roles of nuclear beta-catenin. J Biosci. 2017;42:695–707. doi: 10.1007/s12038-017-9710-9. PubMed DOI

Morgan RG, Ridsdale J, Tonks A, Darley RL. Factors affecting the nuclear localization of β-catenin in normal and malignant tissue. J Cell Biochem. 2014;115:1351–1361. doi: 10.1002/jcb.24803. PubMed DOI

Zuklys S, Gill J, Keller MP, Hauri-Hohl M, Zhanybekova S, Balciunaite G, Na KJ, Jeker LT, Hafen K, Tsukamoto N, et al. Stabilized beta-catenin in thymic epithelial cells blocks thymus development and function. J Immunol. 2009;182:2997–3007. doi: 10.4049/jimmunol.0713723. PubMed DOI

Staal FJ, Luis TC, Tiemessen MM. WNT signalling in the immune system: WNT is spreading its wings. Nat Rev Immunol. 2008;8:581–593. doi: 10.1038/nri2360. PubMed DOI

Pongracz J, Hare K, Harman B, Anderson G, Jenkinson EJ. Thymic epithelial cells provide WNT signals to developing thymocytes. Eur J Immunol. 2003;33:1949–1956. doi: 10.1002/eji.200323564. PubMed DOI

van Loosdregt J, Fleskens V, Tiemessen MM, Mokry M, van Boxtel R, Meerding J, Pals CE, Kurek D, Baert MR, Delemarre EM, et al. Canonical Wnt signaling negatively modulates regulatory T cell function. Immunity. 2013;39:298–310. doi: 10.1016/j.immuni.2013.07.019. PubMed DOI

Evoli A, Lancaster E. Paraneoplastic disorders in thymoma patients. J Thorac Oncol. 2014;9(9 Suppl 2):S143–S147. doi: 10.1097/JTO.0000000000000300. PubMed DOI PMC

Safieddine N, Liu G, Cuningham K, Ming T, Hwang D, Brade A, Bezjak A, Fischer S, Xu W, Azad S, et al. Prognostic factors for cure, recurrence and long-term survival after surgical resection of thymoma. J Thorac Oncol. 2014;9:1018–1022. doi: 10.1097/JTO.0000000000000215. PubMed DOI

Ruffini E, Detterbeck F, Van Raemdonck D, Rocco G, Thomas P, Weder W, Brunelli A, Evangelista A, Venuta F, European Association of Thoracic Surgeons (ESTS) Thymic Working Group Tumours of the thymus: A cohort study of prognostic factors from the European Society of Thoracic Surgeons database. Eur J Cardiothorac Surg. 2014;46:361–368. doi: 10.1093/ejcts/ezt649. PubMed DOI PMC

Engels EA, Pfeiffer RM. Malignant thymoma in the United States: Demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer. 2003;105:546–551. doi: 10.1002/ijc.11099. PubMed DOI

Buske C, Hutchings M, Ladetto M, Goede V, Mey U, Soubeyran P, Spina M, Stauder R, Trnený M, Wedding U, et al. ESMO consensus conference on malignant lymphoma: General perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma. Ann Oncol. 2018;29:544–562. doi: 10.1093/annonc/mdx413. PubMed DOI