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Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

βcatenin is a marker of poor clinical characteristics and suppressed immune infiltration in testicular germ cell tumors

Authors: Michal Chovanec, Zuzana Cierna, Viera Miskovska, Katarina Machalekova, Katarina Kalavska, Katarina Rejlekova, Daniela Svetlovska, Dusan Macak, Stanislav Spanik, Karol Kajo, Pavel Babal, Michal Mego, Jozef Mardiak

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

WNT/βcatenin (WNTβ) pathway is activated in early stages of embryonic development. We aimed to evaluate the significance of βcatenin in germ cell tumors (GCTs) and explore associations with the inflamed environment.

Methods

Surgical specimens from 247 patients were analyzed. Βcatenin expression was detected in the tumor tissue by immunohistochemistry and correlated with clinical characteristics, outcome, PD-L1 expression and systemic immune-inflammation index (SII). The Ingenuity Pathway Analysis (IPA) was used to investigate the immune-cell related effects of βcatenin and PD-L1 encoding genes.

Results

βcatenin was expressed in 86.2% of GCTs. The expression in seminomas was significantly lower compared to all subtypes of non-seminoma (all P <  0.0001). A high expression (weighted histoscore > 150) was associated with primary mediastinal non-seminoma (P = 0.035), intermediate/poor risk disease (P = 0.033) and high tumor markers (P = 0.035). We observed a positive correlation with the PD-L1 in tumor and an inverse correlation with the SII. IPA uncovered relationships of CTNNB (βcatenin) and CD274 (PD-L1) genes and their effects on differentiation, proliferation and activation of lymphocyte subtypes.

Conclusion

Herein, we showed that βcatenin is associated with male adult GCT characteristics as well as supressed immune environment.
Appendix
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Literature
1.
go back to reference Einhorn LH. Treatment of testicular cancer: a new and improved model. J Clin Oncol. 1990;8(11):1777–81.CrossRef Einhorn LH. Treatment of testicular cancer: a new and improved model. J Clin Oncol. 1990;8(11):1777–81.CrossRef
2.
go back to reference Mardiak J, Salek T, Sycova-Mila Z, Obertova J, Reckova M, Mego M, Hlavata Z, Brozmanova K, Risnyovzska Z, Svetlovska D, et al. Paclitaxel, bleomycin, etoposide, and cisplatin (T-BEP) as initial treatment in patients with poor-prognosis germ cell tumors (GCT): a phase II study. Neoplasma. 2007;54(3):240–5.PubMed Mardiak J, Salek T, Sycova-Mila Z, Obertova J, Reckova M, Mego M, Hlavata Z, Brozmanova K, Risnyovzska Z, Svetlovska D, et al. Paclitaxel, bleomycin, etoposide, and cisplatin (T-BEP) as initial treatment in patients with poor-prognosis germ cell tumors (GCT): a phase II study. Neoplasma. 2007;54(3):240–5.PubMed
3.
go back to reference Cierna Z, Mego M, Miskovska V, Machalekova K, Chovanec M, Svetlovska D, Hainova K, Rejlekova K, Macak D, Spanik S, et al. Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors. Ann Oncol. 2016;27(2):300–5.CrossRef Cierna Z, Mego M, Miskovska V, Machalekova K, Chovanec M, Svetlovska D, Hainova K, Rejlekova K, Macak D, Spanik S, et al. Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors. Ann Oncol. 2016;27(2):300–5.CrossRef
4.
go back to reference Chovanec M, Cierna Z, Miskovska V, Machalekova K, Svetlovska D, Kalavska K, Rejlekova K, Spanik S, Kajo K, Babal P, et al. Prognostic role of programmed-death ligand 1 (PD-L1) expressing tumor infiltrating lymphocytes in testicular germ cell tumors. Oncotarget. 2017;8(13):21794–805.CrossRef Chovanec M, Cierna Z, Miskovska V, Machalekova K, Svetlovska D, Kalavska K, Rejlekova K, Spanik S, Kajo K, Babal P, et al. Prognostic role of programmed-death ligand 1 (PD-L1) expressing tumor infiltrating lymphocytes in testicular germ cell tumors. Oncotarget. 2017;8(13):21794–805.CrossRef
5.
go back to reference Chovanec M, Mego M, Cholujova D, Gronesova P, Miskovska V, Sycova-Mila Z, Usakova V, Svetlovska D, Bujdak P, Spanik S, et al. A cytokine and angiogenic factor (CAF) analysis in plasma in testicular germ cell tumor patients (TGCTs). J Clin Oncol. 2015;33(15):e15552. Chovanec M, Mego M, Cholujova D, Gronesova P, Miskovska V, Sycova-Mila Z, Usakova V, Svetlovska D, Bujdak P, Spanik S, et al. A cytokine and angiogenic factor (CAF) analysis in plasma in testicular germ cell tumor patients (TGCTs). J Clin Oncol. 2015;33(15):e15552.
6.
go back to reference Svetlovska D, Miskovska V, Cholujova D, Gronesova P, Cingelova S, Chovanec M, Sycova-Mila Z, Obertova J, Palacka P, Rajec J, et al. Plasma cytokines correlated with disease characteristic, progression free survival and overall survival in testicular germ cell tumour patients. Clin Genitourin Cancer. 2017; Article In Press. Svetlovska D, Miskovska V, Cholujova D, Gronesova P, Cingelova S, Chovanec M, Sycova-Mila Z, Obertova J, Palacka P, Rajec J, et al. Plasma cytokines correlated with disease characteristic, progression free survival and overall survival in testicular germ cell tumour patients. Clin Genitourin Cancer. 2017; Article In Press.
7.
go back to reference Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311–9.CrossRef Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311–9.CrossRef
8.
go back to reference Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28.CrossRef Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28.CrossRef
9.
go back to reference Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.CrossRef Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.CrossRef
10.
go back to reference Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558–62.CrossRef Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558–62.CrossRef
11.
go back to reference Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69(7):3077–85.CrossRef Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69(7):3077–85.CrossRef
12.
go back to reference Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, Alaparthy S, Berman D, Jure-Kunkel M, Siemers NO, et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer immunology, immunotherapy : CII. 2012;61(7):1019–31.CrossRef Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, Alaparthy S, Berman D, Jure-Kunkel M, Siemers NO, et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer immunology, immunotherapy : CII. 2012;61(7):1019–31.CrossRef
13.
go back to reference Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–5.CrossRef Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–5.CrossRef
14.
go back to reference ten Berge D, Kurek D, Blauwkamp T, Koole W, Maas A, Eroglu E, Siu RK, Nusse R. Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells. Nat Cell Biol. 2011;13(9):1070–5.CrossRef ten Berge D, Kurek D, Blauwkamp T, Koole W, Maas A, Eroglu E, Siu RK, Nusse R. Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells. Nat Cell Biol. 2011;13(9):1070–5.CrossRef
15.
go back to reference Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A. The ground state of embryonic stem cell self-renewal. Nature. 2008;453(7194):519–23.CrossRef Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A. The ground state of embryonic stem cell self-renewal. Nature. 2008;453(7194):519–23.CrossRef
16.
go back to reference Bhatia N, Spiegelman VS. Activation of Wnt/beta-catenin/Tcf signaling in mouse skin carcinogenesis. Mol Carcinog. 2005;42(4):213–21.CrossRef Bhatia N, Spiegelman VS. Activation of Wnt/beta-catenin/Tcf signaling in mouse skin carcinogenesis. Mol Carcinog. 2005;42(4):213–21.CrossRef
17.
go back to reference Eger A, Stockinger A, Schaffhauser B, Beug H, Foisner R. Epithelial mesenchymal transition by c-Fos estrogen receptor activation involves nuclear translocation of beta-catenin and upregulation of beta-catenin/lymphoid enhancer binding factor-1 transcriptional activity. J Cell Biol. 2000;148(1):173–88.CrossRef Eger A, Stockinger A, Schaffhauser B, Beug H, Foisner R. Epithelial mesenchymal transition by c-Fos estrogen receptor activation involves nuclear translocation of beta-catenin and upregulation of beta-catenin/lymphoid enhancer binding factor-1 transcriptional activity. J Cell Biol. 2000;148(1):173–88.CrossRef
18.
go back to reference Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, et al. COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in Cancer. Nucleic Acids Res. 2011;39(Database issue):D945–50.CrossRef Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, et al. COSMIC: mining complete cancer genomes in the catalogue of somatic mutations in Cancer. Nucleic Acids Res. 2011;39(Database issue):D945–50.CrossRef
19.
go back to reference Blagodatski A, Poteryaev D, Katanaev VL. Targeting the Wnt pathways for therapies. Mol Cell Ther. 2014;2:28.CrossRef Blagodatski A, Poteryaev D, Katanaev VL. Targeting the Wnt pathways for therapies. Mol Cell Ther. 2014;2:28.CrossRef
20.
go back to reference Potapov S, Sidorenko R, Galata D, Stratiy N, Gargin V. Peculiarities of catenin activity in the embryonal testicular carcinoma. Georgian Med News. 2016;261:68–73. Potapov S, Sidorenko R, Galata D, Stratiy N, Gargin V. Peculiarities of catenin activity in the embryonal testicular carcinoma. Georgian Med News. 2016;261:68–73.
21.
go back to reference Honecker F, Kersemaekers AM, Molier M, Van Weeren PC, Stoop H, De Krijger RR, Wolffenbuttel KP, Oosterhuis W, Bokemeyer C, Looijenga LH. Involvement of E-cadherin and beta-catenin in germ cell tumours and in normal male fetal germ cell development. J Pathol. 2004;204(2):167–74.CrossRef Honecker F, Kersemaekers AM, Molier M, Van Weeren PC, Stoop H, De Krijger RR, Wolffenbuttel KP, Oosterhuis W, Bokemeyer C, Looijenga LH. Involvement of E-cadherin and beta-catenin in germ cell tumours and in normal male fetal germ cell development. J Pathol. 2004;204(2):167–74.CrossRef
22.
go back to reference Fernando G, Paul F, Laura J, Alejandra AM, Gabriela M, Alberto PL. Is the Wnt/beta catenin signalling pathway activated in seminoma?: An immunohistochemical study. J Cancer Res Ther. 2016;12(2):1075–9.CrossRef Fernando G, Paul F, Laura J, Alejandra AM, Gabriela M, Alberto PL. Is the Wnt/beta catenin signalling pathway activated in seminoma?: An immunohistochemical study. J Cancer Res Ther. 2016;12(2):1075–9.CrossRef
23.
go back to reference Chovanec M, Cierna Z, Miskovska V, Machalekova K, Kalavska K, Rejlekova K, Svetlovska D, Macak D, Spanik S, Kajo K, et al. Systemic immune-inflammation index in germ-cell tumours. Br J Cancer. 2018;118(6):831–8.CrossRef Chovanec M, Cierna Z, Miskovska V, Machalekova K, Kalavska K, Rejlekova K, Svetlovska D, Macak D, Spanik S, Kajo K, et al. Systemic immune-inflammation index in germ-cell tumours. Br J Cancer. 2018;118(6):831–8.CrossRef
24.
go back to reference Ulbright TM, Amin MB, Balzer B, Berney DM, Epstein JI, Gu C, Indrees MT, Looijenga LHJ, Paner G, Rajpert-De Meyts E, et al. Tumours of the testis and paratesticular tissue. In: Moch H, Humphrey PA, Ulbright TM, Reuter VE, editors. WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2016. p. 185–258. Ulbright TM, Amin MB, Balzer B, Berney DM, Epstein JI, Gu C, Indrees MT, Looijenga LHJ, Paner G, Rajpert-De Meyts E, et al. Tumours of the testis and paratesticular tissue. In: Moch H, Humphrey PA, Ulbright TM, Reuter VE, editors. WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2016. p. 185–258.
25.
go back to reference Mego M, Cierna Z, Svetlovska D, Macak D, Machalekova K, Miskovska V, Chovanec M, Usakova V, Obertova J, Babal P, et al. PARP expression in germ cell tumours. J Clin Pathol. 2013;66(7):607–12.CrossRef Mego M, Cierna Z, Svetlovska D, Macak D, Machalekova K, Miskovska V, Chovanec M, Usakova V, Obertova J, Babal P, et al. PARP expression in germ cell tumours. J Clin Pathol. 2013;66(7):607–12.CrossRef
26.
go back to reference Ulisse S, Baldini E, Mottolese M, Sentinelli S, Gargiulo P, Valentina B, Sorrenti S, Di Benedetto A, De Antoni E, D'Armiento M. Increased expression of urokinase plasminogen activator and its cognate receptor in human seminomas. BMC Cancer. 2010;10:151.CrossRef Ulisse S, Baldini E, Mottolese M, Sentinelli S, Gargiulo P, Valentina B, Sorrenti S, Di Benedetto A, De Antoni E, D'Armiento M. Increased expression of urokinase plasminogen activator and its cognate receptor in human seminomas. BMC Cancer. 2010;10:151.CrossRef
27.
go back to reference Kirkegaard T, Edwards J, Tovey S, McGlynn LM, Krishna SN, Mukherjee R, Tam L, Munro AF, Dunne B, Bartlett JM. Observer variation in immunohistochemical analysis of protein expression, time for a change? Histopathology. 2006;48(7):787–94.CrossRef Kirkegaard T, Edwards J, Tovey S, McGlynn LM, Krishna SN, Mukherjee R, Tam L, Munro AF, Dunne B, Bartlett JM. Observer variation in immunohistochemical analysis of protein expression, time for a change? Histopathology. 2006;48(7):787–94.CrossRef
28.
go back to reference Hu B, Yang XR, Xu Y, Sun YF, Sun C, Guo W, Zhang X, Wang WM, Qiu SJ, Zhou J, et al. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clinical Cancer Res. 2014;20(23):6212–22.CrossRef Hu B, Yang XR, Xu Y, Sun YF, Sun C, Guo W, Zhang X, Wang WM, Qiu SJ, Zhou J, et al. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clinical Cancer Res. 2014;20(23):6212–22.CrossRef
29.
go back to reference Fritsch MK, Schneider DT, Schuster AE, Murdoch FE, Perlman EJ. Activation of Wnt/beta-catenin signaling in distinct histologic subtypes of human germ cell tumors. Pediatr Dev Pathol. 2006;9(2):115–31.CrossRef Fritsch MK, Schneider DT, Schuster AE, Murdoch FE, Perlman EJ. Activation of Wnt/beta-catenin signaling in distinct histologic subtypes of human germ cell tumors. Pediatr Dev Pathol. 2006;9(2):115–31.CrossRef
30.
go back to reference Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS. Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans. 2005;33(Pt 6):1526–30.CrossRef Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS. Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans. 2005;33(Pt 6):1526–30.CrossRef
31.
go back to reference Abu Dawud R, Schreiber K, Schomburg D, Adjaye J. Human embryonic stem cells and embryonal carcinoma cells have overlapping and distinct metabolic signatures. PLoS One. 2012;7(6):e39896.CrossRef Abu Dawud R, Schreiber K, Schomburg D, Adjaye J. Human embryonic stem cells and embryonal carcinoma cells have overlapping and distinct metabolic signatures. PLoS One. 2012;7(6):e39896.CrossRef
32.
go back to reference Raggioli A, Junghans D, Rudloff S, Kemler R. Beta-catenin is vital for the integrity of mouse embryonic stem cells. PLoS One. 2014;9(1):e86691.CrossRef Raggioli A, Junghans D, Rudloff S, Kemler R. Beta-catenin is vital for the integrity of mouse embryonic stem cells. PLoS One. 2014;9(1):e86691.CrossRef
33.
go back to reference de Jong J, Stoop H, Gillis AJ, Hersmus R, van Gurp RJ, van de Geijn GJ, van Drunen E, Beverloo HB, Schneider DT, Sherlock JK, et al. Further characterization of the first seminoma cell line TCam-2. Genes Chromosomes Cancer. 2008;47(3):185–96.CrossRef de Jong J, Stoop H, Gillis AJ, Hersmus R, van Gurp RJ, van de Geijn GJ, van Drunen E, Beverloo HB, Schneider DT, Sherlock JK, et al. Further characterization of the first seminoma cell line TCam-2. Genes Chromosomes Cancer. 2008;47(3):185–96.CrossRef
34.
go back to reference Adra N, Althouse SK, Liu H, Brames MJ, Hanna NH, Einhorn LH, Albany C. Prognostic factors in patients with poor-risk germ-cell tumors: a retrospective analysis of the Indiana University experience from 1990 to 2014. Ann Oncol. 2016;27(5):875–9.CrossRef Adra N, Althouse SK, Liu H, Brames MJ, Hanna NH, Einhorn LH, Albany C. Prognostic factors in patients with poor-risk germ-cell tumors: a retrospective analysis of the Indiana University experience from 1990 to 2014. Ann Oncol. 2016;27(5):875–9.CrossRef
35.
go back to reference Cohen SB, Smith NL, McDougal C, Pepper M, Shah S, Yap GS, Acha-Orbea H, Jiang A, Clausen BE, Rudd BD, et al. Beta-catenin signaling drives differentiation and proinflammatory function of IRF8-dependent dendritic cells. J Immunol. 2015;194(1):210–22.CrossRef Cohen SB, Smith NL, McDougal C, Pepper M, Shah S, Yap GS, Acha-Orbea H, Jiang A, Clausen BE, Rudd BD, et al. Beta-catenin signaling drives differentiation and proinflammatory function of IRF8-dependent dendritic cells. J Immunol. 2015;194(1):210–22.CrossRef
36.
go back to reference Augustin I, Dewi DL, Hundshammer J, Rempel E, Brunk F, Boutros M. Immune cell recruitment in teratomas is impaired by increased Wnt secretion. Stem Cell Res. 2016;17(3):607–15.CrossRef Augustin I, Dewi DL, Hundshammer J, Rempel E, Brunk F, Boutros M. Immune cell recruitment in teratomas is impaired by increased Wnt secretion. Stem Cell Res. 2016;17(3):607–15.CrossRef
Metadata
Title
βcatenin is a marker of poor clinical characteristics and suppressed immune infiltration in testicular germ cell tumors
Authors
Michal Chovanec
Zuzana Cierna
Viera Miskovska
Katarina Machalekova
Katarina Kalavska
Katarina Rejlekova
Daniela Svetlovska
Dusan Macak
Stanislav Spanik
Karol Kajo
Pavel Babal
Michal Mego
Jozef Mardiak
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4929-x

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