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

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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.

Electronic supplementary material

The online version of this article (10.1186/s12885-018-4929-x) contains supplementary material, which is available to authorized users.

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Most cited references 22

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Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

Helena Harlin, Yuru Meng, Amy C Peterson … (2009)

Despite the frequent detection of circulating tumor antigen-specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8(+) effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8(+) effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8(+) effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8(+) T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.

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Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells.

Derk ten Berge, Dorota Kurek, Tim Blauwkamp … (2011)

Pluripotent stem cells exist in naive and primed states, epitomized by mouse embryonic stem cells (ESCs) and the developmentally more advanced epiblast stem cells (EpiSCs; ref. 1). In the naive state of ESCs, the genome has an unusual open conformation and possesses a minimum of repressive epigenetic marks. In contrast, EpiSCs have activated the epigenetic machinery that supports differentiation towards the embryonic cell types. The transition from naive to primed pluripotency therefore represents a pivotal event in cellular differentiation. But the signals that control this fundamental differentiation step remain unclear. We show here that paracrine and autocrine Wnt signals are essential self-renewal factors for ESCs, and are required to inhibit their differentiation into EpiSCs. Moreover, we find that Wnt proteins in combination with the cytokine LIF are sufficient to support ESC self-renewal in the absence of any undefined factors, and support the derivation of new ESC lines, including ones from non-permissive mouse strains. Our results not only demonstrate that Wnt signals regulate the naive-to-primed pluripotency transition, but also identify Wnt as an essential and limiting ESC self-renewal factor.

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Observer variation in immunohistochemical analysis of protein expression, time for a change?

T Kirkegaard, J. Edwards, S. Tovey … (2006)

Immunohistochemical analysis of protein expression is central to most clinical translational studies and defines patient treatment or selection criteria for novel drugs. Interobserver variation is rarely analysed despite recognition that this is a key area of potential inaccuracy. Therefore our aim was to examine observer variation and suggest the revision of current standards. We analysed inter- and intra-observer variation, by interclass correlation coefficient (ICCC) and kappa statistics, in 8661 samples. Intra-observer assessment of nuclear, cytoplasmic and membrane staining for seven proteins in 1323 samples resulted in an ICCC of 0.94 and a kappa-value of 0.787. Interobserver reproducibility, assessed on 28 proteins by seven observer pairs in 8661 carcinomas, gave an ICCC of 0.90 and a kappa-value of 0.70. No significant effect of either antibody or cellular compartmentalization was observed. We have demonstrated that ICCC is a consistent method to assess observer variation when a continuous scoring system is used, compared with kappa statistics, which depends on a categorical system. Given the importance of accurate assessment of protein expression in diagnostic and experimental medicine, we suggest raising thresholds for observer variation: ICCC of 0.7 should be regarded as the minimum acceptable standard, ICCC of 0.8 as good and ICCC of > or = 0.9 as excellent.

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Author and article information

Contributors

Michal Chovanec:

ORCID: http://orcid.org/0000-0002-5653-2909

+421-2-59378366 , michal.chovanec1@gmail.com

Zuzana Cierna: ciernaz@gmail.com

Viera Miskovska: vieramiskovska@yahoo.fr

Katarina Machalekova: kmachale@ousa.sk

Katarina Kalavska: katarina.hainova@gmail.com

Katarina Rejlekova: k.rejlekova@gmail.com

Daniela Svetlovska: daniela.svetlovska@gmail.com

Dusan Macak: dusan.macak@nou.sk

Stanislav Spanik: sspanik@ousa.sk

Karol Kajo: kkajo@ousa.sk

Pavel Babal: pavel.babal@fmed.uniba.sk

Jozef Mardiak: jmardiak@gmail.com

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 3 November 2018

Publication date PMC-release: 3 November 2018

Publication date Collection: 2018

Volume: 18

Electronic Location Identifier: 1062

Affiliations

[1 ]ISNI 0000 0004 0607 7295, GRID grid.419188.d, 2nd Department of Oncology, Faculty of Medicine, , Comenius University and National Cancer Institute, ; Klenova 1, 833 10 Bratislava, Slovak Republic

[2 ]ISNI 0000 0004 0607 7295, GRID grid.419188.d, National Cancer Institute, ; Klenova 1, 833 10 Bratislava, Slovakia

[3 ]ISNI 0000000109409708, GRID grid.7634.6, Department of Pathology, Faculty of Medicine, , Comenius University, ; Sasinkova 4, 811 08 Bratislava, Slovakia

[4 ]ISNI 0000000109409708, GRID grid.7634.6, 1st Department of Oncology, Faculty of Medicine, , Comenius University, ; Kollarska 12, 812 50 Bratislava, Slovakia

[5 ]St. Elisabeth Cancer Institute, Heydukova 10, 812 50 Bratislava, Slovakia

[6 ]ISNI 0000000109409708, GRID grid.7634.6, Translational Research Unit, Faculty of Medicine, , Comenius University, ; Klenova 1, 833 10 Bratislava, Slovakia

[7 ]ISNI 0000 0001 2106 1943, GRID grid.420087.9, Cancer Research Institute, Slovak Academy of Sciences, ; Dubravska cesta 9, 845 05 Bratislava, Slovakia

[8 ]Faculty Hospital with Policlinics Skalica, a.s, Koreszkova 936/7, 909 01 Skalica, Slovakia

Author information

Michal Chovanec http://orcid.org/0000-0002-5653-2909

Article

Publisher ID: 4929

DOI: 10.1186/s12885-018-4929-x

PMC ID: 6215644

PubMed ID: 30390643

SO-VID: a5af0185-ceb6-4cfb-a810-bd53c31f0adc

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 March 2018

Date accepted : 10 October 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100005357, Agentúra na Podporu Výskumu a Vývoja;

Award ID: APVV-15-0086

Award Recipient : Michal Chovanec

Funded by: FundRef http://dx.doi.org/10.13039/501100006109, Vedecká Grantová Agentúra MŠVVaŠ SR a SAV;

Award ID: VEGA 1/0043/18

Award Recipient : Michal Mego

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: βcatenin,wntβ pathway,pd-l1,systemic-immune inflammation,tumor infiltrating lymphocytes

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: βcatenin, wntβ pathway, pd-l1, systemic-immune inflammation, tumor infiltrating lymphocytes

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

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Abstract

Background

Methods

Results

Conclusion

Electronic supplementary material

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Karger: Oncology

Most cited references 22

Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells.

Observer variation in immunohistochemical analysis of protein expression, time for a change?

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