Phytoestrogens regulate the proliferation and expression of stem cell factors in cell lines of malignant testicular germ cell tumors

333 Background: The purpose of this study was to examine the immunohistochemical expression of OCT3/4, CCND2, DPPA4 and NANOG in primary non-seminomatous germ cell testicular tumors that might be associated with different entities of germ cell tumors. OCT3/4, NANOG, DPPA4 and CCND2 have been identified as key regulators of pluripotency in mammalian embryonic and induced stem cells. Methods: Tissue samples of non seminoma testicular germ cell tumors including carcinoma in situ (CIS, n=10), seminoma component (n=5), embryonic carcinoma (n=20), mature teratoma (n= 7), immature teratoma (n=7), yolk sac tumor (n=5) and choriocarcinoma (n=3) were first analyzed by histological evaluation followed by selection of the appropriate tissue sections prepared from paraffin embedded testicular tissue blocks fixed with buffered formalin. To investigate immunohistochemical expression, of cancer stem cell markers samples tissues were analyzed under central pathological evaluation. Results: In CIS cells all markers were detected with a strong immunohistochemical expression suggesting that CIS cells maintain characteristics of embryonic stem cells. The invasive tumor samples, in comparison, showed a more heterogeneous expression pattern of OCT3/4, NANOG, DPPA4 and CCND2. There was an abundant expression in seminomas and embryonic carcinomas compared to a marked reduction expression in choriocarcinoma and teratomas. The expression of the markers was related to tumoral tissue differentiation. The seminomatous component and the embryonic carcinoma and undifferentiated tissues such as intratubular neoplasia presented elevated expressions. Specialized tissues such as teratoma and choriocarcinoma present low expression levels or absence of studied markers. The teratomatous subtypes do not express NANOG. The sub-type coriocarcinoma tumors do not express CCND2 and NANOG. Conclusions: The immunohistochemical expression of stem cell markers OCT3/4, NANOG, DPPA4 and CCND2 follow a specific pattern that is related to tumoral differentiation and consequent loss of pluripotency characteristics.

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Genetic Factors on Mouse Chromosome 18 Affecting Susceptibility to Testicular Germ Cell Tumors and Permissiveness to Embryonic Stem Cell Derivation

Cancer Research ◽

10.1158/0008-5472.can-09-3342 ◽

2009 ◽

Vol 69 (23) ◽

pp. 9112-9117 ◽

Cited By ~ 15

Author(s):

Philip D. Anderson ◽

Vicki R. Nelson ◽

Paul J. Tesar ◽

Joseph H. Nadeau

Keyword(s):

Stem Cell ◽

Germ Cell ◽

Embryonic Stem Cell ◽

Mouse Chromosome ◽

Genetic Factors ◽

Germ Cell Tumors ◽

Embryonic Stem ◽

Testicular Germ Cell Tumors ◽

Testicular Germ Cell ◽

Stem Cell Derivation

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Abstract 5457: MAD2γ, a new MAD2 isoform, is ubiquitously expressed in distinct cell lines, reduces mitotic arrest, and associates with resistance to cisplatin-based chemotherapy in testicular germ cell tumors

10.1158/1538-7445.am2015-5457 ◽

2015 ◽

Author(s):

Alejandro Lopez-Saavedra ◽

Rodrigo Caceres ◽

Fernando Luna ◽

Irwin Hernandez ◽

Luis Alonso Herrera

Keyword(s):

Germ Cell ◽

Cell Lines ◽

Germ Cell Tumors ◽

Mitotic Arrest ◽

Testicular Germ Cell Tumors ◽

Testicular Germ Cell ◽

Distinct Cell

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Association between ERCC1 and XPA expression and polymorphisms and the response to cisplatin in patients with non-seminomatous testicular germ cell tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4555 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4555-4555

Author(s):

Julia Mendoza ◽

Jorge Martinez-Cedillo ◽

Carlos Alberto Hernández ◽

Delia Pérez-Montiel ◽

Clementina Castro ◽

...

Keyword(s):

Germ Cell ◽

Cell Lines ◽

Cancer Cell ◽

Excision Repair ◽

Cox Model ◽

Germ Cell Tumors ◽

Cancer Cell Lines ◽

Testicular Germ Cell Tumors ◽

Testicular Germ Cell ◽

Ercc1 Expression

4555 Background: Cisplatin-based chemotherapy cures over 80% of testicular germ cell tumors (TGCTs); nucleotide-excision repair (NER) modifies the sensitivity to cisplatin. In this work we explored the association between NER-proteins and their polymorphisms (SNPs) with cisplatin-sensitivity (CPS) and overall survival (OS) of patients with advanced non-seminomatous (ns)-TGCTs treated with bleomycin-etoposide-cisplatin (BEP). Methods: ERCC1, XPA-expression and gammaH2AX-presence, were tested in cisplatin-treated cancer cell lines. ERCC1 and XPA-expression were also analyzed in ns-TGCTs by qPCR. Immunohistochemistry was performed to detect ERCC1 protein in ns-TGCTs specimens. The SNPs were genotyped by PCR-RFLPs technique. Results: High basal ERCC1-expression was observed in non-CPS cancer cell lines; ERCC1-expression augmented further, as well as gammaH2AX, after cisplatin-treatment. Basal ERCC1 expression increases in the non-CPS patients in Mexican and Peruvian populations compared to CPS patients (p<0.001; p=0.002). XPAexpression levels weren’t different. These polymorphisms weren’t associated with CPS or OS. ERCC1-positive immunostaining was observed in 30/108 patients (27.8%). From 76 patients that were CPS, 59 (77.6%) were ERCC1-negative, compared with 17 (22.4%) that were ERCC1-positive (p=0.05). 5-year OS probability was smaller for those patients ERCC1-positive and non-CPS (15.38%) than tumor ERCC1-negative and CPS (89.3%) (p<0.001). Using the Cox Model, adjusted on the prognosis groups, the hazard ratio (HR) of death in patients with ERCC1-negative and non-CPS was >14.43 and in patients ERCC1-positive and non-CPS the HR was >11.86 (p<0.001). Conclusions: High-levels of ERCC1-expression and ERCC1-protein are associated with non-CPS, suggesting the use of ERCC1 as a potential indicator of response to cisplatin-based chemotherapy and the prognosis in patients with ns-TGCTs. Moreover, it’s important to identify patients potentially non-CPS in order to diminish the toxicity of cisplatin and improved quality of life avoiding adverse effects due to this agent. Work supported by CONACYT 83959 and PAPIIT IN213311-3.

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XIST-Promoter Demethylation as Tissue Biomarker for Testicular Germ Cell Tumors and Spermatogenesis Quality

Cancers ◽

10.3390/cancers11091385 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1385 ◽

Cited By ~ 9

Author(s):

Lobo ◽

Nunes ◽

Gillis ◽

Barros-Silva ◽

Miranda-Gonçalves ◽

...

Keyword(s):

Germ Cell ◽

Cell Lines ◽

X Chromosome ◽

Germ Cell Tumors ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Lower Amount ◽

Testicular Germ Cell Tumors ◽

Testicular Germ Cell ◽

Xist Promoter

Background: The event of X chromosome inactivation induced by XIST, which is physiologically observed in females, is retained in testicular germ cell tumors (TGCTs), as a result of a supernumerary X chromosome constitution. X chromosome inactivation also occurs in male germline, specifically during spermatogenesis. We aimed to analyze the promoter methylation status of XIST in a series of TGCT tissues, representative cell lines, and testicular parenchyma. Methods: Two independent cohorts were included, comprising a total of 413 TGCT samples, four (T)GCT cell lines, and 86 testicular parenchyma samples. The relative amount of methylated and demethylated XIST promoter fragments was assessed by quantitative methylation-specific PCR (qMSP) and more sensitive high-resolution melting (HRM) methylation analyses. Results: Seminomas showed a lower amount of methylated XIST fragments as compared to non-seminomas or normal testis (p < 0.0001), allowing for a good discrimination among these groups (area under the curve 0.83 and 0.81, respectively). Seminomas showed a significantly higher content of demethylated XIST as compared to non-seminomas. The percentage of demethylated XIST fragment in cell lines reflected their chromosomal constitution (number of extra X chromosomes). A novel and strong positive correlation between the Johnsen’s score and XIST demethylation was identified (r = 0.75, p < 0.0001). Conclusions: The X chromosome inactivation event and demethylated XIST promoter are promising biomarkers for TGCTs and for assessing spermatogenesis quality.

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