Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours

  title={Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours},
  author={Christiane Rudolph and Cecilie Melau and John Erik Nielsen and Kristina Vile Jensen and Dekang Liu and Javier Pe{\~n}a-Diaz and Ewa Rajpert-De Meyts and Lene Juel Rasmussen and Anne J{\o}rgensen},
  journal={Cellular Oncology},
BackgroundTesticular germ cell tumours (TGCT) are highly sensitive to cisplatin-based chemotherapy, but patients with tumours containing differentiated teratoma components are less responsive to this treatment. The cisplatin sensitivity in TGCT has previously been linked to the embryonic phenotype in the majority of tumours, although the underlying mechanism largely remains to be elucidated. The aim of this study was to investigate the role of the DNA mismatch repair (MMR) system in the… 
Overcoming Chemotherapy Resistance in Germ Cell Tumors
A summary of current knowledge about the molecular mechanisms of cisplatin sensitivity and resistance in GCTs is provided and possible therapeutic approaches that seek to overcome this chemoresistance are outlined.
Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors
Potential mechanisms of TGCT cisplatin sensitivity and resistance to conventional chemotherapeutics are discussed.
Cisplatin Resistance in Testicular Germ Cell Tumors: Current Challenges from Various Perspectives
This work aims to provide a multifaceted overview of cisplatin resistance in testicular germ cell tumors, from the clinical perspective, to the pathobiology (including mechanisms contributing to induction of the resistant phenotype), to experimental models available for studying this occurrence.
Influence of Nodal signalling on pluripotency factor expression, tumour cell proliferation and cisplatin-sensitivity in testicular germ cell tumours
The findings suggest that the Nodal signalling pathway may be involved in regulating pluripotency factor expression in malignant germ cells, but manipulation of the pathway does not appear to affect cisplatin-sensitivity or tumour cell proliferation.
Evaluation of Chemotherapeutic Drugs for Treatment of (Cisplatin-Resistant) Germ Cell Cancer Cell Lines.
In this chapter, in vitro techniques to measure cytotoxic impacts of chemotherapeutic drugs on GCC cell lines are presented and the measurement of relative cell viability by XTT assay, as well as cell cycle distribution and apoptosis assay by Nicoletti- and Annexin V/PI apoptotic assay with subsequent flow cytometry are discussed.
Mismatch repair deficiency occurs very rarely in seminomas.
One single seminoma with MMR deficiency, characterized by protein loss of MLH1 and PMS2, was identified among 536 interpretable seminomas and is not a relevant determinant of lymphocyte influx in seminoma.
Exploring the molecular aspects associated with testicular germ cell tumors: a review
The main genetic and epigenetic events associated with TGCTs development are discussed in order to better define their role in the pathogenesis of these tumors and in cisplatin-acquired resistance.
Analysis of Genetic Alterations Related to DNA Methylation in Testicular Germ Cell Tumors Based on Data Mining
5 genes were found that showed both low expression and high methylation in EC, and were significantly associated with relapse-free survival, and the findings of methylation-based genetic features between EC and SE might be helpful in studying the role of DNAmethylation in cancer development.
Suppression of YAP by DDP disrupts colon tumor progression
DDP was a suitable therapeutic candidate for colon cancer that specifically targets the Mst/Yap signaling pathway, and post-translational regulation of YAP phosphorylation controlled the subcellular distribution between the nucleus and the cytoplasm.
RB1 Germline Variant Predisposing to a Rare Ovarian Germ Cell Tumor: A Case Report
It is pinpointed for the first time that an RB1 leaky variant, not leading to retinoblastoma because of its maternal origin, can predispose in adults to a very rare form of ovarian cancer and that the somatic disruption of few genes contributes to the tumor progression and aggressiveness.


Cisplatin resistance in germ cell tumours: models and mechanisms
Several approaches to overcome resistance have been successfully examined in vitro and in vivo, including PARP inhibitors, especially in cells showing deficient HR‐repair; stabilization of p53 using nutlin‐3; inhibition of several components of the PI3K/pAKT pathway using small molecules; and DNA demethylation by 5‐azacytidine or 5‐aza‐deoxy‐cytidine, among others.
p53 Hypersensitivity Is the Predominant Mechanism of the Unique Responsiveness of Testicular Germ Cell Tumor (TGCT) Cells to Cisplatin
It is shown that siRNA-mediated silencing of p53 is sufficient to completely abrogate hypersensitivity not only to Cisplatin but also to non-genotoxic inducers of p 53 such as the Mdm2 antagonist Nutlin-3 and the proteasome inhibitor Bortezomib.
A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embyronal carcinoma
The data indicate that robust transcriptional activation of p53 is linked to the known hypersensitivity of testicular germ cell tumors to chemotherapy, and many of the gene products may participate in the unique curability of this disease.
Loss of Oct-3/4 Expression in Embryonal Carcinoma Cells Is Associated with Induction of Cisplatin Resistance
It is demonstrated that a lack of expression of Oct-3/4 in TGCT cells is associated with a higher apoptotic threshold and cisplatin resistance which is accompanied by an impaired caspase-9 activation, reduced caspases-3 activity and altered p53 accumulation, and it is hypothesized that in refractory TGCTs the original tumor stem cell population could be replaced by an Oct- 3/4-negative, resistant population in a selection process.
PMS2 expression in epithelial ovarian cancer is posttranslationally regulated by Akt and essential for platinum-induced apoptosis
Findings provide a novel insight into molecular mechanisms linking MMR with chemoresistance and suggest that stabilization of PMS2 expression may be useful in overcoming the cisplatin resistance in EOC.
Influence of hMLH1 methylation, mismatch repair deficiency and microsatellite instability on chemoresistance of testicular germ-cell tumors.
BACKGROUND Cisplatin-based chemotherapy can cure more than 80% of metastatic germ-cell testicular tumors (GCTs). The response to cisplatin-based chemotherapy has been related to Microsatellite
Molecular determinants of treatment response in human germ cell tumors.
  • F. Mayer, H. Stoop, C. Bokemeyer
  • Medicine, Biology
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 2003
A multifactorial basis for the chemosensitivity of GCTs with lack of transporters for cisplatin, of antiapoptotic BCL-2 family members, of p21 induction by p53, and of RB and an intact apoptotic cascade downstream of p53 is indicated.
Cisplatin hypersensitivity of testicular germ cell tumors is determined by high constitutive Noxa levels mediated by Oct-4.
Oct-4-dependent high constitutive levels of this BH3-only protein prime embryonal carcinoma cells to undergo rapid and massive apoptosis in response to p53 activation, indicating that Noxa is a central determinant of hypersensitivity to cisplatin.
Mismatch repair gene expression and genetic instability in testicular germ cell tumor
This work investigated the expression of the two most commonly mutated MMR genes, MSH2 and MLH1 in sporadic testicular germ cell tumor (GCT) to determine the expression pattern and correlate MMR gene expression with genetic instability in GCT and develop a panel of molecular markers that can identify genetically distinct subsets of GCT for prognostic assessment.
Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer.
Targeting cytoplasmic p21, including by modulation of the Oct4/miR-106b/p21 pathway, may offer new strategies for the treatment of chemoresistant testicular and other types of cancer.