Abstract
Germ cell tumors (GCTs) are considered to be highly curable; however, there are major differences in the outcomes related to histology and anatomical localization. GCTs originating from the testis are, overall, sensitive to platinum-based chemotherapy, whereas GCTs originating from the mediastinum show a worse response, which remains largely unexplained. Here, we address the differences among GCTs from two different anatomical locations (testicular versus mediastinal/extragonadal), with a specific focus on the role of the P53 pathway. It was recently shown that GCTs with TP53 mutations most often localize to the mediastinum. To elucidate the underlying mechanism, TP53 knock-out lines were generated in cisplatin-sensitive and -resistant clones of the representative 2102Ep cell line (wild-type TP53 testicular GCT) and NCCIT cell line (hemizygously mutated TP53, mutant TP53 mediastinal GCT). The full knock-out of TP53 in 2102Ep and resistant NCCIT resulted in an increase in cisplatin resistance, suggesting a contributing role for P53, even in NCCIT, in which P53 had been reported to be non-functional. In conclusion, these results suggest that TP53 mutations contribute to the cisplatin-resistant phenotype of mediastinal GCTs and, therefore, are a potential candidate for targeted treatment. This knowledge provides a novel model system to elucidate the underlying mechanism of clinical behavior and possible alternative treatment of the TP53 mutant and mediastinal GCTs.
Highlights
Germ cell tumors (GCTs) are the most common solid malignancies in young men [1,2].Despite the high frequency of these cancers within this defined age group, the discovery of the exceptional sensitivity of these tumors to the platinum DNA crosslinking compound cisplatin has led to the survival of most patients, with the current five-year survival rate exceeding 95% [3,4,5]
We subsequently investigated the difference in cisplatin resistance in these testicular and mediastinal GCT cell lines
We identified a stronger reduction in mouse double minute2 homologue (MDM2) and MDM4 after cisplatin treatment in the parental cell line, most likely related to the already higher cisplatin resistance in the NCCIT-resistant cell line that functions upstream of the DNA-damage sensing response [27,43,44,45]
Summary
Germ cell tumors (GCTs) are the most common solid malignancies in young men [1,2].Despite the high frequency of these cancers within this defined age group, the discovery of the exceptional sensitivity of these tumors to the platinum DNA crosslinking compound cisplatin has led to the survival of most patients, with the current five-year survival rate exceeding 95% [3,4,5]. Germ cell tumors (GCTs) are the most common solid malignancies in young men [1,2]. 2 homologue (MDM2), has been illustrated to be especially important in P53 regulation in GCTs, as it has been shown to hamper the apoptotic response via binding to P53 and can be a putative important clinical target [8,16,17,18,19]. It has already been shown that the inhibition of MDM2 and disruption of the MDM2–P53 interaction can potentiate apoptosis and sensitize GCT cells to cisplatin [16,17]. This is an important issue, as it is currently unclear whether mediastinal
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