Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.
Int J Mol Sci. 2021 Oct 29;22(21):11774. doi: 10.3390/ijms222111774.
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 mutations most often localize to the mediastinum. To elucidate the underlying mechanism, knock-out lines were generated in cisplatin-sensitive and -resistant clones of the representative 2102Ep cell line (wild-type testicular GCT) and NCCIT cell line (hemizygously mutated , mutant mediastinal GCT). The full knock-out of 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 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 mutant and mediastinal GCTs.
生殖细胞肿瘤（GCT）被认为具有高度可治愈性；然而，组织学和解剖学定位相关的结局存在显著差异。源自睾丸的 GCT 总体上对铂类为基础的化疗敏感，而源自纵隔的 GCT 反应较差，这在很大程度上仍未得到解释。在这里，我们研究了来自两个不同解剖部位（睾丸与纵隔/性腺外）的 GCT 之间的差异，特别关注 P53 通路的作用。最近表明，具有 突变的 GCT 最常定位于纵隔。为了阐明潜在的机制，我们在 cisplatin 敏感和耐药的代表性 2102Ep 细胞系（野生型睾丸 GCT）和 NCCIT 细胞系（半合子突变 ，突变的纵隔 GCT）的顺铂耐药克隆中生成了 的敲除系。2102Ep 和耐药 NCCIT 中的 完全敲除导致顺铂耐药性增加，这表明 P53 即使在 NCCIT 中也具有促进作用，尽管先前报道 NCCIT 中的 P53 无功能。总之，这些结果表明 突变导致纵隔 GCT 的顺铂耐药表型，并因此成为潜在的靶向治疗候选物。这一知识为阐明临床行为的潜在机制以及可能替代治疗 突变和纵隔 GCT 提供了一个新的模型系统。
