Exosomes as mediators of platinum resistance in ovarian cancer.
Exosomes as mediators of platinum resistance in ovarian cancer.
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DOI：
10.18632/oncotarget.14440
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发表时间：
2017-02-14
期刊：
影响因子：
--
通讯作者：
Godwin AK
中科院分区：
文献类型：
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作者：
Crow J;Atay S;Banskota S;Artale B;Schmitt S;Godwin AK
外来体与致癌蛋白和遗传物质的细胞-细胞转移有关。我们推测，这可能是一种机制，通过这种机制，一个固有的铂耐药群体的上皮性卵巢癌（EOC）细胞赋予其影响周围的肿瘤细胞。为了探索这种可能性，我们利用了铂敏感性细胞系A2780和源自其抗性亚克隆的外来体，以及铂抗性EOC系OVCAR 10。与对照相比，当预先暴露于来自铂抗性细胞的外来体时，A2780细胞在用卡铂处理后的活力增加约2倍。这与上皮细胞向间质细胞转化（EMT）的增加相一致。EOC细胞系的DNA测序揭示了铂耐药细胞内Mothers Against Decapentaplegic Homolog 4（SMAD 4）中先前未报道的体细胞突变。经工程改造以外源表达这些SMAD 4突变的A2780细胞显示在卡铂处理后EMT标志物的上调，对卡铂更具抗性，并且释放外泌体，与对照相比，所述外泌体在初始A2780受体细胞中赋予约1.7倍的抗性增加。这些研究提供了第一个证据，即获得性SMAD 4突变增强了EOC的化疗耐药性，并提出了一种新的机制，其中肿瘤源性外泌体的交换使EMT表型永久化，导致铂难治性细胞亚群的发展。
Exosomes have been implicated in the cell-cell transfer of oncogenic proteins and genetic material. We speculated this may be one mechanism by which an intrinsically platinum-resistant population of epithelial ovarian cancer (EOC) cells imparts its influence on surrounding tumor cells. To explore this possibility we utilized a platinum-sensitive cell line, A2780 and exosomes derived from its resistant subclones, and an unselected, platinum-resistant EOC line, OVCAR10. A2780 cells demonstrate a ~2-fold increase in viability upon treatment with carboplatin when pre-exposed to exosomes from platinum-resistant cells as compared to controls. This coincided with increased epithelial to mesenchymal transition (EMT). DNA sequencing of EOC cell lines revealed previously unreported somatic mutations in the Mothers Against Decapentaplegic Homolog 4 (SMAD4) within platinum-resistant cells. A2780 cells engineered to exogenously express these SMAD4 mutations demonstrate up-regulation of EMT markers following carboplatin treatment, are more resistant to carboplatin, and release exosomes which impart a ~1.7-fold increase in resistance in naive A2780 recipient cells as compared to controls. These studies provide the first evidence that acquired SMAD4 mutations enhance the chemo-resistance profile of EOC and present a novel mechanism in which exchange of tumor-derived exosomes perpetuates an EMT phenotype, leading to the development of subpopulations of platinum-refractory cells.