Multi-nucleated cells use ROS to induce breast cancer chemoresistance in vitro and in vivo
Multi-nucleated cells use ROS to induce breast cancer chemoresistance in vitro and in vivo
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DOI：
10.1038/s41388-018-0272-6
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发表时间：
2018-08-16
期刊：
影响因子：
8
通讯作者：
Mandal, Mahitosh
中科院分区：
文献类型：
--
作者：
Parekh, Aditya;Das, Subhayan;Mandal, Mahitosh
尽管多核细胞(MNC)与多种癌症的化疗耐药密切相关，但我们对多核细胞如何调节肿瘤微环境的了解有限。我们在一段时间内从三重阴性耐药乳腺癌细胞中捕获了多核细胞，这些细胞不会增殖，但会显著调节其微环境。我们发现，氧化应激通过分泌血管内皮生长因子和MIF在体外和体内诱导化疗耐药。这些因子通过RAS/MAPK途径通过上调抗凋亡蛋白来诱导化疗耐药。在MNC中，升高的活性氧物种(ROS)稳定了HIF-1α，有助于增加VEGF和MIF的产生。这些数据表明，ROS-HIF-1α信号轴在调节MNC的化疗耐药中起着至关重要的作用。未来靶向ROS-HIF-1α可能有助于消除乳腺癌的耐药性。
Although there is a strong correlation between multinucleated cells (MNCs) and cancer chemo-resistance in variety of cancers, our understanding of how multinucleated cells modulate the tumor micro-environment is limited. We captured multinucleated cells from triple-negative chemo-resistant breast cancers cells in a time frame, where they do not proliferate but rather significantly regulate their micro-environment. We show that oxidatively stressed MNCs induce chemo-resistance in vitro and in vivo by secreting VEGF and MIF. These factors act through the RAS/MAPK pathway to induce chemoresistance by upregulating anti-apoptotic proteins. In MNCs, elevated reactive oxygen species (ROS) stabilizes HIF-1 alpha contributing to increase production of VEGF and MIF. Together the data indicate, that the ROS-HIF-1 alpha signaling axis is very crucial in regulation of chemo-resistance by MNCs. Targeting ROS-HIF-1 alpha in future may help to abrogate drug resistance in breast cancer.