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 chemo-resistance by upregulating anti-apoptotic proteins. In MNCs, elevated reactive oxygen species (ROS) stabilizes HIF-1α contributing to increase production of VEGF and MIF. Together the data indicate, that the ROS-HIF-1α signaling axis is very crucial in regulation of chemo-resistance by MNCs. Targeting ROS-HIF-1α in future may help to abrogate drug resistance in breast cancer.

中文翻译：

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多核细胞利用ROS在体外和体内诱导乳腺癌的化学耐药性。

尽管在多种癌症中多核细胞（MNC）与癌症化学耐药性之间存在很强的相关性，但我们对多核细胞如何调节肿瘤微环境的理解仍然有限。我们在一个时间范围内从三阴性化学耐药性乳腺癌细胞中捕获了多核细胞，在这些细胞中它们不会增殖，而是显着调节其微环境。我们显示氧化应激的跨国公司在体外和体内通过分泌VEGF和MIF诱导化学耐药性。这些因子通过上调抗凋亡蛋白，通过RAS / MAPK途径发挥抗化学作用。在跨国公司中，升高的活性氧（ROS）可以稳定HIF-1α，从而有助于增加VEGF和MIF的产生。数据一起表明，ROS-HIF-1α信号轴在跨国公司对化学耐药性的调节中起着至关重要的作用。将来针对ROS-HIF-1α可能有助于消除乳腺癌的耐药性。