Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2.
Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2.
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DOI：
10.1038/ncomms15728
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发表时间：
2017-06-06
影响因子：
16.6
通讯作者：
Hara E
中科院分区：
文献类型：
--
作者：
Takasugi M;Okada R;Takahashi A;Virya Chen D;Watanabe S;Hara E
细胞衰老阻止处于肿瘤转化风险的细胞的增殖。然而，衰老细胞的改变的分泌组可以促进周围癌细胞的生长。虽然细胞外囊泡（EV）已经成为细胞间通讯的新参与者，但它们在衰老细胞分泌组功能中的作用在很大程度上尚未探索。在这里，我们表明外泌体样小EV（sEV）是衰老细胞促肿瘤发生功能的重要介质。从衰老细胞分泌的sEV相关的EphA 2与肝配蛋白-A1结合，即在几种类型的癌细胞中高度表达，并通过EphA 2/肝配蛋白-A1反向信号传导促进细胞增殖。在衰老细胞中EphA 2的sEV分选增加，这是因为其由PTP 1B磷酸酶的氧化失活引起的增强的磷酸化。我们的研究结果证明了活性氧（ROS）调节的货物分选成sEV的一种新机制，这对衰老细胞分泌组的潜在有害生长促进作用至关重要。虽然衰老细胞分泌组可以促进周围癌细胞的生长，但细胞外囊泡在这一过程中的作用尚未得到很好的理解。在这里，作者表明ROS增加了EphA 2在衰老细胞中的细胞外囊泡中的分选，这促进了癌细胞的增殖。
Cellular senescence prevents the proliferation of cells at risk for neoplastic transformation. However, the altered secretome of senescent cells can promote the growth of the surrounding cancer cells. Although extracellular vesicles (EVs) have emerged as new players in intercellular communication, their role in the function of senescent cell secretome has been largely unexplored. Here, we show that exosome-like small EVs (sEVs) are important mediators of the pro-tumorigenic function of senescent cells. sEV-associated EphA2 secreted from senescent cells binds to ephrin-A1, that is, highly expressed in several types of cancer cells and promotes cell proliferation through EphA2/ephrin-A1 reverse signalling. sEV sorting of EphA2 is increased in senescent cells because of its enhanced phosphorylation resulting from oxidative inactivation of PTP1B phosphatase. Our results demonstrate a novel mechanism of reactive oxygen species (ROS)-regulated cargo sorting into sEVs, which is critical for the potentially deleterious growth-promoting effect of the senescent cell secretome. Although senescent cell secretome can promote the growth of surrounding cancer cells, the role of extracellular vesicles in this process has not been well understood. Here the authors show that ROS increase the sorting of EphA2 into extracellular vesicles in senescent cells, which promotes proliferation of cancer cells.