Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2

作者：Masaki Takasugi, Ryo Okada, Akiko Takahashi, David Virya Chen, Sugiko Watanabe, Eiji Hara · 发表于：Nature Communications · 年份：2017 · DOI：10.1038/ncomms15728 · 被引用次数：418 · 研究领域：Circular RNAs in diseases、Extracellular vesicles in disease、MicroRNA in disease regulation

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.