Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer.
Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer.
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DOI：
10.1038/ncomms14470
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发表时间：
2017-03-06
影响因子：
16.6
通讯作者：
Ochiya T
中科院分区：
文献类型：
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作者：
Yokoi A;Yoshioka Y;Yamamoto Y;Ishikawa M;Ikeda SI;Kato T;Kiyono T;Takeshita F;Kajiyama H;Kikkawa F;Ochiya T
晚期卵巢癌由于频繁的腹膜播散而具有高度转移性，导致预后不佳。在这里，我们报道了癌症来源的细胞外囊泡（ev）的功能，它正在成为肿瘤转移的重要介质。来自高转移细胞的ev强烈诱导中度转移肿瘤的转移行为。值得注意的是，肿瘤ev在体内和体外均能有效诱导人间皮细胞凋亡，从而破坏腹膜间皮屏障。全转录组分析显示，MMP1在高转移性癌症ev处理的间皮细胞中显著升高，完整的MMP1 mrna被选择性地包装在ev中。重要的是，MMP1在卵巢癌中的表达与不良预后密切相关。此外，携带MMP1 mrna的ev存在于癌症患者的腹水中，这些ev还能诱导间皮细胞凋亡。我们的研究结果阐明了一种以前未知的通过ev的腹膜传播机制。卵巢癌特别致命，因为在转移前阶段很难发现；另一方面，细胞外囊泡（EVs）参与转移前生态位的制备。在这里，作者表明ev通过靶向间皮介导卵巢癌在腹膜区域的转移。
Advanced ovarian cancers are highly metastatic due to frequent peritoneal dissemination, resulting in dismal prognosis. Here we report the functions of cancer-derived extracellular vesicles (EVs), which are emerging as important mediators of tumour metastasis. The EVs from highly metastatic cells strongly induce metastatic behaviour in moderately metastatic tumours. Notably, the cancer EVs efficiently induce apoptotic cell death in human mesothelial cells in vitro and in vivo, thus resulting in the destruction of the peritoneal mesothelium barrier. Whole transcriptome analysis shows that MMP1 is significantly elevated in mesothelial cells treated with highly metastatic cancer EVs and intact MMP1 mRNAs are selectively packaged in the EVs. Importantly, MMP1 expression in ovarian cancer is tightly correlated with a poor prognosis. Moreover, MMP1 mRNA-carrying EVs exist in the ascites of cancer patients and these EVs also induce apoptosis in mesothelial cells. Our findings elucidate a previously unknown mechanism of peritoneal dissemination via EVs. Ovarian cancer is particularly deadly because it is difficult to detect at the pre-metastatic stage; extracellular vesicles (EVs) on the other hand are involved in the pre-metastatic niche preparation. Here the authors show that EVs mediate ovarian cancer metastasis in the peritoneal area by targeting the mesothelium.