【N.C.B】胰腺癌外泌体(exosome)起始肝脏中转移前微环境的形成

Johnny · 发表于 2015-5-20 21:20:03

本帖最后由 Johnny 于 2016-11-2 11:27 编辑

【最新】Nature cell biology：胰腺癌外泌体起始肝脏中转移前微环境的形成

外泌体领域大牛David Lyden又一篇大作！

5月28日 Nature cell biology上在线发表了康奈尔大学威尔医学院的研究者在外泌体促进胰腺癌向肝脏转移过程中的研究。

胰腺导管腺癌 (PDACs) 具有很高转移能力，由于难以早期监测而预后差。Costa-Silva, B.等发现胰腺导管腺癌 (PDACs)来源的外泌体诱导肝脏中转移前微环境的形成，从而增加了肝脏转移性负担。胰腺导管腺癌 (PDACs)来源的外泌体被肝脏中的Kupffer细胞吸收了后引起了Kupffer细胞分泌TGFβ，进而促进了肝星状细胞（hepatic stellate cells）纤连蛋白（fibronectin）的产生。这种纤维化的微环境增强了骨髓来源的巨噬细胞的招募。巨噬细胞游走抑制因子（MIF）在PDACs来源的外泌体中高表达，抑制MIF可减轻肝脏中转移前微环境的形成和癌细胞的转移。临床数据显示MIF在PDACs来源的外泌体中的胰腺导管腺癌早期病人在后期会发展为肝转移。这些研究发现表明外泌体MIF可促进肿瘤的肝转移，并且可能开发为PDAC肝转移的早期诊断标志物。

Costa-Silva, B., Aiello, N. M., Ocean, A. J., Singh, S., Zhang, H., Thakur, B. K., . . . Lyden, D. (2015). Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. doi: 10.1038/ncb3169

Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found
that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.
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