Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
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DOI：
10.1038/ncb3169
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发表时间：
2015-06
影响因子：
21.3
通讯作者：
Lyden D
中科院分区：
文献类型：
--
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
胰腺导管腺癌（PDAC）转移性高，预后差，主要是由于延迟检测。我们假设细胞间通讯是转移进展的关键。在这里，我们表明PDAC衍生的外泌体在幼稚小鼠中诱导肝转移前小生境形成，并因此增加肝转移负荷。枯否细胞摄取PDAC衍生的外泌体引起肝星状细胞分泌转化生长因子β和上调纤连蛋白的产生。这种纤维化微环境增强了骨髓源性巨噬细胞的募集。我们发现巨噬细胞移动抑制因子（MIF）在PDAC衍生的外泌体中高度表达，其阻断可防止肝转移前小生境的形成和转移。与胰腺肿瘤没有进展的患者相比，来自后来发生肝转移的I期PDAC患者的外泌体中的MIF显著更高。这些发现表明，外泌体MIF启动肝脏转移，可能是PDAC肝转移发展的预后标志物。
Pancreatic ductal adenocarcinomas (PDAC) 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 naïve 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 to patients whose pancreatic tumors 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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影响因子：
6.4
作者：
Grzesiak, John J.;Cao, Hop S. Tran;Burton, Douglas W.;Kaushal, Sharmeela;Vargas, Fabian;Clopton, Paul;Snyder, Cynthia S.;Deftos, Leonard J.;Hoffman, Robert M.;Bouvet, Michael
通讯作者：
Bouvet, Michael
影响因子：
5.7
作者：
Chen, Pei-Fen;Luo, Ya-ling;Al-Abed, Yousef
通讯作者：
Al-Abed, Yousef
影响因子：
11.2
作者：
Hezel AF;Deshpande V;Zimmerman SM;Contino G;Alagesan B;O'Dell MR;Rivera LB;Harper J;Lonning S;Brekken RA;Bardeesy N
通讯作者：
Bardeesy N
影响因子：
15.9
作者：
Duffield, JS;Forbes, SJ;Iredale, JP
通讯作者：
Iredale, JP
影响因子：
11.2
作者：
Ellermeier, Jonathan;Wei, Jiwu;Schnurr, Max
通讯作者：
Schnurr, Max