Tumour exosome integrins determine organotropic metastasis.
Tumour exosome integrins determine organotropic metastasis.
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DOI：
10.1038/nature15756
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发表时间：
2015-11-19
期刊：
影响因子：
64.8
通讯作者：
Lyden D
中科院分区：
文献类型：
--
作者：
Hoshino A;Costa-Silva B;Shen TL;Rodrigues G;Hashimoto A;Tesic Mark M;Molina H;Kohsaka S;Di Giannatale A;Ceder S;Singh S;Williams C;Soplop N;Uryu K;Pharmer L;King T;Bojmar L;Davies AE;Ararso Y;Zhang T;Zhang H;Hernandez J;Weiss JM;Dumont-Cole VD;Kramer K;Wexler LH;Narendran A;Schwartz GK;Healey JH;Sandstrom P;Labori KJ;Kure EH;Grandgenett PM;Hollingsworth MA;de Sousa M;Kaur S;Jain M;Mallya K;Batra SK;Jarnagin WR;Brady MS;Fodstad O;Muller V;Pantel K;Minn AJ;Bissell MJ;Garcia BA;Kang Y;Rajasekhar VK;Ghajar CM;Matei I;Peinado H;Bromberg J;Lyden D
自从斯蒂芬·佩吉特1889年提出转移性器官倾向假说以来，转移性器官倾向一直是癌症最大的谜团之一。本研究表明，小鼠和人类嗜肺、嗜肝和嗜脑肿瘤细胞的外泌体优先与预期目的地的常驻细胞融合，即肺成纤维细胞和上皮细胞、肝库普弗细胞和脑内皮细胞。我们发现肿瘤来源的外泌体被器官特异性细胞吸收，准备转移前生态位。用嗜肺模型的外泌体治疗可重定向嗜骨肿瘤细胞的转移。外泌体蛋白质组学显示出不同的整合素表达模式，其中外泌体整合素α6β4和α6β1与肺转移相关，外泌体整合素αvβ5与肝转移相关。靶向整合素α6β4和αvβ5分别减少外泌体摄取，减少肺和肝转移。我们证明外泌体整合素被驻留细胞摄取激活Src磷酸化和促炎性S100基因表达。最后，我们的临床数据表明外泌体整合素可用于预测器官特异性转移。
Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.