自从1889年Stephen Paget提出假说，转移的器官倾向性依然是肿瘤最大的谜团之一。来自康奈尔大学的研究人员David Lyden等在Nature发表文章揭示了来自小鼠和人的肺、肝、脑等器官倾向性的肿瘤细胞外泌体倾向于与它们预计转移的目的器官的细胞（肺纤维细胞和上皮细胞、肝的kupffer细胞和脑的内皮细胞）相结合。研究表明被特定器官的细胞获取的肿瘤外泌体可为肿瘤的转移准备转移前微环境。用肺转倾向的肿瘤细胞来源的外泌体处理小鼠后可是骨转倾向的肿瘤细胞重新定向。外泌体的蛋白质组学分析发现不同器官倾向性的肿瘤细胞来源的外泌体具有不同的整合素（integrin）表达谱，整合素α6β4和α6β1与肺转有关，而整合素αvβ5与肝转有关。Knock down整合素α6β4和αvβ5可减少外泌体被靶器官细胞获取，进而分别降低了肺和肝的转移。进一步研究发现外泌体整合素被细胞获取后激活了Src的磷酸化和促炎的S100基因的表达。最后通过临床数据分析显示外泌体整合素和作为预测肿瘤转移的器官倾向性的诊断指标。
原文来源： Hoshino, A., et al. (2015).Tumour exosome integrins determine organotropic metastasis. Nature advance online publication.
Abstract: Organotropism has remainedone of cancer’s greatest mysteries. Here we demonstrate that exosomes frommouse and human lung-, liver- and brain-tropic tumour cells fuse preferentiallywith resident cells at their predicted destination, namely lung fibroblasts andepithelial cells, liver Kupffer cells and brain endothelial cells. We show thattumour-derived exosomesuptaken by organ-specific cells prepare thepre-metastatic niche. Treatment with exosomes from lung-tropic modelsredirected the metastasis of bone-tropic tumour cells. Exosome proteomicsrevealed distinct integrin expression patterns, in which the exosomalintegrinsα6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreasedexosome uptake, as well as lung and liver metastasis, respectively. Wedemonstrate that exosome integrin uptake by resident cells activates Srcphosphorylation and pro-inflammatory S100 gene expression. Finally, ourclinical data indicate that exosomalintegrins could be used to predictorgan-specific metastasis.
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外泌体资讯网 Nature：外泌体整合素分子决定了肿瘤转移的器官倾向性
