Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis
Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis
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结直肠癌衍生的小细胞外囊泡在肝转移中建立了转移前炎症生态位。
DOI：
10.1093/carcin/bgy115
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发表时间：
2018-11-01
期刊：
影响因子：
4.7
通讯作者：
Zheng, Shu
中科院分区：
文献类型：
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作者：
Shao, Yingkuan;Chen, Ting;Zheng, Shu
超过一半的结直肠癌 (CRC) 患者会发生肝转移，并且与不良预后相关。影响结直肠癌肝转移的因素尚不清楚，但迫切需要这些信息。我们现在发现，源自 CRC 的小细胞外囊泡（sEV；外泌体）可以特异性靶向肝组织，并诱导肝巨噬细胞极化为分泌白细胞介素 6 (IL-6) 的促炎表型。更重要的是，我们发现 microRNA-21-5p (miR-21) 在 CRC 衍生的 sEV 中高度富集，对于产生 CRC 肝脏促炎表型和肝转移至关重要。沉默 CRC-sEV 中的 miR-21 或巨噬细胞中与 miR-21 结合的 Toll 样受体 7 (TLR7)，消除了 CRC-sEV 对促炎巨噬细胞的诱导。此外，血浆来源的 sEV 中 miR-21 的表达与 CRC 患者的肝转移呈正相关。总的来说，我们的数据证明了 CRC-sEV 通过 miR-21-TLR7-IL-6 轴诱导炎症转移前生态位，在促进肝转移中发挥关键作用。因此，sEVs-miR-21代表了肝转移CRC患者的潜在预后标志物和治疗靶点。
Liver metastases develop in more than half of the patients with colorectal cancer (CRC) and are associated with a poor prognosis. The factors influencing liver metastasis of CRC are poorly characterized, but this information is urgently needed. We have now discovered that small extracellular vesicles (sEVs; exosomes) derived from CRC can be specifically targeted to liver tissue and induce liver macrophage polarization toward an interleukin-6 (IL-6)-secreting proinflammatory phenotype. More importantly, we found that microRNA-21-5p (miR-21) was highly enriched in CRC-derived sEVs and was essential for creating a liver proinflammatory phenotype and liver metastasis of CRC. Silencing either miR-21 in CRC-sEVs or Toll-like receptor 7 (TLR7) in macrophages, to which miR-21 binds, abolished CRC-sEVs' induction of proinflammatory macrophages. Furthermore, miR-21 expression in plasma-derived sEVs was positively correlated with liver metastasis in CRC patients. Collectively, our data demonstrate a pivotal role of CRC-sEVs in promoting liver metastasis by inducing an inflammatory premetastatic niche through the miR-21-TLR7-IL-6 axis. Thus, sEVs-miR-21 represents a potential prognostic marker and therapeutic target for CRC patients with liver metastasis.