Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Medical Oncology, The Union Hospital of Fujian Medical University, Fujian, China.
Carcinogenesis. 2018 Dec 13;39(11):1368-1379. doi: 10.1093/carcin/bgy115.
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.
结直肠癌（CRC）患者中超过一半会发生肝转移，且预后不良。影响 CRC 肝转移的因素尚未完全阐明，但目前急需了解这些信息。我们现已发现，CRC 来源的小细胞外囊泡（sEV；外泌体）可特异性靶向肝脏组织，并诱导肝脏巨噬细胞向分泌白细胞介素 6（IL-6）的促炎表型极化。更重要的是，我们发现 microRNA-21-5p（miR-21）在 CRC 来源的 sEV 中高度富集，对于形成肝脏促炎表型和 CRC 肝转移至关重要。沉默 CRC-sEV 中的 miR-21 或其结合的 Toll 样受体 7（TLR7），均可消除 CRC-sEV 诱导促炎巨噬细胞的作用。此外，CRC 患者血浆来源的 sEV 中 miR-21 的表达与肝转移呈正相关。综上，我们的数据表明，CRC-sEV 通过 miR-21-TLR7-IL-6 轴诱导炎症前转移微环境，在促进肝转移中起关键作用。因此，sEV-miR-21 可能成为 CRC 肝转移患者的一种潜在预后标志物和治疗靶点。
