Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis

Carcinogenesis. 2018 Dec 13;39(11):1368-1379. doi: 10.1093/carcin/bgy115.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Extracellular Vesicles / immunology
  • Extracellular Vesicles / pathology*
  • Female
  • HEK293 Cells
  • Humans
  • Inflammation / pathology
  • Interleukin-6 / metabolism
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary*
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / genetics*
  • RAW 264.7 Cells
  • THP-1 Cells
  • Toll-Like Receptor 7 / genetics

Substances

  • IL6 protein, human
  • Interleukin-6
  • MIRN21 microRNA, human
  • MicroRNAs
  • TLR7 protein, human
  • Toll-Like Receptor 7