Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer

Nat Commun. 2017 Mar 6;8:14470. doi: 10.1038/ncomms14470.

Abstract

Advanced ovarian cancers are highly metastatic due to frequent peritoneal dissemination, resulting in dismal prognosis. Here we report the functions of cancer-derived extracellular vesicles (EVs), which are emerging as important mediators of tumour metastasis. The EVs from highly metastatic cells strongly induce metastatic behaviour in moderately metastatic tumours. Notably, the cancer EVs efficiently induce apoptotic cell death in human mesothelial cells in vitro and in vivo, thus resulting in the destruction of the peritoneal mesothelium barrier. Whole transcriptome analysis shows that MMP1 is significantly elevated in mesothelial cells treated with highly metastatic cancer EVs and intact MMP1 mRNAs are selectively packaged in the EVs. Importantly, MMP1 expression in ovarian cancer is tightly correlated with a poor prognosis. Moreover, MMP1 mRNA-carrying EVs exist in the ascites of cancer patients and these EVs also induce apoptosis in mesothelial cells. Our findings elucidate a previously unknown mechanism of peritoneal dissemination via EVs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Ascites / genetics*
  • Ascites / metabolism
  • Ascites / pathology
  • Cell Line, Tumor
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Epithelium / metabolism
  • Epithelium / pathology
  • Extracellular Vesicles / metabolism*
  • Extracellular Vesicles / pathology
  • Female
  • Fluorescent Dyes / chemistry
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Matrix Metalloproteinase 1 / genetics*
  • Matrix Metalloproteinase 1 / metabolism
  • Mice
  • Mice, SCID
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Optical Imaging
  • Organic Chemicals / chemistry
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Ovary / metabolism
  • Ovary / pathology
  • Peritoneal Neoplasms / genetics*
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / pathology
  • Peritoneum / metabolism
  • Peritoneum / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Survival Analysis

Substances

  • Fluorescent Dyes
  • Neoplasm Proteins
  • Organic Chemicals
  • PKH67
  • RNA, Messenger
  • MMP1 protein, human
  • Matrix Metalloproteinase 1