Mesenchymal Gene Program-Expressing Ovarian Cancer Spheroids Exhibit Enhanced Mesothelial Clearance

J Clin Invest. 2014 Jun;124(6):2611-25. doi: 10.1172/JCI69815. Epub 2014 Apr 24.

Abstract

Metastatic dissemination of ovarian tumors involves the invasion of tumor cell clusters into the mesothelial cell lining of peritoneal cavity organs; however, the tumor-specific factors that allow ovarian cancer cells to spread are unclear. We used an in vitro assay that models the initial step of ovarian cancer metastasis, clearance of the mesothelial cell layer, to examine the clearance ability of a large panel of both established and primary ovarian tumor cells. Comparison of the gene and protein expression profiles of clearance-competent and clearance-incompetent cells revealed that mesenchymal genes are enriched in tumor populations that display strong clearance activity, while epithelial genes are enriched in those with weak or undetectable activity. Overexpression of transcription factors SNAI1, TWIST1, and ZEB1, which regulate the epithelial-to-mesenchymal transition (EMT), promoted mesothelial clearance in cell lines with weak activity, while knockdown of the EMT-regulatory transcription factors TWIST1 and ZEB1 attenuated mesothelial clearance in ovarian cancer cell lines with strong activity. These findings provide important insights into the mechanisms associated with metastatic progression of ovarian cancer and suggest that inhibiting pathways that drive mesenchymal programs may suppress tumor cell invasion of peritoneal tissues.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Epithelial-Mesenchymal Transition
  • Epithelium / metabolism
  • Epithelium / pathology
  • Female
  • Gene Knockdown Techniques
  • Homeodomain Proteins / antagonists & inhibitors
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Mesoderm / metabolism
  • Mesoderm / pathology
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology*
  • Ovarian Neoplasms / secondary
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / secondary
  • Protein Array Analysis
  • Snail Family Transcription Factors
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptome
  • Tumor Cells, Cultured
  • Twist-Related Protein 1 / antagonists & inhibitors
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • Homeodomain Proteins
  • Nuclear Proteins
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • TWIST1 protein, human
  • Transcription Factors
  • Twist-Related Protein 1
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1