Mesothelial cells differentiate into fibroblast-like cells under the scirrhous gastric cancer microenvironment and promote peritoneal carcinomatosis in vitro and in vivo

Mol Cell Biochem. 2013 May;377(1-2):177-85. doi: 10.1007/s11010-013-1583-0. Epub 2013 Feb 8.

Abstract

Peritoneal metastases are one reason for the poor prognosis of scirrhous gastric cancer (SGC), and myofibroblast provides a favorable environment for the peritoneal dissemination of gastric cancer. The aim of this study was to determine whether myofibroblast originates from peritoneal mesothelial cells under the influence of the tumor microenvironment. Immunohistochemical studies of peritoneal biopsy specimens from patients with peritoneal lavage cytological (+) status demonstrate the expression of the epithelial markers cytokeratin in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells. To confirm this hypothesis in vitro, we co-incubated mesothelial cells with SGC or non-SGC to investigate morphology and function changes. As we expected, mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with loss of epithelial morphology and decrease in the expression of cytokeratin and E-cadherin when exposed to conditioned medium from HSC-39, and the induction of mesothelial cells can be abolished using a neutralizing antibody to transforming growth factor-beta1 (TGF-β1) as well as by pre-treatment with SB431542. Moreover, we found that these mesothelial cells-derived cells exhibit functional properties of myofibroblasts, including the ability to increase adhesion and invasion of SGC. In summary, our current data demonstrated that mesothelial cells are a source of myofibroblasts under the SGC microenvironment which provide a favorable environment for the dissemination of gastric cancer; TGF-β1 produced by autocrine/paracrine in peritoneal cavity may play a central role in this pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Scirrhous / metabolism
  • Adenocarcinoma, Scirrhous / secondary*
  • Cell Adhesion
  • Coculture Techniques
  • Culture Media, Conditioned
  • Epithelial-Mesenchymal Transition*
  • Epithelium / pathology*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Humans
  • Neoplasm Invasiveness
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / secondary*
  • Peritoneum / pathology
  • Smad2 Protein / metabolism
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Transforming Growth Factor beta1 / metabolism
  • Tumor Cells, Cultured
  • Tumor Microenvironment

Substances

  • Culture Media, Conditioned
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta1