Normal fibroblasts induce E-cadherin loss and increase lymph node metastasis in gastric cancer

PLoS One. 2014 May 20;9(5):e97306. doi: 10.1371/journal.pone.0097306. eCollection 2014.

Abstract

Background: A tumor is considered a heterogeneous complex in a three-dimensional environment that is flush with pathophysiological and biomechanical signals. Cell-stroma interactions guide the development and generation of tumors. Here, we evaluate the contributions of normal fibroblasts to gastric cancer.

Methodology/principal findings: By coculturing normal fibroblasts in monolayers of BGC-823 gastric cancer cells, tumor cells sporadically developed short, spindle-like morphological characteristics and demonstrated enhanced proliferation and invasive potential. Furthermore, the transformed tumor cells demonstrated decreased tumor formation and increased lymphomatic and intestinal metastatic potential. Non-transformed BGC-823 cells, in contrast, demonstrated primary tumor formation and delayed intestinal and lymph node invasion. We also observed E-cadherin loss and the upregulation of vimentin expression in the transformed tumor cells, which suggested that the increase in metastasis was induced by epithelial-to-mesenchymal transition.

Conclusion: Collectively, our data indicated that normal fibroblasts sufficiently induce epithelial-to-mesenchymal transition in cancer cells, thereby leading to metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / metabolism*
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Epithelial-Mesenchymal Transition*
  • Female
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Infant
  • Lymph Nodes / metabolism*
  • Lymph Nodes / pathology
  • Lymphatic Metastasis
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Proteins
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology

Substances

  • Cadherins
  • Neoplasm Proteins

Grants and funding

This research was supported by grants from the National Health Key Special Fund (http://program.most.gov.cn; No.200802112), the National Science Fund Committee (http://www.nsfc.gov.cn; general project No.81372302 No.81272120), the Health Department Fund (http://program.most.gov.cn; No.2007A093), the Key Project of Zhejiang Province (http://www.zjkjt.gov.cn; No.2013C030445 2009C030125). The Natural Science Fund of Zhejiang Province (http://www.zjnsf.gov.cn; No.Y2080001, Y12H160121, and Z2080514), and the Traditional Chinese Medicine Bureau Fund (http://wst.zj.gov.cn; No.2007ZA019). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.