Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers

Oncol Res. 2019 Jun 21;27(6):713-727. doi: 10.3727/096504018X15433161908259. Epub 2019 Mar 8.

Abstract

The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE+ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11-RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE-MyD88-mTOR-p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.

MeSH terms

  • Animals
  • Cancer-Associated Fibroblasts / metabolism
  • Cancer-Associated Fibroblasts / pathology
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Extracellular Space / metabolism
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Immunohistochemistry
  • Mice
  • Models, Biological
  • Myeloid Differentiation Factor 88 / metabolism
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Receptor for Advanced Glycation End Products / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • S100 Proteins / metabolism*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Microenvironment

Substances

  • AGER protein, human
  • Myeloid Differentiation Factor 88
  • Receptor for Advanced Glycation End Products
  • S100 Proteins
  • S100A11 protein, human
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa