Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia

Cancer Cell. 2014 May 12;25(5):621-37. doi: 10.1016/j.ccr.2014.03.014.

Abstract

Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we found that Kras(G12D) induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional in vivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.

Publication types

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

MeSH terms

  • Animals
  • Carcinoma in Situ / genetics
  • Carcinoma in Situ / metabolism
  • Carcinoma in Situ / prevention & control
  • Cell Transformation, Neoplastic
  • Chemoprevention
  • Epithelial Cells / metabolism*
  • Hematopoietic System / cytology
  • Hematopoietic System / metabolism*
  • Humans
  • Inflammation
  • Interleukin-17 / antagonists & inhibitors
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • Mice
  • Mice, Transgenic
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / prevention & control
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Receptors, Antigen, T-Cell, gamma-delta / biosynthesis
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • Receptors, Interleukin-17 / biosynthesis
  • Receptors, Interleukin-17 / metabolism
  • Signal Transduction / genetics
  • Th17 Cells / immunology

Substances

  • Il17a protein, mouse
  • Interleukin-17
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Interleukin-17
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)

Associated data

  • GEO/GSE54753