Tumour-derived Interleukin 35 promotes pancreatic ductal adenocarcinoma cell extravasation and metastasis by inducing ICAM1 expression

Nat Commun. 2017 Jan 19;8:14035. doi: 10.1038/ncomms14035.

Abstract

Interleukin 35 (IL-35) is a novel member of the IL-12 family, consisting of an EBV-induced gene 3 (EBI3) subunit and a P35 subunit. IL-35 is an immune-suppressive cytokine mainly produced by regulatory T cells. However, the role of IL-35 in cancer metastasis and progression is not well understood. Here we demonstrate that IL-35 is overexpressed in human pancreatic ductal adenocarcinoma (PDAC) tissues, and that IL-35 overexpression is associated with poor prognosis in PDAC patients. IL-35 has critical roles in PDAC cell extravasation and metastasis by facilitating the adhesion to endothelial cells and transendothelial extravasation. Mechanistically, IL-35 promotes ICAM1 overexpression through a GP130-STAT1 signalling pathway, which facilitates endothelial adhesion and transendothelial migration via an ICAM1-fibrinogen-ICAM1 bridge. In an orthotopic xenograft model, IL-35 promotes spontaneous pancreatic cancer metastasis in an ICAM1-dependent manner. Together, our results indicate additional functions of IL-35 in promoting PDAC metastasis through mediating ICAM1 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology*
  • Animals
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Gene Expression Regulation, Neoplastic / physiology*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Mice
  • Mice, SCID
  • Neoplasm Metastasis / physiopathology
  • Neoplasms, Experimental
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Up-Regulation

Substances

  • ICAM1 protein, human
  • Icam1 protein, mouse
  • Interleukins
  • interleukin-35, human
  • interleukin-35, mouse
  • Intercellular Adhesion Molecule-1

Supplementary concepts

  • Pancreatic Carcinoma