Molecular mechanisms of IL-33-mediated stromal interactions in cancer metastasis

JCI Insight. 2018 Oct 18;3(20):e122375. doi: 10.1172/jci.insight.122375.

Abstract

Molecular mechanisms underlying the cancer stroma in metastasis need further exploration. Here, we discovered that cancer-associated fibroblasts (CAFs) produced high levels of IL-33 that acted on tumor-associated macrophages (TAMs), causing them to undergo the M1 to M2 transition. Genomic profiling of metastasis-related genes in the IL-33-stimulated TAMs showed a >200-fold increase of MMP9. Signaling analysis demonstrated the IL-33-ST2-NF-κB-MMP9-laminin pathway that governed tumor stroma-mediated metastasis. In mouse and human fibroblast-rich pancreatic cancers, genetic deletion of IL-33, ST2, or MMP9 markedly blocked metastasis. Pharmacological inhibition of NF-κB and MMP9 also blocked cancer metastasis. Deletion of IL-33, ST2, or MMP9 restored laminin, a key basement membrane component associated with tumor microvessels. Together, our data provide mechanistic insights on the IL-33-NF-κB-MMP9-laminin axis that mediates the CAF-TAM-committed cancer metastasis. Thus, targeting the CAF-TAM-vessel axis provides an outstanding therapeutic opportunity for cancer treatment.

Keywords: Cancer; Cell Biology; Macrophages; Oncology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cancer-Associated Fibroblasts / immunology
  • Cancer-Associated Fibroblasts / metabolism
  • Cell Communication / immunology
  • Cell Line, Tumor
  • Female
  • Gene Expression Profiling
  • Humans
  • Interleukin-1 Receptor-Like 1 Protein / genetics
  • Interleukin-1 Receptor-Like 1 Protein / metabolism
  • Interleukin-33 / genetics
  • Interleukin-33 / immunology
  • Interleukin-33 / metabolism*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Mice
  • Mice, Knockout
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Signal Transduction / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology*
  • Xenograft Model Antitumor Assays

Substances

  • IL1RL1 protein, human
  • IL33 protein, human
  • Il1rl1 protein, mouse
  • Il33 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Matrix Metalloproteinase Inhibitors
  • NF-kappa B
  • MMP9 protein, human
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse

Grants and funding

Dr.Yunlong Yang