IL-33 activates tumor stroma to promote intestinal polyposis

Proc Natl Acad Sci U S A. 2015 May 12;112(19):E2487-96. doi: 10.1073/pnas.1422445112. Epub 2015 Apr 27.

Abstract

Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in the Apc(Min/+) mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL-33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, in Apc(Min/+) polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation in Apc(Min/+) polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment.

Keywords: ApcMin; IL-33; Th2 immunity; colorectal cancer; wound healing.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Cell Proliferation
  • Colonic Neoplasms / metabolism*
  • Colonic Polyps / metabolism
  • Colorectal Neoplasms / metabolism*
  • Epithelial Cells / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interleukin-33
  • Interleukins / metabolism*
  • Intestinal Polyposis / metabolism*
  • Mast Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myofibroblasts / metabolism
  • Neovascularization, Pathologic
  • Oligonucleotide Array Sequence Analysis
  • Signal Transduction
  • Th2 Cells / metabolism
  • Transcriptome
  • Wound Healing

Substances

  • IL33 protein, human
  • Il33 protein, mouse
  • Interleukin-33
  • Interleukins