Reference SummaryMaywald RL, Proc Natl Acad Sci U S A 2015 May 12;112(19):E2487-96

Title

IL-33 activates tumor stroma to promote intestinal polyposis.

Authors

Maywald RL; Doerner SK; Pastorelli L; De Salvo C; Benton SM; Dawson EP; Lanza DG; Berger NA; Markowitz SD; Lenz HJ; Nadeau JH; Pizarro TT; Heaney JD

Journal

Proc Natl Acad Sci U S A

Volume

112

Issue

19

Year

2015

Pages

E2487-96

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.

Links

J:221412 – MGI References
25918379 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6J-ApcMin/+ Intestine adenoma Intestine

observed

C57BL/6J-ApcMin/+ Intestine polyp Intestine

observed

C57BL/6J Intestine polyp Intestine

observed

C57BL/6J-ApcMin/+ Intestine polyp
  • anti-IL1RL1 (mu-IgG1-FC–anti-muST2, Amgen)
Intestine

observed

C57BL/6J-ApcMin/+ Intestine polyp
  • anti-IgG (4D2-mu-IgG1–anti-huAGP3-Pb, Amgen)
Intestine

observed

C57BL/6-ApcMin/+ Il33tm1.1(KOMP)Vlcg Intestine polyp Intestine

observed

C57BL/6-ApcMin/+ Il33tm1.1(KOMP)Vlcg/+ Intestine polyp Intestine

100

C57BL/6-ApcMin/+ Intestine polyp Intestine

100

C57BL/6J-ApcMin/+ Intestine polyp - adenomatous Intestine

observed

C57BL/6J-ApcMin/+ Intestine tumor Intestine

observed

C57BL/6J Intestine tumor Intestine

observed

C57BL/6-ApcMin/+ Il33tm1.1(KOMP)Vlcg Intestine tumor Intestine

observed

C57BL/6-ApcMin/+ Il33tm1.1(KOMP)Vlcg/+ Intestine tumor Intestine

observed

C57BL/6-ApcMin/+ Intestine tumor Intestine

observed

C57BL/6J-ApcMin/+ Intestine tumor
  • anti-IL1RL1 (mu-IgG1-FC–anti-muST2, Amgen)
Intestine

observed

C57BL/6J-ApcMin/+ Intestine tumor
  • anti-IgG (4D2-mu-IgG1–anti-huAGP3-Pb, Amgen)
Intestine

observed