IL-33 activates tumor stroma to promote intestinal polyposis
Year: 2015
Type: article
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.
Institutions: University of Milan, IRCCS Policlinico San Donato, Case Comprehensive Cancer Center, University Hospitals Cleveland Medical Center, Case Western Reserve University, University of Southern California, Texas Medical Center, Baylor College of Medicine, Dan L Duncan Comprehensive Cancer Center
Language: English
Topic: IL-33, ST2, and ILC Pathways
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: Crohn's and Colitis Foundation, National Institutes of Health, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1081826082, G1147702603, G1201304535, G2320528803, G2538640567, G356341971, G4091526950, Role of IL-18 in Crohn's Disease (CD), G5136147547, G5465708471, G5716778331, G579812685, G6871967381, G806902274, Clinical and Translational Science Collaborative of Cleveland, G857943612, Case GI SPORE, G9000227542, G9000284690, The Cleveland Digestive Diseases Research Core Center (DDRCC), Baylor College of Medicine Cancer Center - Cancer Center Support Grant
OpenAlex ID: W2097745561