IL-33 activates tumor stroma to promote intestinal polyposis.
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.
Department of Molecular and Human Genetics.
Rebecca L
RL
Maywald
Departments of Genetics and Genome Sciences.
Stephanie K
SK
Doerner
Pathology, Department of Biomedical Sciences for Health, University of Milan, Milan 20133, Italy; Gastroenterology and Gastrointestinal Endoscopy Unit, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato, San Donato Milanese 20097, Italy;
Luca
L
Pastorelli
Pathology.
Carlo
C
De Salvo
Department of Molecular and Human Genetics.
Susan M
SM
Benton
Department of Molecular and Human Genetics.
Emily P
EP
Dawson
Department of Molecular and Human Genetics.
Denise G
DG
Lanza
Departments of Genetics and Genome Sciences, Biochemistry, and Center for Science, Health and Society, Case Comprehensive Cancer Center, and.
Nathan A
NA
Berger
Case Comprehensive Cancer Center, and Medicine, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
Sanford D
SD
Markowitz
Division of Medical Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
Heinz-Josef
HJ
Lenz
Pacific Northwest Research Institute, Seattle, WA 98122; and.
Joseph H
JH
Nadeau
Pathology.
Theresa T
TT
Pizarro
Department of Molecular and Human Genetics, Dan L. Duncan Cancer Center, and Texas Medical Center Digestive Diseases Center, Baylor College of Medicine, Houston, TX 77030; heaney@bcm.edu.
Jason D
JD
Heaney
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism*; D003111:Colonic Polyps / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D044483:Intestinal Polyposis / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D018418:Th2 Cells / Q000378:metabolism; D059467:Transcriptome; D014945:Wound Healing
C506536:IL33 protein, human; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins
ApcMin; IL-33; Th2 immunity; colorectal cancer; wound healing