title: The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice.
abstract: Colorectal cancer (CRC) develops through a multistep process and is modulated by inflammation. However, the inflammatory pathways that support intestinal tumors at different stages remain incompletely understood. Interleukin (IL)-33 signaling plays a role in intestinal inflammation, yet its contribution to the pathogenesis of CRC is unknown. Using immunohistochemistry on 713 resected human CRC specimens, we show here that IL-33 and its receptor ST2 are expressed in low-grade and early-stage human CRCs, and to a lesser extent in higher-grade and more advanced-stage tumors. In a mouse model of CRC, ST2-deficiency protects from tumor development. Moreover, bone marrow (BM) chimera studies indicate that engagement of the IL-33/ST2 pathway on both the radio-resistant and radio-sensitive compartment is essential for CRC development. Mechanistically, activation of IL-33/ST2 signaling compromises the integrity of the intestinal barrier and triggers the production of pro-tumorigenic IL-6 by immune cells. Together, this data reveals a tumor-promoting role of IL-33/ST2 signaling in CRC.
authors.affiliation: Institute of Pathology, Cantonal Hospital Baselland , Liestal, Switzerland.
authors.forename: Kirsten D
authors.initials: KD
authors.lastname: Mertz
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Lukas F
authors.initials: LF
authors.lastname: Mager
authors.affiliation: Institute of Pathology, University of Bern , Bern, Switzerland.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Wasmer
authors.affiliation: Institute of Pathology, University Hospital Bonn , Bonn, Germany.
authors.forename: Thore
authors.initials: T
authors.lastname: Thiesler
authors.affiliation: Institute of Pathology, University of Bern , Bern, Switzerland.
authors.forename: Viktor H
authors.initials: VH
authors.lastname: Koelzer
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG , Basel, Switzerland.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ruzzante
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG , Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Joller
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG , Basel, Switzerland.
authors.forename: Jenna R
authors.initials: JR
authors.lastname: Murdoch
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG , Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brümmendorf
authors.affiliation: Institute of Pathology, University of Bern , Bern, Switzerland.
authors.forename: Vera
authors.initials: V
authors.lastname: Genitsch
authors.affiliation: Institute of Pathology, University of Bern , Bern, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
authors.affiliation: Institute of Pathology, Cantonal Hospital Baselland , Liestal, Switzerland.
authors.forename: Gieri
authors.initials: G
authors.lastname: Cathomas
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich , Zurich, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich , Zurich, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institute of Pathology, University of Bern , Bern, Switzerland.
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG , Basel, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Junt
authors.affiliation: Institute of Pathology, University of Bern , Bern, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Krebs
keywords: Colorectal cancer; IL-33; ST2; inflammation; mouse model; tissue microarray; tumor microenvironment