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The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice

Mertz, Kirsten D. and Mager, Lukas and Wasmer, Marie-Helene and Thiesler, Thore and Koelzer, Viktor H. and Ruzzante, Giulia and Joller, Stefanie and Murdoch, Jenna R. and Bruemmendorf, Thomas and Genitsch, Vera and Lugli, Alessandro and Cathomas, Gieri and Moch, Holger and Weber, Achim and Zlobec, Inti and Junt, Tobias and Krebs, Philippe (2015) The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice. Oncoimmunology.

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 overexpressed in low-grade and early-stage human CRCs, but not in higher-grade and more advanced-stage tumors. In a mouse model of CRC, ST2-deficiency protects from tumor development. Moreover, bone marrow 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, these data reveal an essential role of IL-33/ST2 signaling for early CRC. They also suggest that therapeutic blockade of the IL-33/ST2 axis might halt CRC progression in its earliest stages.

Item Type: Article
Keywords: IL-33, Colon cancer
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11
URI: https://oak.novartis.com/id/eprint/24534

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