Mertz, Kirsten D; Mager, Lukas F.; Wasmer, Marie-Hélène; Thiesler, Thore; Kölzer, Viktor H.; Ruzzante, Giulia; Joller, Stefanie; Murdoch, Jenna R; Brümmendorf, Thomas; Genitsch Gratwohl, Vera; Lugli, Alessandro; Cathomas, Gieri; Moch, Holger; Weber, Achim; Zlobec, Inti; Junt, Tobias; Krebs, Philippe (2016). The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice. Oncoimmunology, 5(1), e1062966. Landes Bioscience 10.1080/2162402X.2015.1062966
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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.
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