Abstract
The protein kinase p38α plays a key role in cell homeostasis, and p38α signaling in intestinal epithelial cells protects against colitis‐induced tumorigenesis. However, little is known on the contribution of p38α signaling in intestinal stromal cells. Here, we show that myeloid cell‐specific downregulation of p38α protects mice against inflammation‐associated colon tumorigenesis. The reduced tumorigenesis correlates with impaired detection in the colon of crucial chemokines for immune cell recruitment. We identify insulin‐like growth factor‐1 (IGF‐1) as a novel mediator of the p38α pathway in macrophages. Moreover, using genetic and pharmacological approaches, we confirm the implication of IGF‐1 produced by myeloid cells in colon inflammation and tumorigenesis. We also show a correlation between IGF‐1 pathway activation and the infiltration of myeloid cells with active p38α in colon samples from patients with ulcerative colitis or colon cancer. Altogether, our results uncover an important role for myeloid IGF‐1 downstream of p38α in colitis‐associated tumorigenesis and suggest the interest in evaluating IGF‐1 therapies for inflammation‐associated intestinal diseases, taking into consideration IGF‐1 signaling and immune cell infiltration in patient biopsies.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related mortality
We have identified insulin-like growth factor-1 (IGF-1) as a novel mediator of p38a signaling in macrophages and showed that IGF-1 produced by myeloid cells contributes to pathological progression of CAC
The liver is the major source of circulating IGF-1, but this molecule can be produced locally and macrophages have been proposed as an important source of extrahepatic IGF-1 (Gow et al, 2010), which is consistent with our results showing downregulation of IGF-1 signaling in the intestines of IGF1-DMC mice
Summary
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related mortality. The equilibrium between immune activation and suppression (intestinal tolerance) is marked by a situation of controlled “physiological inflammation”, where distinct populations of resident and inflammatory macrophages in the gut maintain a balance and ensure protective immunity when required (Fiocchi, 2008; Mowat & Bain, 2011). Deregulation of this equilibrium, as it happens in IBD, implicates an imbalance between pro- and anti-inflammatory cytokines, impeding the resolution of inflammation and leading to disease perpetuation and tissue destruction (Neurath, 2014). Cytokines play an important role in the repair of the intestinal epithelia, but have been implicated in tumor promotion (Schneider et al, 2017)
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