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The Role of Chronic Inflammation in the Promotion of Gastric Tumourigenesis

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Chronic Inflammation

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Abstract

Cyclooxigenase-2 (COX-2) is an inducible enzyme for prostaglandin biosynthesis which plays a key role in inflammatory responses. The expression of COX-2 is induced in most cancer tissues, and plays a key role in tumourigenesis through the production of inflammatory mediator, prostaglandin E2 (PGE2). We investigated the role of COX-2/PGE2 pathway-associated inflammation in gastric tumourigenesis using Gan mice, which develop gastric tumours through the activation of both the COX-2/PGE2 pathway and oncogenic Wnt signalling. Notably, the induction of the COX-2/PGE2 pathway induces chronic inflammation in the stomach, which leads to the generation of the inflammatory tumour microenvironment. We found that macrophage-derived tumour necrosis factor-α (TNF-α) hyperactivates the Wnt activation level of the adjacent tumour epithelial cells. Wnt signalling is important for the maintenance of stemness in gastrointestinal stem cells, and activation of Wnt signalling causes tumour formation. Moreover, TNF-α induces the expression of Noxo1 in tumour cells (a component of the NADPH oxidase 1 [NOX1] complex), resulting in the activation of reactive oxygen species (ROS) signalling. NOX1-derived ROS have been shown to be important for cancer stem cell ability. Accordingly, in tumour tissues, the COX-2/PGE2 pathway promotes gastric tumourigenesis through the generation of the inflammatory microenvironment; where TNF-α activates the NOX1 complex in tumour cells, resulting in the maintenance of stemness. Thus the inhibition of the inflammatory pathways from COX-2/PGE2 to NOX1/ROS will be an effective strategy for preventing gastric cancer development.

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Authors and Affiliations

  1. Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, 920-1192, Japan

    Hiroko Oshima, Kanae Echizen, Yusuke Maeda & Masanobu Oshima

  2. AMED-CREST, Kanazawa, 920-1192, Japan

    Kanae Echizen & Masanobu Oshima

  3. Division of Gene Regulation, Institute for Advanced Medical Research, Keio University, Tokyo, 160-8582, Japan

    Yusuke Maeda

Authors
  1. Hiroko Oshima
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  2. Kanae Echizen
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  3. Yusuke Maeda
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  4. Masanobu Oshima
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Correspondence to Masanobu Oshima .

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Editors and Affiliations

  1. Interdisciplinary Program for Biomedical Sciences Institute for Academic Initiatives, Osaka University, Suita, Japan

    Masayuki Miyasaka

  2. Department of Immunobiology and Pharmacological Genetics Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Kiyoshi Takatsu

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Oshima, H., Echizen, K., Maeda, Y., Oshima, M. (2016). The Role of Chronic Inflammation in the Promotion of Gastric Tumourigenesis. In: Miyasaka, M., Takatsu, K. (eds) Chronic Inflammation. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56068-5_14

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