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Cell Stem Cell. 2016 Jul 7;19(1):38-51. doi: 10.1016/j.stem.2016.05.023. Epub 2016 Jun 9.

Secreted Phospholipases A2 Are Intestinal Stem Cell Niche Factors with Distinct Roles in Homeostasis, Inflammation, and Cancer.

Author information

1
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands.
2
Department of Urology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands.
3
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands; Erasmus Optical Imaging Centre, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands.
4
Institute of Molecular and Cellular Pharmacology, Centre National de la Recherche Scientifique and University of Nice Sophia Antipolis, Valbonne 06560, France.
5
Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, MN 55812-3031, USA.
6
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40506-9983, USA.
7
Department of Chemistry, University of Washington, Seattle, WA 98195-1700, USA.
8
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam 3000CA, The Netherlands. Electronic address: r.fodde@erasmusmc.nl.

Abstract

The intestinal stem cell niche provides cues that actively maintain gut homeostasis. Dysregulation of these cues may compromise intestinal regeneration upon tissue insult and/or promote tumor growth. Here, we identify secreted phospholipases A2 (sPLA2s) as stem cell niche factors with context-dependent functions in the digestive tract. We show that group IIA sPLA2, a known genetic modifier of mouse intestinal tumorigenesis, is expressed by Paneth cells in the small intestine, while group X sPLA2 is expressed by Paneth/goblet-like cells in the colon. During homeostasis, group IIA/X sPLA2s inhibit Wnt signaling through intracellular activation of Yap1. However, upon inflammation they are secreted into the intestinal lumen, where they promote prostaglandin synthesis and Wnt signaling. Genetic ablation of both sPLA2s improves recovery from inflammation but increases colon cancer susceptibility due to release of their homeostatic Wnt-inhibitory role. This "trade-off" effect suggests sPLA2s have important functions as genetic modifiers of inflammation and colon cancer.

PMID:
27292189
DOI:
10.1016/j.stem.2016.05.023
[Indexed for MEDLINE]
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