Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion
Anisa Shaker, … , Marc S. Levin, Deborah C. Rubin
Anisa Shaker, … , Marc S. Levin, Deborah C. Rubin
Published May 10, 2010
Citation Information: J Clin Invest. 2010;120(6):2081-2093. https://doi.org/10.1172/JCI40676.
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Research Article Gastroenterology

Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion

Abstract

Epithelial-mesenchymal interactions regulate normal gut epithelial homeostasis and have a putative role in inflammatory bowel disease and colon cancer pathogenesis. Epimorphin is a mesenchymal and myofibroblast protein with antiproliferative, promorphogenic effects in intestinal epithelium. We previously showed that deletion of epimorphin partially protects mice from acute colitis, associated with an increase in crypt cell proliferation. Here we explored the potential therapeutic utility of modulating epimorphin expression by examining the effects of epimorphin deletion on chronic inflammation–associated colon carcinogenesis using the azoxymethane/dextran sodium sulfate (AOM/DSS) model. We found that mice in which epimorphin expression was absent had a marked reduction in incidence and extent of colonic dysplasia. Furthermore, epimorphin deletion in myofibroblasts altered the morphology and growth of cocultured epithelial cells. Loss of epimorphin affected secretion of soluble mesenchymal regulators of the stem cell niche such as Chordin. Importantly, IL-6 secretion from LPS-treated epimorphin-deficient myofibroblasts was completely inhibited, and stromal IL-6 expression was reduced in vivo. Taken together, these data show that epimorphin deletion inhibits chronic inflammation–associated colon carcinogenesis in mice, likely as a result of increased epithelial repair, decreased myofibroblast IL-6 secretion, and diminished IL-6–induced inflammation. Furthermore, we believe that modulation of epimorphin expression may have therapeutic benefits in appropriate clinical settings.

Authors

Anisa Shaker, Elzbieta A. Swietlicki, Lihua Wang, Shujun Jiang, Birce Onal, Shashi Bala, Katherine DeSchryver, Rodney Newberry, Marc S. Levin, Deborah C. Rubin

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Figure 1

Protection from tumorigenesis in Epim–/– mice.

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Protection from tumorigenesis in Epim–/– mice. (A) Tumor load was de...
(A) Tumor load was decreased in AOM/DSS-treated Epim–/– versus WT mice. Data are expressed as percent of total colonic surface area with tumor: WT, 14.45% (n = 11); Epim–/–, 4.96% (n = 11). (B and C) Reduced polyposis in Epim–/– compared with WT mice. (B) Polyps in WT mice coalesced together with minimal normal intervening colonic mucosa. (C) In contrast, polyps in Epim–/– mice were separated by normal mucosa, and lesions had distinct boundaries. Scale bars: 625 μm. (D) Reduced dysplastic lesion diameter in Epim–/– mice. Sections were stained with H&E, and the diameter of each area of dysplasia was measured: Epim–/–, 1,075 μm (n = 11); WT, 2,040 μm (n = 11). (E) Reduced number of dysplastic lesions per field of vision in Epim–/– mice: Epim–/–, 0.15 (n = 11); WT, 0.33 (n = 11). (F and G) H&E staining of dysplastic mucosa from WT (F) and Epim–/– (G) descending colon. Original magnification, ×200. *P < 0.05.