Abstract
Gut-associated inflammation plays a crucial role in the progression of colon cancer. Here, we identify a novel pathogen-host interaction that promotes gut inflammation and the development of colon cancer. We find that enteropathogenic bacteria-secreted particles (ET-BSPs) stimulate intestinal epithelium to produce IDENs (intestinal mucosa-derived exosome-like nanoparticles) containing elevated levels of sphingosine-1-phosphate, CCL20 and prostaglandin E2 (PGE2). CCL20 and PGE2 are required for the recruitment and proliferation, respectively, of Th17 cells, and these processes also involve the MyD88-mediated pathway. By influencing the recruitment and proliferation of Th17 cells in the intestine, IDENs promote colon cancer. We demonstrate the biological effect of sphingosine-1-phosphate contained in IDENs on tumour growth in spontaneous and transplanted colon cancer mouse models. These findings provide deeper insights into how host-microbe relationships are mediated by particles secreted from both bacterial and host cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / etiology
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Adenocarcinoma / immunology*
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Adenocarcinoma / pathology
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Animals
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Azoxymethane / toxicity
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Bacteroides fragilis / immunology*
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Bacteroides fragilis / metabolism
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Blotting, Western
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Carcinogenesis / immunology*
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Carcinogens / toxicity
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Cell Line, Tumor
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Cell Proliferation
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Chemokine CCL20 / genetics
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Chemokine CCL20 / immunology
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Colitis / chemically induced
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Colitis / complications
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Colitis / immunology*
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Colonic Neoplasms / etiology
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Colonic Neoplasms / immunology*
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Colonic Neoplasms / pathology
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Dextran Sulfate / toxicity
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Dinoprostone / genetics
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Dinoprostone / immunology
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Disease Models, Animal
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Enterobacteriaceae / immunology*
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Enterobacteriaceae / metabolism
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Exosomes / immunology*
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Immunohistochemistry
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In Situ Hybridization, Fluorescence
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Inflammation
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Intestinal Mucosa / immunology*
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Lysophospholipids / immunology*
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Mice
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / immunology
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Nanoparticles
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Neoplasm Transplantation
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Reverse Transcriptase Polymerase Chain Reaction
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Sphingosine / analogs & derivatives*
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Sphingosine / immunology
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Th17 Cells / immunology*
Substances
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CCL20 protein, mouse
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Carcinogens
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Chemokine CCL20
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Lysophospholipids
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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sphingosine 1-phosphate
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Dextran Sulfate
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Dinoprostone
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Azoxymethane
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Sphingosine