Abstract
Chronic inflammation is a risk factor for several different cancers including colorectal cancer (CRC). However, the mechanisms underlying the contribution of inflammation to cancer remain elusive. Pro-inflammatory mediators such as cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) contribute to cancer progression. Here, we show that COX-2 is an immediate-early response gene induced by growth factors and pro-inflammatory cytokines and its levels are elevated in human CRCs. Furthermore, we show that COX-2-derived PGE2 promotes colonic tumor growth via silencing certain tumor suppressors and DNA repair genes by DNA methylation in colonic epithelial tumor cells. We also report that C-X-C motif chemokine receptor 2 accelerates colonic inflammation and colitis-associated tumorigenesis by mediating myeloid-derived suppressor cell recruitment to the tumor microenvironment. These findings not only support a rationale to target these pro-inflammatory pathways for cancer prevention and treatment but also provide support for developing new therapeutic approaches to subvert chronic inflammation- and tumor-induced immunosuppression.
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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Adenoma / genetics
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Adenoma / immunology
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Adenoma / metabolism*
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Adenoma / pathology
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Animals
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Azoxymethane
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Colitis / chemically induced
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Colitis / genetics
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Colitis / immunology
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Colitis / metabolism*
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Colitis / pathology
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Colitis / prevention & control
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Colon / immunology
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Colon / metabolism*
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Colon / pathology
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / immunology
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Colorectal Neoplasms / metabolism*
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Colorectal Neoplasms / pathology
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Colorectal Neoplasms / prevention & control
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Cyclooxygenase 2 / metabolism
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Dextran Sulfate
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Dinoprostone / metabolism
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Disease Models, Animal
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Genes, APC
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Humans
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Inflammation Mediators / immunology
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Inflammation Mediators / metabolism*
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Intestinal Mucosa / immunology
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Intestinal Mucosa / metabolism*
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Intestinal Mucosa / pathology
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Mice, Inbred BALB C
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Mice, Knockout
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Rats
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Receptors, Interleukin-8B / deficiency
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Receptors, Interleukin-8B / genetics
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Receptors, Interleukin-8B / metabolism
Substances
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Inflammation Mediators
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Receptors, Interleukin-8B
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Dextran Sulfate
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Cyclooxygenase 2
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PTGS2 protein, human
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Ptgs2 protein, rat
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Dinoprostone
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Azoxymethane