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The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer.

ABSTRACT: Chronic inflammation is a risk factor for colon cancer (CC). Lysophosphatidic acid (LPA), a naturally produced phospholipid, mediates multiple effects that are vital to disease process, including inflammation and cancer. The expression of LPA receptor 2 (LPA2) is up-regulated in several types of cancer, including ovarian and colon cancer, but the importance of LPA and LPA2 in the development and progression of CC is unclear. In this study, we sought to determine whether LPA and LPA2 regulate the progression of CC in vivo.We examined the potential role of LPA in CC progression by administering LPA to mice heterozygous for the adenomatous polyposis coli (Apc) allele. We determined the loss of LPA2 function in tumorigenesis in the colon by treating mice with genetic deletion of LPA2 (LPA2-/-) with azoxymethane and dextran sulfate sodium.We found that LPA increased tumor incidence in Apc(min/+) mice. LPA2-/- mice showed reduced mucosal damage and fewer tumors than wild-type (WT) mice. Reduced epithelial cell proliferation and decreases in beta-catenin, Krüppel-like factor 5, and cyclooxygenase-2 expression were observed in LPA2-/- mice. Unlike WT mice, induction of monocyte chemoattractant protein-1 and macrophage migration inhibitory factor was significantly attenuated in LPA2-/- mice with reduced infiltration by macrophages.These results show that LPA is capable of promoting tumorigenesis in the colon. The absence of LPA2 attenuates several effects that contribute to cancer progression in vivo, and, hence, the current study identifies LPA2 as an important modulator of CC.

SUBMITTER: Lin S

PROVIDER: S-EPMC2691721 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer.

Lin Songbai S Wang Dongsheng D Iyer Smita S Ghaleb Amr M AM Shim Hyunsuk H Yang Vincent W VW Chun Jerold J Yun C Chris CC

Gastroenterology 20090109 5

<h4>Background & aims</h4>Chronic inflammation is a risk factor for colon cancer (CC). Lysophosphatidic acid (LPA), a naturally produced phospholipid, mediates multiple effects that are vital to disease process, including inflammation and cancer. The expression of LPA receptor 2 (LPA2) is up-regulated in several types of cancer, including ovarian and colon cancer, but the importance of LPA and LPA2 in the development and progression of CC is unclear. In this study, we sought to determine whether ...[more]

PMID: 19328876

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Project description:The endoribonuclease RNase-L is a type-I interferon (IFN)-regulated component of the innate immune response that functions in antiviral, antibacterial, and antiproliferative activities. RNase-L produces RNA agonists of RIG-I-like receptors, sensors of cytosolic pathogen-associated RNAs that induce cytokines including IFN-?. IFN-? and RIG-I-like receptors signaling mediate protective responses against experimental colitis and colitis-associated cancer and contribute to gastrointestinal homeostasis. Therefore, we investigated a role for RNase-L in murine colitis and colitis-associated cancer and its association with RIG-I-like receptors signaling in response to bacterial RNA.Colitis was induced in wild type-deficient and RNase-L-deficient mice (RNase-L?/?) by administration of dextran sulfate sodium (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM). Histological analysis and immunohistochemistry were performed on colon tissue to analyze immune cell infiltration and tissue damage after induction of colitis. Expression of cytokines was measured by quantitative real-time-PCR and ELISA.DSS-treated RNase-L?/? mice exhibited a significantly higher clinical score, delayed leukocyte infiltration, reduced expression of IFN-?, tumor necrosis factor ?, interleukin-1?, and interleukin-18 at early times post-DSS exposure, and increased mortality as compared with wild-type mice. DSS/AOM-treated RNase-L?/? mice displayed an increased tumor burden. Bacterial RNA triggered IFN-? production in an RNase-L-dependent manner and provided a potential mechanism by which RNase-L contributes to the gastrointestinal immune response to microbiota and protects against experimental colitis and colitis-associated cancer.RNase-L promotes the innate immune response to intestinal damage and ameliorates murine colitis and colitis-associated cancer. The RNase-L-dependent production of IFN-? stimulated by bacterial RNA may be a mechanism to protect against gastrointestinal inflammatory disease.

Project description:ObjectiveEosinophils reside in the colonic mucosa and increase significantly during disease. Although a number of studies have suggested that eosinophils contribute to the pathogenesis of GI inflammation, the expanding scope of eosinophil-mediated activities indicate that they also regulate local immune responses and modulate tissue inflammation. We sought to define the impact of eosinophils that respond to acute phases of colitis in mice.DesignAcute colitis was induced in mice by administration of dextran sulfate sodium, 2,4,6-trinitrobenzenesulfonic acid or oxazolone to C57BL/6J (control) or eosinophil deficient (PHIL) mice. Eosinophils were also depleted from mice using antibodies against interleukin (IL)-5 or by grafting bone marrow from PHIL mice into control mice. Colon tissues were collected and analysed by immunohistochemistry, flow cytometry and reverse transcription PCR; lipids were analysed by mass spectroscopy.ResultsEosinophil-deficient mice developed significantly more severe colitis, and their colon tissues contained a greater number of neutrophils, than controls. This compensatory increase in neutrophils was accompanied by increased levels of the chemokines CXCL1 and CXCL2, which attract neutrophils. Lipidomic analyses of colonic tissue from eosinophil-deficient mice identified a deficiency in the docosahexaenoic acid-derived anti-inflammatory mediator 10, 17- dihydroxydocosahexaenoic acid (diHDoHE), namely protectin D1 (PD1). Administration of an exogenous PD1-isomer (10S, 17S-DiHDoHE) reduced the severity of colitis in eosinophil-deficient mice. The PD1-isomer also attenuated neutrophil infiltration and reduced levels of tumour necrosis factor-α, IL-1β, IL-6 and inducible NO-synthase in colons of mice. Finally, in vitro assays identified a direct inhibitory effect of PD1-isomer on neutrophil transepithelial migration.ConclusionsEosinophils exert a protective effect in acute mouse colitis, via production of anti-inflammatory lipid mediators.

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The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer.

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The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer.

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