ZIA BC 010793 (ZIA) | |||
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Title | Role of inflammation, innate resistance, and immunity in carcinogenesis | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Trinchieri, Giorgio | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $716,912 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (20.0%) Cancer (100.0%) Digestive Diseases (50.0%) Inflammatory Bowel Disease (20.0%) Interferon (20.0%) |
Colon/Rectum (50.0%) Lung (5.0%) |
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Research Type | |||
Exogenous Factors in the Origin and Cause of Cancer Endogenous Factors in the Origin and Cause of Cancer |
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Abstract | |||
Progress has been made in several of the aims of the project. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Chronic inflammation drives liver cancer pathogenesis, invasion, and metastasis. Liver Kupffer cells have crucial roles in mediating the inflammatory processes that promote liver cancer, but the mechanistic basis for their contributions are not fully understood. In collaboration with Anatolij Horuzsko, Georgia Health Sciences University we found that the TREM1 innate receptor control Kuppfer cell activation and development of hepatocellular carcinoma in the diethylnitrosamine (DEN) model. We recently reported that TREM1 is also a master activator of Kuppfer cells regulating inflammation, liver injury and fibrinogenesis in a mouse model of chronic liver injury induced by CCl4. In collaboration with Tim Greten, CCR, we performed microbiota analysis and gnotobiotic experiments to support the finding that altering commensal gut bacteria in mice induces a liver-selective antitumor effect, with an increase of hepatic CXCR6+ natural killer T (NKT) cells and heightened IFN-gamma production. In vivo studies showed that NKT cells mediated liver-selective tumor inhibition. NKT cell accumulation was regulated by CXCL16 expression in liver sinusoidal endothelial cells, which was controlled by gut microbiome-mediated primary-to-secondary bile acid conversion. A very extensive investigation has been initiated to study the role of inflammatory receptors and cytokines in skin and colon chemical carcinogenesis. Signaling through the adaptor protein MyD88 promotes carcinogenesis in several cancer models. In contrast, MyD88 signaling has a protective role in the development of azoxymethane (AOM)/ dextran sodium sulfate (DSS) colitis-associated cancer (CAC). The inability of Myd88-/- mice to heal ulcers generated upon injury creates an altered inflammatory environment that induces early alterations in expression of genes encoding pro-inflammatory factors as well as pathways regulating cell proliferation, apoptosis, and DNA repair resulting in a dramatic increase in adenoma formation and progression to infiltrating adenocarcinomas with frequent clonal mutations in the beta-catenin gene. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that impact tissue homeostasis and carcinogenesis. IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis (J Exp Med. 2012;209:1689-702 ). Constitutively active RAS plays a central role in the development of human cancer and is sufficient to induce tumors in two-stage skin carcinogenesis. RAS-mediated tumor formation is commonly associated with up-regulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. In this study, we reported that mice lacking IL-1R or MyD88 are less sensitive to topical skin carcinogenesis than their respective wild-type (WT) controls. MyD88(-/-) or IL-1R(-/-) keratinocytes expressing oncogenic RAS are hyperproliferative and fail to up-regulate proinflammatory genes or down-regulate differentiation markers characteristic of RAS-expressing WT keratinocytes. Although RAS-expressing MyD88(-/-) keratinocytes form only a few small tumors in orthotopic grafts, IL-1R-deficient RAS-expressing keratinocytes retain the ability to form tumors in orthotopic grafts. Using both genetic and pharmacological approaches, we find that the differentiation and proinflammatory effects of oncogenic RAS in keratinocytes require the establishment of an autocrine loop through IL-1alpha, IL-1R, and MyD88 leading to phosphorylation of IkBalpha and NF-kB activation. Blocking IL-1alpha-mediated NF-kB activation in RAS-expressing WT keratinocytes reverses the differentiation defect and inhibits proinflammatory gene expression. Collectively, these results demonstrate that MyD88 exerts a cell-intri |