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      Deletion of macrophage migration inhibitory factor inhibits murine oral carcinogenesis: Potential role for chronic pro-inflammatory immune mediators : Deletion of MIF inhibits murine oral carcinogenesis

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          Abstract

          <p class="first" id="P1">Oral cancer kills about 1 person every hour, each day in the United States and is the 6 <sup>th</sup> most prevalent cancer worldwide. The pro-inflammatory cytokine ‘macrophage migration inhibitory factor’ (MIF) has been shown to be expressed in oral cancer patients, yet its precise role in oral carcinogenesis is not clear. In this study, we examined the impact of global <i>Mif</i> deletion on the cellular and molecular process occurring during oral carcinogenesis using a well-established mouse model of oral cancer with the carcinogen 4-nitroquinoline-1-oxide (4NQO). C57BL/6 Wild-type (WT) and <i>Mif</i> knock-out mice were administered with 4NQO in drinking water for 16 weeks, then regular drinking water for 8 weeks. <i>Mif</i> knock-out mice displayed fewer oral tumor incidence and multiplicity, accompanied by a significant reduction in the expression of pro-inflammatory cytokines <i>Il-1β</i>, <i>Tnf-α</i>, chemokines <i>Cxcl1</i>, <i>Cxcl6</i> and <i>Ccl3</i> and other molecular biomarkers of oral carcinogenesis <i>Mmp1</i> and <i>Ptgs2</i>. Further, systemic accumulation of myeloid-derived tumor promoting immune cells was inhibited in <i>Mif</i> knock-out mice. Our results demonstrate that genetic <i>Mif</i> deletion reduces the incidence and severity of oral carcinogenesis, by inhibiting the expression of chronic pro-inflammatory immune mediators. Thus, targeting MIF is a promising strategy for the prevention or therapy of oral cancer. </p>

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          Most cited references 39

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          Myeloid-derived suppressor cells: linking inflammation and cancer.

          Many cancer immunotherapies developed in experimental animals have been tested in clinical trials. Although some have shown modest clinical effects, most have not been effective. Recent studies have identified myeloid-origin cells that are potent suppressors of tumor immunity and therefore a significant impediment to cancer immunotherapy. "Myeloid-derived suppressor cells" (MDSC) accumulate in the blood, lymph nodes, and bone marrow and at tumor sites in most patients and experimental animals with cancer and inhibit both adaptive and innate immunity. MDSC are induced by tumor-secreted and host-secreted factors, many of which are proinflammatory molecules. The induction of MDSC by proinflammatory mediators led to the hypothesis that inflammation promotes the accumulation of MDSC that down-regulate immune surveillance and antitumor immunity, thereby facilitating tumor growth. This article reviews the characterization and suppressive mechanisms used by MDSC to block tumor immunity and describes the mechanisms by which inflammation promotes tumor progression through the induction of MDSC.
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            Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers.

            CD4(+) T cells play a central role in initiating and maintaining anticancer immune responses. However, regulatory CD4(+)CD25(+) T cells which express Foxp3 have also been shown to inhibit antitumor effector T cells. In view of these heterogeneous CD4(+) T-cell populations, this study was designed to determine the prognostic value of various tumor-infiltrating CD4(+) T-cell populations in head and neck squamous cell carcinoma. Eighty-four newly diagnosed untreated patients with histologically proven primary head and neck squamous cell carcinoma were included in this study. Double or triple immunofluorescence staining was done to assess and quantify the activated CD4(+)CD69(+) T cells, regulatory CD4(+)Foxp3(+) T cells, and mixed CD4(+)CD25(+) T cells comprising both activated and regulatory T cells. On univariate analysis, high levels of tumor-infiltrating CD4(+)CD69(+) T cells were correlated with both better locoregional control (P = 0.01) and longer survival (P = 0.01). Infiltration by regulatory Foxp3(+)CD4(+) T cells was positively associated with a better locoregional control of the tumor. Multivariate analysis showed that the only significant prognostic factors related to locoregional control were T stage (P = 0.02) and CD4(+)Foxp3(+) T-cell infiltration of the tumor (P = 0.02). In the Cox multivariate analysis, only two variables influenced overall survival probability: T stage (P = 0.036) and CD4(+)CD69(+) T-cell infiltration (P = 0.017). This study shows that tumor-infiltrating activated CD4(+)CD69(+) T cells are associated with a good prognosis in head and neck squamous cell carcinoma. In addition, regulatory Foxp3(+)CD4(+) T cells are positively correlated with locoregional control may be through down-regulation of harmful inflammatory reaction, which could favor tumor progression.
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              Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response.

              The importance of the macrophage in innate immunity is underscored by its secretion of an array of powerful immunoregulatory and effector molecules. We report herein that macrophage migration inhibitory factor (MIF), a product of activated macrophages, sustains macrophage survival and function by suppressing activation-induced, p53-dependent apoptosis. Endotoxin administration to MIF(-/-) mice results in decreased macrophage viability, decreased proinflammatory function, and increased apoptosis when compared with wild-type controls. Moreover, inhibition of p53 in endotoxin-treated, MIF-deficient macrophages suppresses enhanced apoptosis and restores proinflammatory function. MIF inhibits p53 activity in macrophages via an autocrine regulatory pathway, resulting in a decrease in cellular p53 accumulation and subsequent function. Inhibition of p53 by MIF coincides with the induction of arachidonic acid metabolism and cyclooxygenase-2 (Cox-2) expression, which is required for MIF regulation of p53. MIF's effect on macrophage viability and survival provides a previously unrecognized mechanism to explain its critical proinflammatory action in conditions such as sepsis, and suggests new approaches for the modulation of innate immune responses.
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                Author and article information

                Journal
                International Journal of Cancer
                Int. J. Cancer
                Wiley
                00207136
                September 15 2016
                September 15 2016
                June 16 2016
                : 139
                : 6
                : 1379-1390
                Affiliations
                [1 ]Division of Environmental Health Sciences, College of Public Health; Ohio State University; Columbus OH
                [2 ]Comprehensive Cancer Center; The Ohio State University; Columbus OH
                [3 ]Department of Pathology; Ohio State University Medical Center; Columbus OH
                Article
                10.1002/ijc.30177
                4939094
                27164411
                © 2016
                Product
                Self URI (article page): http://doi.wiley.com/10.1002/ijc.30177

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