Tumor-derived macrophage migration inhibitory factor modulates the biology of head and neck cancer cells via neutrophil activation.
ABSTRACT Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that has been reported to enhance the aggressiveness and metastatic potential of tumor cells. However, the mechanisms through which MIF influences tumor development and progression are not understood. The objectives of our study were to assess the effects of tumor-derived MIF on neutrophils in head and neck cancer (HNC) and to identify possible feedback effects on tumor cells. To this end, we used an in vitro system to model the interaction between human HNC cells and neutrophils. In addition, we analyzed expression of MIF in tissues from HNC patients in relation to neutrophilic infiltration and clinical parameters. Our results show that human HNC is infiltrated by neutrophils proportional to the levels of tumoral MIF. Strong MIF expression by the tumor is associated with higher lymph node metastasis and reduced survival in HNC patients. In vitro, MIF modulated functions of human neutrophils by inducing chemokine CXC motif receptor 2(CXCR2)-dependent chemotaxis, enhancing neutrophil survival and promoting release of chemokine C-C Motif Ligand 4 (CCL4) and matrix metalloprotease 9(MMP9). Further, neutrophils activated with tumor-derived MIF enhanced migratory properties of HNC cells. In conclusion, our data indicate that the effects of tumor-derived MIF on neutrophils represent an additional mechanism by which MIF might contribute to tumor progression.
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ABSTRACT: Macrophage migration inhibitory factor is a critical proinflammatory cytokine produced by cells of innate and adaptive immune system. MIF plays a key role in cell cycle regulation and in the pathogenesis of many cancers. Recently, MIF has been studied in the upper aerodigestive tract cancer for its involvement in tumor progression, invasion, proliferation and cell motility. In addition, MIF appears to be a mediator in angiogenesis and in the development of metastasis and locoregional lymph node, which are often associated with a poor prognosis. The mechanisms of action responsible for MIF involvement in tumor progression are not completely eluci da - ted. However, the main effects of MIF are mediated by the CD74 receptor. MIF binding to its receptor is responsible for the activation of several signaling pathways (ERK1 / 2 - MAPK, JAB1 - CSN5, PI3K - Akt), the inhibition of p53 and the stimu - la tion of angiogenic factors including VEGF and IL-8. The overexpression of MIF also causes a reduction of the anti-tumor activity of the immune system. Finally, MIF could be an inte res - ting biomarker in the diagnosis and monitoring of upper aerodigestive tract cancers. In this paper, we assess the state of knowledge of MIF involvement in upper aero-digestive tract cancers and we analyze the therapeutic perspectives.Revue de laryngologie - otologie - rhinologie 12/2013; 134(2):67-74.
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ABSTRACT: The tumor microenvironment (TME) of head and neck squamous cell carcinoma (HNSCC) is comprised of cancer-associated fibroblasts (CAFs), immune cells, and other supporting cells. Genetic changes in the carcinoma cells, such as alterations to TP53, NOTCH1, and specific gene expression profiles, contribute to derangements in cancer and microenvironment cells such as increased ROS, overproduction of cytokines, and epithelial to mesenchymal transition (EMT). CAFs are among the most critical elements of the TME contributing to proliferation, invasion, and metastasis. The adaptive immune response is suppressed in HNSCC through overexpression of cytokines, triggered apoptosis of T cells, and alterations in antigen processing machinery. Overexpression of critical cytokines, such as transforming growth factor-β (TGF-β), contributes to EMT, immune suppression, and evolution of CAFs. Inflammation and hypoxia are driving forces in angiogenesis and altered metabolism. HNSCC utilizes glycolytic and oxidative metabolism to fuel tumorigenesis via coupled mechanisms between cancer cell regions and cells of the TME. Increased understanding of the TME in HNSCC illustrates that the long-held notion of "condemned mucosa" reflects a process that extends beyond the epithelial cells to the entire tissue comprised of each of these elements.Seminars in Oncology 04/2014; 41(2):217-234. · 4.33 Impact Factor
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ABSTRACT: Neutrophils are myeloid cells that constitute 50-70 % of all white blood cells in the human circulation. Traditionally, neutrophils are viewed as the first line of defense against infections and as a major component of the inflammatory process. In addition, accumulating evidence suggest that neutrophils may also play a key role in multiple aspects of cancer biology. The possible involvement of neutrophils in cancer prevention and promotion was already suggested more than half a century ago, however, despite being the major component of the immune system, their contribution has often been overshadowed by other immune components such as lymphocytes and macrophages. Neutrophils seem to have conflicting functions in cancer and can be classified into anti-tumor (N1) and pro-tumor (N2) sub-populations. The aim of this review is to discuss the varying nature of neutrophil function in the cancer microenvironment with a specific emphasis on the mechanisms that regulate neutrophil mobilization, recruitment and activation.Cancer microenvironment : official journal of the International Cancer Microenvironment Society. 06/2014;