title: 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.
authors.affiliation: Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Dumitru
authors.forename: Hossein
authors.initials: H
authors.lastname: Gholaman
authors.forename: Sokratis
authors.initials: S
authors.lastname: Trellakis
authors.forename: Kirsten
authors.initials: K
authors.lastname: Bruderek
authors.forename: Nina
authors.initials: N
authors.lastname: Dominas
authors.forename: Xiang
authors.initials: X
authors.lastname: Gu
authors.forename: Agnes
authors.initials: A
authors.lastname: Bankfalvi
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: Stephan
authors.initials: S
authors.lastname: Lang
authors.forename: Sven
authors.initials: S
authors.lastname: Brandau
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D054407:Chemokine CCL4 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018375:Neutrophil Activation / Q000276:immunology*; D015996:Survival Rate; D014945:Wound Healing
chemical_list: C066507:CCL4 protein, human; D054407:Chemokine CCL4; D018925:Chemokines; D016207:Cytokines; D008263:Macrophage Migration-Inhibitory Factors; D020780:Matrix Metalloproteinase 9; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human