Chronic Macrophage Migration Inhibitory Factor Exposure Induces Mesenchymal Epithelial Transition and Promotes Gastric and Colon Cancers

Abstract

Macrophage Migration Inhibitory Factor (MIF) is an inflammatory cytokine that is highly produced in gastrointestinal cancers. Since chronic inflammation is a risk factor for tumorigenesis in these cancers, in this study, the role of MIF in pro-tumorigenic events was examined. MIF and its receptor, CD74, were examined in gastric and colon tumors and found to be increased in most tumors with significantly higher expression in tumors from patients with lymph node metastasis. MIF was also found to be highly produced by cancer associated fibroblasts isolated from human tumors compared to fibroblasts from matched normal tissues from uninvolved areas. Fibroblast-produced MIF highly increased GI cancer cell proliferation, which was decreased upon neutralizing MIF or CD74. Chronic MIF treatment led to sustained proliferation and signaling events in non-transformed GI fibroblast cells, which was maintained upon removing MIF treatment for 8 weeks. Additionally, chronic treatment of normal GI cells expressing fibroblast markers for up to 16 weeks with MIF led to a drastic decrease of fibroblast markers with concurrent increase of epithelial markers. Transformation was examined by telomerase and focus forming assays. These results suggest the MIF promotes mesenchymal epithelial transition, cell transformation and tumorigenesis in GI cancers, and thus may be an important link between chronic inflammation and tumorigenesis.

Role of macrophage migration inhibitory factor (MIF) in the effects of oxidative stress on human retinal pigment epithelial cells

“…Migration inhibitory factor is an inflammatory cytokine that is produced at high levels in the gastrointestinal tract during inflammatory disease and has been implicated in gastric and colon carcinogenesis . Expression of MIF has also been detected in human corneal basal epithelial cells and endothelial cells as well as in the iris, ciliary body, and retina, suggesting that MIF might play an important role in inflammation and immunity in the eye.…”

“…Migration inhibitory factor is an inflammatory cytokine that is produced at high levels in the gastrointestinal tract during inflammatory disease and has been implicated in gastric and colon carcinogenesis. 32…”

Neutralization of macrophage migration inhibitory factor improves host survival after Clostridium difficile infection

“…Macrophage migration inhibitory factor (MIF) is a ubiquitously expressed, pleiotropic, pro-inflammatory cytokine that is part of the innate immune response to a wide range of infectious and inflammatory diseases, and can aggravate disease pathology [12, 13]. MIF promotes production and release of inflammatory mediators [for example, tumor necrosis factor alpha, TNFα; interferon-gamma, IFN-γ; interleukin (IL)-1β, IL-2, IL-6, and IL-8], inhibits macrophage and neutrophil apoptosis, and counteracts the anti-inflammatory functions of glucocorticoids [14–17].…”

Prognostic value of several biomarkers for the patients with malignant pleural mesothelioma

“…Recent data have shown that CD74 protein is upregulated in cancer cells, indicating its role in carcinogenesis and angiogenesis [63][64][65][66]. Moreover, it is well known that there is a close link between chronic inflammation and malignancies, which could be initiated by recruitment of inflammatory cells and production of inflammatory mediators.…”