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.
Highlights
Gastric and colorectal cancers are, respectively, the third and fourth leading causes of cancer related death worldwide [1]. Chronic inflammatory states such as Helicobacter pylori infection for gastric cancer and inflammatory bowel disease for colorectal cancer are key risk factors associated with the development of these malignancies [2]
We have previously shown that it is highly produced by gastric epithelial cells when exposed to H. pylori and acts in an autocrine manner to induce transactivation of the epidermal growth factor receptor, which suggests an important link to pro-carcinogenic mechanisms [3,4]
All of the gastric cancer samples exhibited more than 2-fold increase in Migration Inhibitory Factor (MIF) gene expression while 27 of 30 colon cancer samples exhibited greater than 2-fold increase in MIF gene expression (Figure 1A and B)
Summary
Gastric and colorectal cancers are, respectively, the third and fourth leading causes of cancer related death worldwide [1] Chronic inflammatory states such as Helicobacter pylori infection for gastric cancer and inflammatory bowel disease for colorectal cancer are key risk factors associated with the development of these malignancies [2]. Other groups have shown MIF to be a potential diagnostic or prognostic marker in gastric and colon cancers [6,7,8]. Despite these associations, investigation of the mechanisms by which MIF is implicated in gastrointestinal cancers is not yet complete
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