Macrophage Migration Inhibitory Factor Promotes Colorectal Cancer

Abstract

A growing body of evidence implicates macrophage migration inhibitory factor (MIF) in tumorigenesis and metastasis. In this study, we investigated whether MIF expression was associated with clinicopathologic features of colorectal carcinoma (CRC), especially in tumors with hepatic metastasis, and whether neutralization of endogenous MIF using anti-MIF therapeutics would inhibit tumor growth and/or decrease the frequency of colorectal hepatic metastases in a mouse colon carcinoma model. The concentration of serum MIF was positively correlated with an increased risk of hepatic metastasis in human patients with CRC (R = 1.25, 95% confidence internal = 1.02-1.52, P = 0.03). MIF was also dramatically upregulated in human colorectal tissue, with 20-40 times as many MIF-positive cells found in the mucosa of patients with CRC than in normal tissue (P < 0.001 ANOVA). Moreover, in those patients with metastatic colorectal cancer in the liver, MIF-positive cells were similarly increased in the diseased hepatic tissue. This increased MIF expression was restricted to diseased tissue and not found in areas of the liver with normal morphology. In subsequent in vitro experiments, we found that addition of recombinant MIF to colonic cell lines significantly increased their invasive properties and the expression of several genes (for example, matrix metalloproteinase 9 and vascular endothelial growth factor) known to be upregulated in cancerous tissue. Finally, we treated mice that had been given CT26 colon carcinoma cell transplants with anti-MIF therapeutics-either the MIF-specific inhibitor ISO-1 or neutralizing anti-MIF antibodies-and observed a significant reduction in tumor burden relative to vehicle-treated animals. Taken together, these data demonstrate that MIF expression was not only correlated with the presence of colorectal cancer but also may play a direct role in cancer development.

Time-series analysis of gene expression profiles induced by nitrosamides and nitrosamines elucidates modes of action underlying their genotoxicity in human colon cells

“…As shown in Suppl. Tables A.5-A.7, several cytokine signaling pathways, such as MIF and interleukin-1, 6, 12, 22 and 27 signaling are modified, many of which are implicated in colon cancer development (He et al, 2009;Terzic et al, 2010). The four nitrosamines do not always affect the same pathways and the net effect on immune modulation may not always be the same for all nitrosamines.…”

“…Nitrosamides have been reported to have immunosuppressive effects (Schoental and Bensted, 1989) and intestinal epithelial cells, including the Caco-2 cell line, excrete pro-inflammatory cytokines and express cytokine receptors (Varilek et al, 1994;Vitkus et al, 1998). Interleukin-6, for example, plays an important role in the induction of the acute phase response and the intestinal inflammatory response (Akira et al, 1993) and also has immunosuppressive properties (Hegde et al, 2004), while MIF is associated with colorectal cancer development (He et al, 2009). …”

Characterization, epitope identification and mechanisms of the anti-septic capacity of monoclonal antibodies against macrophage migration inhibitory factor

“…Mouse IgG antibody was used as a negative control, and PBS was used as a blank control. The assay reagent for 2.4 mM L-dopachrome methyl ester was freshly prepared with a 4 mM solution of L-3,4-dihydroxyphenylalanine methyl ester and 20 mM sodium periodate, which were incubated in 1 mM ethylenediamine tetraacetic acid (EDTA, pH6.2) at RT for 30 min [22]. Finally, 0.3 ml of dopachrome methyl ester was mixed with 0.7 ml of the immunoreactant, and tautomerase activities were determined via the continuous monitoring method using a semi-automatic biochemistry analyser set at the 475 nm wavelength.…”

Microdialysis Combined with Proteomics for Protein Identification in Breast Tumor Microenvironment In Vivo

“…Other proteases and protease inhibitors, such as urokinasetype plasminogen activator (uPA) and tissue inhibitor of metalloproteinase 2 (TIMP2), are known to regulate breast tumor invasion and metastasis, and are suggested to have prognostic value [59,60]. Among cytokines identified in this study, macrophage migration inhibitory factor (MIF) is known to exert pleiotropic functions including control of cell proliferation and differentiation [61]. Overexpression of MIF is observed in human breast cancer and is suggested to induce angiogenesis [62].…”