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.
Highlights
Despite advances in diagnosis and treatment, colorectal cancer remains a major cause of cancer death worldwide
Logistic regression analysis showed that higher serum migration inhibitory factor (MIF) levels were associated with elevated risk of hepatic metastasis (R = 1.25, 95% confidence interval = 1.02–1.52, P = 0.03)
We demonstrated that increased MIF expression was correlated with an increase in both tumor differentiation and the extent of metastases, suggesting that MIF may play a crucial role in colorectal carcinogenesis and metastasis
Summary
Despite advances in diagnosis and treatment, colorectal cancer remains a major cause of cancer death worldwide. In addition to the pivotal effects of MIF on the immune system and inflammatory response, several reports have linked MIF to fundamental processes that control cell proliferation, differentiation, angiogenesis, tumor progression, and metastasis [4,5,6,7,8,9,10,11]. Increased MIF expression is associated with both enhanced proliferation of MIF AND COLORECTAL CANCER murine colon cancer cells in response to growth factors [6] and with loss of cell differentiation and lymph node metastases [16]. Tumorderived MIF, acting as an autocrine factor, enhanced the production of vascular endothelial growth factor (VEGF) and interleukin-8, and promoted angiogenesis and tumor growth in esophageal cancer [16]
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