Macrophage Migration Inhibitory Factor Promotes Colorectal Cancer
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.
This project was supported by the National Natural Science Foundation of China (NSFC) (30470435), the Provincial Natural Science Foundation of Guangdong (06022450 and 710173), the Provincial Science and technology Grant of Guangdong (2008A030201001), and the Science and technology Grant of Zhongshan Science & Technology Bureau (20073A185) to Dr. XingXiang He. We appreciate the support of Yiwen Deng and Chuyuan Hong in the Department of Gastroenterosurgery in collecting the colorectal carcinoma specimens. We thank Hang Su in the Clinical Laboratory Center of Molecular Medicine and Degui Liao in the Department of Pathology for technical assistance.
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