Targeting MIF in Cancer: Therapeutic Strategies, Current Developments, and Future Opportunities

Strong evidence has been presented linking chronic inflammation to the onset and pathogenesis of cancer. The multifunctional pro-inflammatory protein macrophage migration inhibitory factor (MIF) occupies a central role in the inflammatory pathway and has been implicated in the tumorigenesis, angiogenesis, and metastasis of many cancer phenotypes. This review highlights the current state of the art, which presents MIF, and the second member of the MIF structural superfamily, d-DT (MIF2), as significant mediators in the inflammatory-cancer axis. Although the mechanism by which MIF asserts its biological activity has yet to be fully understood, it has become clear in recent years that for certain phenotypes of cancer, MIF represents a valid therapeutic target. Current research efforts have focused on small molecule approaches that target MIF's unique tautomerase active site and neutralization of MIF with anti-MIF antibodies. These approaches have yielded promising results in a number of preclinical murine cancer models and have helped to increase our understanding of MIF biological activity. More recently, MIF's involvement in a number of key protein-protein interactions, such as with CD74 and HSP90, has been highlighted and provides a novel platform for the development of anti-MIF chemotherapeutic strategies in the future.