The inflammatory cytokine, Macrophage Migration Inhibitory Factor (MIF) is a critical mediator of numerous inflammatory disease processes. In addition, MIF is overexpressed in many cancers and the degree of expression correlates with tumor aggressiveness. We identified MIF as a target for inhibition by sulforaphane (SFN), a cancer chemopreventive agent prevalent in broccoli. Based on this observation and the correlation between MIF expression and poor prognosis in human patients, we set out to determine how MIF might contribute to tumor growth and progression.

We hypothesized that, as an inflammatory cytokine, MIF may regulate the interaction between the tumor and the host immune response, rather than impacting an intrinsic property of the tumor cells. We are exploring these questions using the syngeneic 4T1 model of breast carcinoma. This model recapitulates many aspects of human breast tumor progression, including spontaneous metastasis from the mammary fat pad to similar target organs. We found that MIF expression in the tumor cells increases tumor growth and metastasis in an orthotopic tumor model. Importantly, the MIF dependent growth differences are only manifested in vivo, as the MIF depleted cell line is not compromised in growth or colony formation in vitro, suggesting that MIF may be contributing to the interaction between the tumor and the host immune response. This was confirmed by demonstrating that MIF depleted and MIF containing tumors exhibit similar growth and metastasis properties in immunodeficient animals. Evaluation of the immune cell infiltrates in the MIF containing and MIF deficient tumors reveal that the abundance of monocytic MDSC within the tumor is dependent on MIF expression. Finally, we demonstrate that depletion of MDSCs abolishes the impact of MIF on tumor growth, suggesting that these cells are critical for MIF to mediate its effects. We are currently exploring the mechanisms by which MIF controls the abundance of monocytic MDSCs in the tumor microenvironment and how this relates to promotion of tumor metastasis. Our work establishes MIF as a potentially valuable therapeutic target in tumor metastasis and supports a potential alternative mechanism for chemoprevention in which SFN may target the inflammatory tumor microenvironment through inhibition of this cytokine.

Citation Format: Kendra D. Simpson, Dennis J. Templeton, Janet V. Cross. Macrophage Migration Inhibitory Factor (MIF) regulates monocytic MDSC abundance to contribute to tumor growth and metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2812. doi:10.1158/1538-7445.AM2013-2812