A Role for MIF in Tumor Growth and Metastasis

The chemopreventive isothiocyanate sulforaphane (SFN) covalently binds Macrophage Migration Inhibitory Factor (MIF) and inhibits its tautomerase activity. MIF is overexpressed in many cancer types, and the degree of expression correlates with tumor progression. MIF is also overexpressed in many states of chronic inflammation, where it has been shown to contribute to disease progression. Because inflammation has been shown to increase tumor progression, we hypothesized that MIF promotes tumor growth and metastasis by influencing the tumor microenvironment rather than directly impacting the tumor cells. Using syngeneic tumor models, we observed that tumor-derived MIF increased tumor growth in vivo, while having no effect upon proliferation and colony formation in vitro. MIF also increased spontaneous metastasis in the 4T1 model, a highly aggressive orthotopic model of breast cancer, for which the tautomerase activity was required. Tautomerase activity was also required for the recruitment of monocytic myeloid derived suppressor cells (MDSCs), which suppress anti-tumor immune responses. MDSCs were able to enhance seeding of 4T1 cells in the lung in an experimental metastasis assays dependent upon MIF expression in the tumor cells. Depletion of MDSCs negated the effect of MIF on tumor growth and metastasis. SFN treatment of tumor bearing mice also decreased the proportion of these suppressive cells in the tumor. Culture of myeloid cells with conditioned media from MIF-containing 4T1 cells resulted in a higher proprortion of monocytic MDSCs than similar cultures with conditioned media from MIF-deficient cells. Host-derived MIF significantly increased tumor growth, metastasis, and monocytic MDSC abundance.   Similar to the 4T1 model, the CT26 and LLC models also showed MIF-dependent tumor growth. Altogether these results suggest that MIF promotes tumor growth and metastasis. In the 4T1 and CT26 models, this effect was concurrent with an increase in monocytic MDSCs. We demonstrated that MDSCs are vital for the effect of MIF on both spontaneous and experimental metastasis. This provides evidence for the immune system and MIF as therapeutic targets in the treatment of cancer growth and metastasis. As SFN inhibits MIF tautomerase activity, this data suggests a mechanism of action of isothiocyanates and may support their utility as a therapeutic approach.

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