Mechanisms of macrophage migration inhibitory factor (MIF)-dependent tumor microenvironmental adaptation

Abstract

Since its activity was first reported in the mid-1960s, macrophage migration inhibitory factor (MIF) has gone from a cytokine activity modulating monocyte motility to a pleiotropic regulator of a vast array of cellular and biological processes. Studies in recent years suggest that MIF contributes to malignant disease progression on several different levels. Both circulating and intracellular MIF protein levels are elevated in cancer patients and MIF expression reportedly correlates with stage, metastatic spread and disease-free survival. Additionally, MIF expression positively correlates with angiogenic growth factor expression, microvessel density and tumor-associated neovascularization. Not coincidentally, MIF has recently been shown to contribute to tumoral hypoxic adaptation by promoting hypoxia-induced HIF-1alpha stabilization. Intriguingly, hypoxia is a strong regulator of MIF expression and secretion, suggesting that hypoxia-induced MIF acts as an amplifying factor for both hypoxia and normoxia-associated angiogenic growth factor expression in human malignancies. Combined, these findings suggest that MIF overexpression contributes to tumoral hypoxic adaptation and, by extension, therapeutic responsiveness and disease prognosis. This review summarizes recent literature on the contributions of MIF to tumor-associated angiogenic growth factor expression, neovascularization and hypoxic adaptation. We also will review recent efforts aimed at identifying and employing small-molecule antagonists of MIF as a novel approach to cancer therapeutics.

Figure 1

Scheme demonstrating hypoxic/normoxic contributions to tumor microenvironmental adaptation by macrophage migration inhibitory factor (MIF). Hypoxia induces HIF-1α-dependent MIF transcription and secretion in human cancers. When over-expressed, MIF functionally enhances hypoxia-induced HIF-1α stabilization (Winner et al., 2007) and subsequent hypoxic adaptive responses thus contributing to angiogenic, metabolic, cell cycle and metastatic responses to low oxygen tension. Hypoxia-induced MIF diffuses into normoxic regions of the tumor where it can additionally modulate angiogenic growth factor expression, cell cycle progression and migration/invasion of normoxic malignant cells (Coleman et. al., 2008; Rendon et al., 2007).