Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, which was shown to be upregulated in cancers and to exhibit tumor promoting properties. Unlike other cytokines, MIF is ubiquitously present in the circulation and tissue of healthy subjects. We recently described a previously unrecognized, disease-related isoform of MIF, designated oxMIF, which is present in the circulation of patients with different inflammatory diseases. In this article, we report that oxMIF is also linked to different solid tumors as it is specifically expressed in tumor tissue from patients with colorectal, pancreatic, ovarian and lung cancer. Furthermore, oxMIF can be specifically targeted by a subset of phage display-derived fully human, monoclonal anti-MIF antibodies (mAbs) that were shown to neutralize pro-tumorigenic activities of MIF in vivo. We further demonstrate that anti-oxMIF mAbs sensitize human cancer cell lines (LNCaP, PC3, A2780 and A2780ADR) to the action of cytotoxic drugs (mitoxantrone, cisplatin and doxorubicin) in vitro and in an A2780 xenograft mouse model of ovarian cancer. We conclude that oxMIF is the disease related isoform of MIF in solid tumors and a potential new diagnostic marker and drug target in cancer.
Highlights
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that promotes tumor growth and metastasis in vivo by multiple modes of action [1,2,3,4,5,6,7,8,9,10,11]
We recently described the identification of oxidized MIF (oxMIF), a disease-related isoform of MIF that is predominantly expressed in patients with inflammatory diseases, whereas reduced MIF (redMIF) represents the ubiquitous isoform of MIF that is abundantly expressed even in healthy subjects
OxMIF was detected in the circulation of patients, representing a systemic marker of inflammation [40]
Summary
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that promotes tumor growth and metastasis in vivo by multiple modes of action [1,2,3,4,5,6,7,8,9,10,11]. MIF plays a key role in angiogenesis and neovascularization: it is associated with hypoxic adaptation and stabilization of hypoxia-inducible factor 1-alpha (HIF-1α) [6]. In this context, MIF was shown to contribute to the upregulation of vascular endothelial growth factor (VEGF), IL-8 and matrix metalloproteinases (MMPs) [7, 18, 19]. Chemokine functions of MIF are expected to play an important role in altering the TME as they contribute to the infiltration of leukocytes into tumors, thereby promoting cancer related inflammation [20, 23]
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