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MIF family proteins in genitourinary cancer: tumorigenic roles and therapeutic potential

Nature Reviews Urology volume 16, pages 318–328 (2019)Cite this article

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Abstract

Genitourinary cancers encompass some of the most common solid tumours and have high rates of morbidity and mortality. Inflammation is associated with enhanced tumorigenesis, and a number of pro-inflammatory mediators, such as macrophage migration inhibitory factor (MIF), also promote tumorigenesis. Studies of the role of MIF (which largely functions via the type II transmembrane receptor CD74) in prostate, bladder and kidney cancers suggest that it is a pro-tumorigenic factor in genitourinary malignancy. Inhibiting MIF activity in cell culture and in preclinical animal models of genitourinary cancers reduces the phenotypic hallmarks of cancer, such as proliferation, angiogenesis and tumour aggressiveness, by downregulating signalling pathways such as those regulated by extracellular signal-regulated kinase (ERK), protein kinase B and p53, and MIF may also reverse immunosuppression. Progress has been made in our understanding of the role of MIF (and its family member d-dopachrome tautomerase (DDT)) in genitourinary cancers and how it can be therapeutically targeted.

Key points

  • Macrophage migration inhibitory factor (MIF) and its homologue d-dopachrome tautomerase (DDT) are pleiotropic cytokines with multiple functions in tumorigenesis.

  • The receptor CD74, and co-receptors such as CD44, CXC-chemokine receptor 2 (CXCR2) and CXCR4, mediate the effects of MIF in tumour cells, including the activation of pro-tumorigenic signalling.

  • The cellular levels of CD74 and the serum and cellular levels of MIF are elevated in genitourinary cancers.

  • The pharmacological and genetic inhibition of MIF, or the blockade of CD74–MIF interactions, reduces tumorigenesis in multiple genitourinary cancers through a variety of mechanisms.

  • Data indicate that MIF may have roles in immunosuppression in addition to its role in directly promoting tumour growth.

  • MIF may be a valid therapeutic target in genitourinary malignancies; inhibiting MIF-mediated pathways that directly promote tumorigenesis or those that enhance immunotherapy could be clinically beneficial.

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Fig. 1: MIF signalling in cancer cells.
Fig. 2: MIF in the microenvironment.

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Acknowledgements

The authors thank the Leo and Anne Albert Trust for supporting this work.

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Nature Reviews Urology thanks J. Lathia and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA

    Justin C. Penticuff, Benjamin L. Woolbright & John A. Taylor III

  2. Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, KS, USA

    Thais M. Sielecki

  3. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA

    Scott J. Weir

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Contributions

J.A.T., J.P. and B.L.W. researched data for the article. J.A.T., J.P., B.L.W. and T.M.S. made substantial contributions to discussion of the article contents. J.A.T., J.P. and B.L.W. wrote the manuscript. All authors reviewed and/or edited the manuscript before submission.

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Glossary

Delayed-type hypersensitivity reactions

Cell-mediated immune responses associated with foreign antigen recognition.

Innate immune response

An initial immune response mounted by the innate immune system (neutrophils, monocytes and macrophages) that happens immediately upon antigen recognition.

Adaptive immune response

An adaptive immune response is carried out after antigen recognition by adaptive immune cells (B cells and T cells) after long-term antigen recognition and memory.

Arachidonic acid metabolism

Arachidonic acid is the primary precursor to multiple prostaglandins that serve as primary inflammatory mediators as well as mediators of pain, muscle contraction and pro-tumorigenic signalling pathways.

G protein-coupled receptor

A protein receptor that transmits signalling through guanine nucleotide binding proteins.

Transcellular pathway

A poorly understood method for macrophage migration inhibitory factor (MIF) to cross the cellular barrier that does not appear to be receptor-mediated.

Lethal endotoxaemia

A type of shock in which the body undergoes organ failure owing to an uncontrolled immune response to high levels of bacteria or bacterial particles.

Antibody–drug conjugates

(ADCs). Conjugates of an antibody and a chemotherapeutic designed to enhance the therapeutic potential of both.

Gleason scores

A system of scoring prostate cancer to predict tumour invasiveness and size.

Transdifferentiation

Differentiation to a new somatic cell type without undergoing transfer to a typical pluripotent state.

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Penticuff, J.C., Woolbright, B.L., Sielecki, T.M. et al. MIF family proteins in genitourinary cancer: tumorigenic roles and therapeutic potential. Nat Rev Urol 16, 318–328 (2019). https://doi.org/10.1038/s41585-019-0171-9

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