Role of MIF1/MIF2/CD74 interactions in bladder cancer

Abstract

Macrophage migration inhibitory factor (MIF1) is a pleiotropic cytokine involved in inflammation and cancer. Genetic knockout of Mif1 in the validated N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine (BBN) model of bladder cancer (BCa) resulted in stage arrest at non‐muscle‐invasive disease in prior studies. Small‐molecule inhibition of MIF1 reduced cancer‐associated outcomes, but it did not fully recapitulate genetic models. D‐dopachrome tautomerase (gene symbol DDT), commonly referred to as MIF2, is a functional homolog of MIF1, and both MIF1 and MIF2 can bind the cell surface receptor CD74 on multiple cell types to initiate a signaling cascade. It has been proposed that this interaction mediates part of the protumorigenic effects of MIF1 and MIF2 and may explain the discordance in prior studies. We hypothesized that MIF2 functions redundantly with MIF1 in BCa development and progression. The Cancer Genome Atlas (TCGA) analysis indicated MIF and DDT expression were increased in BCa patients compared to control. 4‐Iodopyridine (4‐IPP), a combined MIF1/MIF2 inhibitor, was more efficacious than ISO‐1, a MIF1‐only inhibitor, in preventing cellular proliferation in BCa cell lines. To evaluate these findings in vivo, wild‐type (WT) and Mif1−/− animals were exposed to 0.05% BBN in drinking water for 16 weeks to initiate tumorigenesis and then evaluated over the subsequent 4 weeks for tumor formation and progression in the presence or absence of 4‐IPP. 4‐IPP reduced bladder weights in WT animals and bladder weights/tumor stage in Mif1−/− animals. To determine whether MIF1/MIF2 functioned through CD74 in BCa, WT or Cd74−/− animals were used in the same BBN model. Although these animals were partially protected against BBN‐induced BCa, 4‐IPP did not enhance this effect. In conclusion, our data suggest that MIF2 mechanistically functions in a similar protumorigenic manner to MIF1, and this is at least partially through CD74. Dual inhibition of MIF homologs is more efficacious at reducing tumor burden in this model of BCa. © 2022 The Pathological Society of Great Britain and Ireland.

CD74 as a prognostic and M1 macrophage infiltration marker in a comprehensive pan-cancer analysis

“…It has also been proposed to be predictive of both metastasis and clinical outcomes in various cancers 14 , 21 . Inhibition of MIF1/MIF2 reduces the tumor burden of bladder cancer in preclinical models, an effect that was found to be accomplished in part through activation of CD74, suggesting the significance of CD74 in tumor development 22 . However, there is minimal information on its function in other cancers.…”

Blocking the MIF-CD74 axis augments radiotherapy efficacy for brain metastasis in NSCLC via synergistically promoting microglia M1 polarization

“…In cancer, MIF/CD74 axis is considered to be a signaling pathway that pro-tumor. Benjamin et al found that MIF expression is increased in bladder cancer patients, and the use of the MIF inhibitor 4-IPP can suppress tumor growth [ 70 ]. Israel et al discovered that MIF is highly expressed in Luminal B, HER2, and Basal subtypes of breast cancer, but its expression is not prognostically relevant in any subtype of breast cancer [ 71 ].…”

Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT): Pathways to Tumorigenesis and Therapeutic Opportunities

“…MIF-KO murine bladder cancer models demonstrated decreased vascularization and tumor stage [91]. 4-IPP treatment in murine bladder cancer models resulted in decreased tumor weights in MIF-KO versus WT mice, suggesting an additive contribution of DDT inhibition [198]. In bladder cancer cells, MIF knockdown produced a dose-dependent reduction in growth [203].…”

“…Urogenital Cancers 4.8.1. Bladder Cancer MIF and DDT overexpression has been observed in TCGA analysis of bladder cancers [198,199]. Similarly, CD74 overexpression is detected in high-grade invasive bladder cancer and is associated with proliferation, invasion, and angiogenesis of HT-1376 bladder cancer cells [200][201][202].…”