Abstract
Neuroblastoma (NB) is the most frequent extracranial pediatric tumor. Despite the current available multiple therapeutic options, the prognosis for high-risk NB patients remains unsatisfactory and makes the disease a clear unmet medical need. Thus, more tailored therapeutic approaches are warranted to improve both the quality of life and the survival of the patients. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that plays a key role in several diseases, including cancer. Preclinical and clinical studies in NB patients convergently indicate that MIF exerts pro-tumorigenic properties in NB. MIF is upregulated in NB tumor tissues and cell lines and it contributes to NB aggressiveness and immune-escape. To date, there are only a few data about the role of the second member of the MIF family, the MIF homolog d-dopachrome tautomerase (DDT), in NB. Here, we review the preclinical and clinical studies on the role of the MIF family of cytokines in NB and suggest that MIF and possibly DDT inhibitors may be promising novel prognostic and therapeutic targets in NB management.
Highlights
IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy; Department of Educational Sciences, University of Catania, Via Teatro Greco 84, 95124 Catania, Italy; Department of Medical and Surgical Sciences and Advanced Technologies, University of Catania, Via S
We and others have shown that migration inhibitory factor (MIF) and d-dopachrome tautomerase (DDT) are involved in several diseases of different origins such as immunoinflammatory and autoimmune diseases, neurodegenerative and neuropsychiatric diseases, and cancer [24,25,26,27,28,29,30,31]
4‘NB samples and we found that patients with higher MIF and DDT expression levels are correlated with a poorer prognosis, independently from MYCN amplification [57]
Summary
We and others have shown that MIF and DDT are involved in several diseases of different origins such as immunoinflammatory and autoimmune diseases, neurodegenerative and neuropsychiatric diseases, and cancer [24,25,26,27,28,29,30,31]. The interaction of MIF and CD74 promotes the complex, the Src kinase is activated, leading to phosphorylation of the extracellular-signal-regulated activation of the AKT/PI3K pathway with the consequent inactivation of the pro-apoptotic proteins kinase ERK/MAP and inhibition of p53 expression. It has been shown that the knockdown of DDT and MIF in the pancreatic cell line, PANC-1, correlated with reduced activation of ERK1/2 and AKT, augmented p53 expression, and inhibited tumor growth in vitro and in vivo [15,69]. Recent evidence indicates that this drug possesses a pleiotropic immunopharmacological mode of action that entails, among others, inhibition of tautomerasic activity of MIF and blockade of Toll-like receptor 4 This has propelled several studies aimed at repurposing ibudilast for neuroinflammatory conditions. Other drugs that are being repurposed as MIF inhibitors are ebselen and iguratimod [77]
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