Emerging Role of the Macrophage Migration Inhibitory Factor Family of Cytokines in Neuroblastoma. Pathogenic Effectors and Novel Therapeutic Targets?

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.

The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration

“…Tailored MIF inhibitors that are already in clinical trials or already approved for other conditions deserve particular attention due to their possible faster translation to the clinical setting. Among these there are the anti-MIF mAb inhibitor Bax69 that is in Phase I/II clinical trials for cancer patients, the anti-CD74 mAb milatuzumab that is approved for hematological malignancies, and the tautomerase inhibitor Ibudilast that is clinically used in bronchial asthma treatment and is being repurposed for immunoinflammatory conditions [7,20].…”

“…In addition, MIF acts as a ligand for the chemokine receptors, CXCR2, CXCR4, and CXCR7 [6]. In turn, MIF receptors interact with each other and establish four different units composed of two or more receptors to transduce the signaling pathway, such as CD74/CD44, CD74/CXCR2, CD74/CXCR4, and CD74/CXCR4/CXCR7 [7]. The interaction of MIF with the CD74-CD44 complex leads to the activation of the Src kinase, with consequent phosphorylation of the 1 2 kinase (ERK1/2) and mitogen-activated protein kinase (MAPK/ERK) [6].…”

“…AKT activation determines the phosphorylation and inactivation of the pro-apoptotic proteins BAD and BAX, with inhibition of apoptosis. By activating AKT, MIF increases the expression of NF-kB and of the anti-apoptotic proteins Bcl-xL and Bcl-2 in lymphoid cells [7]. Furthermore, MIF stimulates the expression of cytoplasmic phospholipase A2 (cPLA2) [3] that favors the consequent expression of arachidonate and the subsequent release of prostaglandins E2 [3].…”

“…Initial studies by ourselves and others have primarily evaluated the role of MIF in the pathogenesis of immunoinflammatory and autoimmune diseases and cancer [7,[21][22][23][24][25][26].…”

Macrophage Migration Inhibitory Factor (MIF) and Its Homologue D-Dopachrome Tautomerase (DDT) Inversely Correlate with Inflammation in Discoid Lupus Erythematosus

“…Along this line of research, several studies by ourselves and others have proposed a pathogenetic role of MIF, and possibly DDT, in certain cancers such as melanoma, neuroblastoma, head and neck cancer, and glioblastoma [ 9 , 22 , 23 , 24 , 25 , 26 ].…”