Abstract
Neuroblastoma (NB) represents one of the most frequent pediatric solid tumors. Macrophage migration inhibitory factor (MIF) is a cytokine exerting multiple biological functions. More recently, a second member of the MIF family of cytokine has been identified, the D-dopachrome tautomerase (DDT), that exerts several overlapping functions with MIF. Growing evidence suggests a key role for MIF and DDT in the development of cancer. The aim of this study is to characterize the prognostic value of MIF and DDT in NB. We show that higher expression levels of MIF and DDT in Stage 4 NB samples are associated with a poorer prognosis, independently of the presence of MYCN amplification. Moreover, higher levels of MIF are mostly enriched by Th1 cells, while lower levels of MIF are associated with an increased proportion of B cells, Cytotoxic T cells, Dendritic cells and Natural Killer T cells. We also show that treatment with the histone deacetylase (HDAC) inhibitor, vorinostat, of the NB cell line, SH-SY5Y, determines a significant reduction in the expression of both MIF and DDT. Finally, MIF and DDT inhibition by short interfering RNA is able to revert vincristine sensitivity in vitro. Overall, our data suggest that MIF exert pro-tumorigenic properties in NB, likely by dampening antigen presentation and cytotoxic immune responses, and we propose the HDAC inhibitors as a potential therapeutic strategy for NB patients.
Highlights
Neuroblastoma (NB) is a neoplasm originating from neural crest cells and represents one of the most frequent pediatric solid tumors, as it accounts for 7% of malignancies diagnosed in children from 0 to 14 years of age
Patients were stratified in quartiles based on the expression of migration inhibitory factor (MIF) and D-dopachrome tautomerase (DDT) genes and samples in the upper and lower quartiles were selected for comparison
No significant differences were instead observed among samples with various Mitosis–Karyorrhexis index (MKI) score (Figure 1B)
Summary
Neuroblastoma (NB) is a neoplasm originating from neural crest cells and represents one of the most frequent pediatric solid tumors, as it accounts for 7% of malignancies diagnosed in children from 0 to 14 years of age. NB is responsible for nearly 15% of pediatric cancer-related mortality [1]. The International Neuroblastoma Staging Series (INSS) classifies NB patients by risk level, tumor location and dissemination, and MYCN amplification [2]. For NB consists of surgery, chemo-radiotherapy, and more recently, antidisialoganglioside (anti-GD2). While the 5-year survival rate for patients with low-risk NB is higher than 95%, it drops to 40%–50% in high-risk patients [5]. Results from a recent Phase 3 trial (NCT00567567) have shown that high-risk neuroblastoma patients treated with tandem autologous stem-cell transplant with thiotepa/cyclophosphamide followed by dose-reduced carboplatin/etoposide/melphalan had
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