Abstract
Neuroblastoma (NBL) is a heterogeneous tumor characterized by a wide range of clinical manifestations. A high tumor cell differentiation grade correlates to a favorable stage and positive outcome. Expression of the hypoxia inducible factors HIF1-α (HIF1A gene) and HIF2-α (EPAS1 gene) and/or hypoxia-regulated pathways has been shown to promote the undifferentiated phenotype of NBL cells. Our hypothesis is that HIF1A and EPAS1 expression represent one of the mechanisms responsible for the lack of responsiveness of NBL to differentiation therapy. Clinically, high levels of HIF1A and EPAS1 expression were associated with inferior survival in two NBL microarray datasets, and patient subgroups with lower expression of HIF1A and EPAS1 showed significant enrichment of pathways related to neuronal differentiation. In NBL cell lines, the combination of all-trans retinoic acid (ATRA) with HIF1A or EPAS1 silencing led to an acquired glial-cell phenotype and enhanced expression of glial-cell differentiation markers. Furthermore, HIF1A or EPAS1 silencing might promote cell senescence independent of ATRA treatment. Taken together, our data suggest that HIF inhibition coupled with ATRA treatment promotes differentiation into a more benign phenotype and cell senescence in vitro. These findings open the way for additional lines of attack in the treatment of NBL minimal residue disease.
Highlights
Neuroblastoma (NBL) is manifested in childhood as an extracranial solid tumor of the sympathetic nervous system, and it accounts for 15% of pediatric cancer deaths
To determine the neuronal differentiation, we investigated multiple factors that are known to be involved in axon guidance: beta-III-tubulin (TUJ-1) and microtubule-associated protein 2 (MAP-2), which are involved in microtubule assembly; neuronal light intermediate filament (NEFL), which is expressed during neuronal differentiation; glial fibrillary acidic protein (GFAP), which is expressed by astrocytes, and S100, which is expressed in cells derived from the neural crest (Schwann cells, melanocytes), both of which are implicated in the dynamics of cytoskeleton constituents
Hypoxia is a condition of low oxygen tension that can push NBL cells toward an immature, stem-cell-like phenotype
Summary
Neuroblastoma (NBL) is manifested in childhood as an extracranial solid tumor of the sympathetic nervous system, and it accounts for 15% of pediatric cancer deaths. Improved knowledge of the neuronal differentiation pathways and the mechanisms of resistance might provide new and attractive targets for the development of new therapies that avoid tumor recurrence[10,11]. In a number of cancers, evidence has correlated HIF-1α overexpression under normoxia with poor prognosis, as an independent prognostic factor for poor chemotherapeutic response and shortened patient survival time. Factors such as nitric oxide[14] and the cytokines interleukin-1beta (IL-1B) and tumor necrosis factor α (TNF-α )[15], and trophic stimuli such as serum and the insulin-like growth factors[16], might modulate HIF-1α up-regulation under normoxic conditions. Inhibition of the HIFs might provide more effective methods to enhance the NBL cell propensity to differentiate
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