Neuroblastoma (NB) is the most common extracranial solid
tumor of childhood. The
clinical course may range from
spontaneous regression towards
ganglioneuroblastoma/
ganglioneuroma or maturation to a very aggressive form characterized by an extensive hypoxic area. In solid
tumors, extracellular microenvironment
hypoxia induces the transcription of
hypoxia-inducible factors (HIFs) leading to synthesis of pro-
angiogenic factor,
VEGF; also, it increases extracellular
adenosine production from
ATP breakdown. To date, the role of this
nucleoside in the hypoxic/angiogenic pathway characterizing the core of
cancer mass has not been investigated yet. Therefore, the aim of the present study was to analyze the
adenosine effect on modulation of the HIF-1α/2α/
VEGF pathway mediated through A3 AR binding. To this end, we have used a selective A3 AR agonist
IB-MECA or antagonist VUF 5574 in an in vitro model of malignant undifferentiated and
all-trans retinoic acid (RA)-differentiated SH-SY5Y cells, representing the benign form of NB. Our results have shown that specific A3 AR stimulation induces HIF and
VEGF expression through the activation of
mitogen-activated protein kinase/Erk
kinase signaling cascade. In conclusion, the data suggest that A3 AR may represent a marker of NB
malignancy as well as a drug target for treatment of this solid
tumor. Graphical Abstract.