Implication of Prokineticin signaling in neuroblastoma cancer stem cells

Abstract

Neuroblastoma (NB), derived from improperly differentiated neural crest cells (NCCs), possesses a unique propensity to exhibit either a spontaneously regression or an unrestrained growth. Emerging evidence indicates that the cancer stem cells (CSC) are the critical determinants for these enigmatic clinical outcomes. Commitment of CSCs to the smooth muscle lineage gives a favorable outcome, while to the neuronal lineage results in a malignant tumor progression. However, the molecular basis of CSCs in the NB progression is still poorly understood. Evidence from our recent works has shown that Prokineticin signaling is crucial in the growth and neuronal differentiation of NCCs and is implicated in the NB progression. More recently, we found that the Prokineticin receptors (PK-R1 and PK-R2) are differentially expressed in various malignant NB stem cell and neuronal subclones. In particular, these receptors are expressed at higher level in a neuronal subclone (SH-SY-5Y) than its parental clone (SK-N-SH), further suggesting the implication of Prokineticins in the growth of the malignant neuroblastic subpopulation. Subsequent flow cytometric analysis directly showed that Prokineticin-1 (Prok-1) profoundly increases the CSC population of SH-SY-5Y cells, which is c-kit, GD2 and CD133 positive. Isolated CSCs consistently expressed both PK-R1 and PK-R2 and these CSCs were still highly responsive to Prok-1 treatment. In addition to promoting the growth of CSCs in this neuronal subclone, Prok-1 also increased the p75NTR+ subpopulation in two other NB stem cell lines, implying that Prok-1 also promotes CSC progression through the malignant neuroblastic lineage. These p75NTR+ cells were highly proliferative and migratory, may contribute to the malignant phenotype of the NB. In sum, our current data suggests that Prokineticin signalling favours the tumor growth by promoting a) the growth of CSCs and b) differentiation to highly proliferative neuroblast. Understanding the novel roles of Prokineticin signaling will have profound implications for the diagnosis and therapeutic interventions for NB.