Neuroblastoma: A Malignancy Due to Cell Differentiation Block

Neuroblastoma originates from precursor neuroblasts of the sympathetic nervous system. Unlike most other cancer types, neuroblastoma is characterized by a unique capacity for spontaneous complete regression, at least partly through neuronal differentiation, in a proportion of patients, and is therefore regarded as a cancer due to cell differentiation block. The first demonstration of in vitro differentiation of human neuroblastoma cells was published 30 years ago, when human SK-N-SH and SH-SY5Y neuroblastoma cells were shown to differentiate morphologically (neurite outgrowth) and biochemically in response to 12-O-tetradecanoyl-phorbol-13-acetate (TPA) treatment (Påhlman et al., 1981). The differentiated cells showed an increased expression of noradrenaline, adrenaline and neuron-specific enolase (NSE), differentiation markers which are employed for the diagnosis of neuroblastoma in patients. In 1982, retinoic acid (RA) was shown to induce concentrationdependent morphologic differentiation and growth inhibition in the LA-N-1 human neuroblastoma cell line (Sidell, 1982). The RA-induced morphologic differentiation and growth inhibition persisted despite removal of the drug. These observations demonstrate that RA promotes the differentiation of LA-N-1 neuroblastoma cells and results in a reduced expression of the malignant phenotype, and suggest that patients with advanced neuroblastoma may be successfully treated by RA to induce their tumour cells to differentiate and to undergo growth inhibition. In the last three decades, a number of factors, such as up-regulation of the expression of retinoic acid receptors, have been identified as crucial for the induction or blockage of neuroblastoma cell differentiation. Importantly, naturally occurring and synthetic retinoids have shown great promise in the clinic when used as differentiation agents in neuroblastoma patients with minimal residual disease, while the mechanism of retinoid anticancer signalling in neuroblastoma is still not fully understood (Liu et al., 2005; Reynolds et al., 2003).