Neuroblastoma: the result of multistep transformation?

Genetic and molecular abnormalities, in association with malignant phenotypes, have been previously demonstrated in a variety of human tumors. Although the multistep theory fits well for some cancers such as retinoblastoma and colon carcinoma, for many others it still remains to be proven. Neuroblastoma, a tumor found in pediatric patients, seems to fall into the multistep model. Nonrandom chromosome abnormalities have been found with 1p deletion, loss of heterozygosity for short arm of chromosome 1 and for chromosome 11q and 14q. Amplification of N-myc oncogene and an increased level of Ras protein have also been demonstrated. Therefore, even if it is not possible to show that these mutations happen as discrete events in their order of appearance, the multistep model seems involved in neuroblastoma development. Neuroblastoma has a peculiar aspect, however, that makes this tumor a natural model of defect of cell differentiation. In fact, there is a particular subset of metastatic tumors that show spontaneous regression. In vitro, neuroblastoma cell lines can be induced to differentiate along the neural pathway using retinoic acid. Other natural and chemical substances are also able to induce cell differentiation. During retinoic acid treatment, N-myc oncogene expression decreases and other genes are deregulated. p53 and MDR1 gene expression increases. These two different aspects, failure of cell differentiation pathway and genetic mutations, make the neuroblastoma one of the most difficult problems of modern molecular biology.