Identification of Cancer Stem Cells and Its Clinical Application for Treating Aggressive Neuroblastomas

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1. Identification of neuroblastoma stem-like cells marker genesThree cell lines with characteristic phenotype, N-, I-and S-type cells, were subcloned from the neuroblastoma cell lines at Sloan-kettering Cancer Hospital. By using our in-house cDNA microarray carrying 5300 cDNAs, we have identified more than several genes specifically expressed in I-type cells which are believed to be very close to the neuroblastoma stem cell.2. Expression of cancer stem cells markers in neuroblastomas in primary cultureTo search for the neuroblastoma stem cells, we used 34 neuroblastomas in primary culture as well as 6 neuroblastoma cell lines. Most of the primary neuroblastoma cells formed spheres, in which some cells were positive for sustained BrdU labeling, suggesting the presence of cancer stem cells of neuroblastoma. We then tested the significance of the potential markers of neuroblastoma stem cells in primary culture cells. Both nestin and TUJ1 were preferentially positive in favorable tumor cells as compared to unfavorable cells. Especially, expression of nestin was significantly high in tumor cells obtained from patients under one year of age. Expression of p75NTR also showed the similar pattern, but its expression levels were relatively low. Interestingly, both p63 and p73, the variants of p53 tumor suppressor, were highly expressed in many. neuroblastoma cells in primary culture independently of the tumor stages. Therefore, they could be new stem cell markers which might initiate the genesis of neuroblastoma. The further study about the functional roles of their variants, the TA form and the delta-N form, should be needed.