Microarray analyses reveals “what’s up” in human neuroblastoma malignant stem cells

2006 
Proc Amer Assoc Cancer Res, Volume 47, 2006 4337 Human neuroblastoma cell lines comprise three different phenotypes: neuroblastic (N), substrate adherent (S), and stem cell (I), each having distinct morphological, biochemical and tumorigenic characteristics. The I-type malignant stem cells can undergo continuous self-renewal or can differentiate into N-type or S-type cells, spontaneously or when induced with various differentiating agents. Previous studies measuring plating efficiency in soft agar and tumor formation in athymic mice showed that I-type cells are significantly more malignant than either N or S, regardless of N-myc expression or amplification status. To better characterize these I-type cells and explore the mechanisms underlying their malignant potential, microarray expression data are being analyzed to identify genes that are differentially expressed in the I cells compared to the N and S cells. To date, more than 300 possible candidates have been identified with the Affymetrix Gene Chip Human Genome U 95 Set and Human Genome U 133 Plus 2.0 Arrays. Semi-quantitative RT-PCR confirmed consistently elevated expression in I versus N or S cells in only 5 candidates (CD133, KIT, HUMNF1ISO, GPRC5C, and NOTCH1). Almost 50 gene candidates showing either increased or decreased expression in I cells on the above mentioned microarray platforms were not differentially expressed when studied by RT-PCR. Western blot analyses of the CD133, c-kit, and Notch1 proteins confirm their greater expression in I cells compared to N and S cells. Most of these proteins are expressed by normal (non-transformed) stem cells and thus their increased expression may reflect the stem cell nature of I cells. The role(s) that these proteins play in the malignant potential of the cancer stem cell remains to be determined. Since recent evidence suggests that the malignant stem cell may be the causative agent in tumor progression in human neuroblastoma, the I-type cancer stem cell may be a crucial therapeutic target in the management of this devastating childhood cancer.
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