title: Temporally regulated neural crest transcription factors distinguish neuroectodermal tumors of varying malignancy and differentiation.
abstract: Neuroectodermal tumor cells, like neural crest (NC) cells, are pluripotent, proliferative, and migratory. We tested the hypothesis that genetic programs essential to NC development are activated in neuroectodermal tumors. We examined the expression of transcription factors PAX3, PAX7, AP-2alpha, and SOX10 in human embryos and neuroectodermal tumors: neurofibroma, schwannoma, neuroblastoma, malignant nerve sheath tumor, melanoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, and Ewing's sarcoma. We also examined the expression of P0, ERBB3, and STX, targets of SOX10, AP-2alpha, and PAX3, respectively. PAX3, AP-2alpha, and SOX10 were expressed sequentially in human NC development, whereas PAX7 was restricted to mesoderm. Tumors expressed PAX3, AP-2alpha, SOX10, and PAX7 in specific combinations. SOX10 and AP-2alpha were expressed in relatively differentiated neoplasms. The early NC marker, PAX3, and its homologue, PAX7, were detected in poorly differentiated tumors and tumors with malignant potential. Expression of NC transcription factors and target genes correlated. Transcription factors essential to NC development are thus present in neuroectodermal tumors. Correlation of specific NC transcription factors with phenotype, and with expression of specific downstream genes, provides evidence that these transcription factors actively influence gene expression and tumor behavior. These findings suggest that PAX3, PAX7, AP-2alpha, and SOX10 are potential markers of prognosis and targets for therapeutic intervention.
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. gershont@mskcc.org
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Gershon
authors.forename: Orit
authors.initials: O
authors.lastname: Oppenheimer
authors.forename: Steven S
authors.initials: SS
authors.lastname: Chin
authors.forename: William L
authors.initials: WL
authors.lastname: Gerald
mesh_terms: D014408:Biomarkers, Tumor; D002454:Cell Differentiation; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006609:High Mobility Group Proteins / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D008648:Mesoderm / Q000378:metabolism; D009432:Neural Crest / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D055757:SOXE Transcription Factors; D012583:Schwann Cells / Q000166:cytology; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; D014157:Transcription Factors