title: A study of embryonic stem cell-related proteins in human astrocytomas: identification of Nanog as a predictor of survival.
abstract: Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO Grade II) and 98 high-grade human gliomas (WHO Grades III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low- and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n = 42) with high levels of Nanog protein (p = 0.0067) and of Klf4 protein (p = 0.0368), in high-grade astrocytomas (n = 85) with high levels of Nanog (p = 0.0042), Klf4 (p = 0.0447), and c-Myc (p = 0.0078) and in glioblastomas only (n = 71) with high levels of Nanog (p = 0.0422) and of c-Myc (p = 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p = 0.0039), high-grade astrocytomas (p = 0.0124) and glioblastomas only (p = 0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.
authors.affiliation: Department of Neuroscience, Neurology, Uppsala University, University Hospital, S-751 85, Uppsala; Karolinska Institute, Department of Oncology-Pathology, CCK R8:05, Karolinska University Hospital, S-17176, Stockholm, Sweden.
authors.forename: Tamador
authors.initials: T
authors.lastname: Elsir
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Edqvist
authors.forename: Joseph
authors.initials: J
authors.lastname: Carlson
authors.forename: Dan
authors.initials: D
authors.lastname: Ribom
authors.forename: Michael
authors.initials: M
authors.lastname: Bergqvist
authors.forename: Simon
authors.initials: S
authors.lastname: Ekman
authors.forename: Svetlana N
authors.initials: SN
authors.lastname: Popova
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ponten
authors.forename: Monica
authors.initials: M
authors.lastname: Nistér
authors.forename: Anja
authors.initials: A
authors.lastname: Smits
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001254:Astrocytoma / Q000737:chemistry* / Q000401:mortality; D001932:Brain Neoplasms / Q000737:chemistry* / Q000401:mortality; D053595:Embryonic Stem Cells / Q000737:chemistry*; D005260:Female; D018398:Homeodomain Proteins / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000032:analysis; D008297:Male; D008875:Middle Aged; D000071317:Nanog Homeobox Protein; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D046888:Tissue Array Analysis
chemical_list: D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D016271:Proto-Oncogene Proteins c-myc; D007521:Isocitrate Dehydrogenase
keywords: Nanog; astrocytoma; embryonic stem cells (ESC); glioma; survival