title: Activation of neural and pluripotent stem cell signatures correlates with increased malignancy in human glioma.
abstract: The presence of stem cell characteristics in glioma cells raises the possibility that mechanisms promoting the maintenance and self-renewal of tissue specific stem cells have a similar function in tumor cells. Here we characterized human gliomas of various malignancy grades for the expression of stem cell regulatory proteins. We show that cells in high grade glioma co-express an array of markers defining neural stem cells (NSCs) and that these proteins can fulfill similar functions in tumor cells as in NSCs. However, in contrast to NSCs glioma cells co-express neural proteins together with pluripotent stem cell markers, including the transcription factors Oct4, Sox2, Nanog and Klf4. In line with this finding, in high grade gliomas mesodermal- and endodermal-specific transcription factors were detected together with neural proteins, a combination of lineage markers not normally present in the central nervous system. Persistent presence of pluripotent stem cell traits could only be detected in solid tumors, and observations based on in vitro studies and xenograft transplantations in mice imply that this presence is dependent on the combined activity of intrinsic and extrinsic regulatory cues. Together these results demonstrate a general deregulated expression of neural and pluripotent stem cell traits in malignant human gliomas, and indicate that stem cell regulatory factors may provide significant targets for therapeutic strategies.
authors.affiliation: Ludwig Institute for Cancer Research, Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. johan.holmberg@licr.ki.se
authors.forename: Johan
authors.initials: J
authors.lastname: Holmberg
authors.forename: Xiaobing
authors.initials: X
authors.lastname: He
authors.forename: Inti
authors.initials: I
authors.lastname: Peredo
authors.forename: Abiel
authors.initials: A
authors.lastname: Orrego
authors.forename: Göran
authors.initials: G
authors.lastname: Hesselager
authors.forename: Christer
authors.initials: C
authors.lastname: Ericsson
authors.forename: Outi
authors.initials: O
authors.lastname: Hovatta
authors.forename: Sueli Mieko
authors.initials: SM
authors.lastname: Oba-Shinjo
authors.forename: Suely Kazue Nagahashi
authors.initials: SK
authors.lastname: Marie
authors.forename: Monica
authors.initials: M
authors.lastname: Nistér
authors.forename: Jonas
authors.initials: J
authors.lastname: Muhr
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D000071317:Nanog Homeobox Protein; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D055748:SOXB1 Transcription Factors