title: Cripto-1 is a cell surface marker for a tumorigenic, undifferentiated subpopulation in human embryonal carcinoma cells.
abstract: Deregulation of stem cells is associated with the generation and progression of malignant tumors. In addition, genes that are associated with early embryogenesis are frequently expressed in cancer. Cripto-1 (CR-1), a glycosylphosphatidylinositol-linked glycoprotein, is expressed during early embryogenesis and in various human carcinomas. We demonstrated that human embryonal carcinoma (EC) cells are heterogeneous for CR-1 expression and consist of two distinct subpopulations: a CR-1(High) and a CR-1(Low) population. By segregating CR-1(High) and CR-1(Low) populations of NTERA2/D1 EC cells by fluorescence-activated cell sorting, we demonstrated that CR-1(High) cells were more tumorigenic than CR-1(Low) cells by an in vitro tumor sphere assay and by in vivo xenograft formation. The CR-1(High) population was enriched in mRNA expression for the pluripotent embryonic stem (ES) cell genes Oct4, Sox2, and Nanog. CR-1 expression in NTERA2/D1 cells was regulated by a Smad2/3-dependent autocrine loop, by the ES cell-related transcription factors Oct4/Nanog, and partially by the DNA methylation status of the promoter region. These results demonstrate that CR-1 expression is enriched in an undifferentiated, tumorigenic subpopulation and is regulated by key regulators of pluripotent stem cells.
authors.affiliation: Mammary Biology and Tumorigenesis Laboratory, Robert H. LurieCancer Center Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Watanabe
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Meyer
authors.forename: Luigi
authors.initials: L
authors.lastname: Strizzi
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Lee
authors.forename: Monica
authors.initials: M
authors.lastname: Gonzales
authors.forename: Caterina
authors.initials: C
authors.lastname: Bianco
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Nagaoka
authors.forename: Shahram S
authors.initials: SS
authors.lastname: Farid
authors.forename: Naira
authors.initials: N
authors.lastname: Margaryan
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Vonderhaar
authors.forename: David S
authors.initials: DS
authors.lastname: Salomon
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D054278:Embryonal Carcinoma Stem Cells / Q000166:cytology* / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D058851:GPI-Linked Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C070636:TDGF1 protein, human; D004815:Epidermal Growth Factor