title: Human neuroblastoma I-type cells are malignant neural crest stem cells.
abstract: Human neuroblastoma I-type cells isolated from cell lines in vitro are morphologically intermediate between neuroblastic (N) cells, with properties of embryonic sympathoblasts, and substrate-adherent (S) cells having properties of embryonic Schwann/glial/melanocytic cells of the neural crest. I cells have biochemical features of both N and S cells. We propose that the I-type cell represents a malignant neural crest stem cell. The strongest evidence in support of this hypothesis is that: (a) I cells can generate progeny that have neuronal properties, i.e., are committed neuroblasts, or properties of nonneuronal, embryonic neural crest-derived cells; and (b) I-type cells can generate multipotent I-type progeny, indicating their capacity for self-renewal, a feature of stem cells. We report here that I-type cells, derived from four different human neuroblastoma cell lines and experimentally induced to differentiate, give rise to cells with distinct N or S cell phenotypes, indicative of I cell multipotentiality. Experiments with a large panel of I-type subclones, isolated from clonal I-type BE(2)-C cells and exposed to retinoic acid to induce neuronal differentiation or 5-bromo-2'-deoxyuridine to obtain S-type cells, demonstrated that differentiation occurs via induction and selection and not by selection of spontaneously arising variants. The differentiation phenotype was stable. We conclude that human neuroblastoma I-type cells are multipotent embryonic precursor cells of the peripheral nervous system, capable of either neuronal or nonneuronal neural crest cell differentiation.
authors.affiliation: Department of Biological Sciences, Fordham University, Bronx, New York 10458, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Ross
authors.forename: B A
authors.initials: BA
authors.lastname: Spengler
authors.forename: C
authors.initials: C
authors.lastname: Domènech
authors.forename: M
authors.initials: M
authors.lastname: Porubcin
authors.forename: W J
authors.initials: WJ
authors.lastname: Rettig
authors.forename: J L
authors.initials: JL
authors.lastname: Biedler
mesh_terms: D001973:Bromodeoxyuridine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells; D006801:Humans; D009432:Neural Crest / Q000473:pathology*; D009447:Neuroblastoma / Q000473:pathology*; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D014212:Tretinoin; D001973:Bromodeoxyuridine