title: Oncogenic signaling is dominant to cell of origin and dictates astrocytic or oligodendroglial tumor development from oligodendrocyte precursor cells.
abstract: Stem cells, believed to be the cellular origin of glioma, are able to generate gliomas, according to experimental studies. Here we investigated the potential and circumstances of more differentiated cells to generate glioma development. We and others have shown that oligodendrocyte precursor cells (OPCs) can also be the cell of origin for experimental oligodendroglial tumors. However, the question of whether OPCs have the capacity to initiate astrocytic gliomas remains unanswered. Astrocytic and oligodendroglial tumors represent the two most common groups of glioma and have been considered as distinct disease groups with putatively different origins. Here we show that mouse OPCs can give rise to both types of glioma given the right circumstances. We analyzed tumors induced by K-RAS and AKT and compared them to oligodendroglial platelet-derived growth factor B-induced tumors in Ctv-a mice with targeted deletions of Cdkn2a (p16(Ink4a-/-), p19(Arf-/-), Cdkn2a(-/-)). Our results showed that glioma can originate from OPCs through overexpression of K-RAS and AKT when combined with p19(Arf) loss, and these tumors displayed an astrocytic histology and high expression of astrocytic markers. We argue that OPCs have the potential to develop both astrocytic and oligodendroglial tumors given loss of p19(Arf), and that oncogenic signaling is dominant to cell of origin in determining glioma phenotype. Our mouse data are supported by the fact that human astrocytoma and oligodendroglioma display a high degree of overlap in global gene expression with no clear distinctions between the two diagnoses.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, SE-75185 Uppsala, Sweden, Department of Cancer Biology and Genetics, and The Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, Human Biology Division and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, lene.uhrbom@igp.uu.se nlindber@fhcrc.org.
authors.forename: Nanna
authors.initials: N
authors.lastname: Lindberg
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, SE-75185 Uppsala, Sweden.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, SE-75185 Uppsala, Sweden.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Human Biology Division and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
authors.forename: Hamid
authors.initials: H
authors.lastname: Bolouri
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, SE-75185 Uppsala, Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Kastemar
authors.affiliation: The National Board of Forensic Medicine, Department of Forensic Medicine, SE-75140 Uppsala, Sweden, and.
authors.forename: Tommie
authors.initials: T
authors.lastname: Olofsson
authors.affiliation: Department of Cancer Biology and Genetics, and The Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, Human Biology Division and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, Department of Neurosurgery and Alvord Brain Tumor Center, University of Washington, Seattle, Washington 98195.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, SE-75185 Uppsala, Sweden, lene.uhrbom@igp.uu.se nlindber@fhcrc.org.
authors.forename: Lene
authors.initials: L
authors.lastname: Uhrbom
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D019070:Cell Lineage; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D009837:Oligodendroglioma / Q000378:metabolism / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D014746:Vimentin; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: PDGF; astrocytoma; cell of origin; glioma; low-grade glioma; oligodendroglioma