title: Oligodendrocyte/type-2 astrocyte progenitor cells and glial-restricted precursor cells generate different tumor phenotypes in response to the identical oncogenes.
abstract: Despite the great interest in identifying the cell-of-origin for different cancers, little knowledge exists regarding the extent to which the specific origin of a tumor contributes to its properties. To directly examine this question, we expressed identical oncogenes in two types of glial progenitor cells, glial-restricted precursor (GRP) cells and oligodendrocyte/type-2 astrocyte progenitor cells (O-2A/OPCs), and in astrocytes of the mouse CNS (either directly purified or generated from GRP cells). In vitro, expression of identical oncogenes in these cells generated populations differing in expression of antigens thought to identify tumor initiating cells, generation of 3D aggregates when grown as adherent cultures, and sensitivity to the chemotherapeutic agent BCNU. In vivo, cells differed in their ability to form tumors, in malignancy and even in the type of host-derived cells infiltrating the tumor mass. Moreover, identical genetic modification of these different cells yielded benign infiltrative astrocytomas, malignant astrocytomas, or tumors with characteristics seen in oligodendrogliomas and small-cell astrocytomas, indicating a contribution of cell-of-origin to the characteristic properties expressed by these different tumors. Our studies also revealed unexpected relationships between the cell-of-origin, differentiation, and the order of oncogene acquisition at different developmental stages in enabling neoplastic growth. These studies thus provide multiple novel demonstrations of the importance of the cell-of-origin in respect to the properties of transformed cells derived from them. In addition, the approaches used enable analysis of the role of cell-of-origin in tumor biology in ways that are not accessible by other more widely used approaches.
authors.affiliation: Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, New Jersey Center for Biomaterials, Piscataway, New Jersey 08854, Cleveland Clinic, Cleveland, Ohio, 44109, Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Jared
authors.initials: J
authors.lastname: Bushman
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Margot
authors.initials: M
authors.lastname: Mayer-Proschel
authors.forename: Mahlon
authors.initials: M
authors.lastname: Johnson
authors.forename: Mark
authors.initials: M
authors.lastname: Noble
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D018014:Gene Transfer Techniques; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C541485:EGFR protein, mouse; D066246:ErbB Receptors