title: Akt and c-Myc induce stem-cell markers in mature primary p53⁻/⁻ astrocytes and render these cells gliomagenic in the brain of immunocompetent mice.
abstract: Astrocytomas and their most malignant variant glioblastoma multiforme (GBM) represent the vast majority of primary brain tumors. Despite the current progress in neurosurgery, radiation therapy and chemotherapy, most astrocytomas remain fatal disorders. Although brain tumor biology is a matter of intense research, the cell-of-origin and the complete astrocytoma-inducing signaling pathway remain unknown. To further identify the mechanisms leading to gliomagenesis, we transduced primary astrocytes on a p53(-/-) background with c-Myc, constitutively active myr-Akt or both, myr-Akt and c-Myc. Transduced astrocytes showed oncogene-specific alterations of morphology, proliferation and differentiation. Following prolonged periods of cultivation, oncogene-transduced astrocytes expressed several stem-cell markers. Furthermore, astrocytes coexpressing c-Myc and Akt were tumorigenic when implanted into the brain of immunocompetent C57BL/6 mice. Our results reveal that the loss of p53 combined with oncogene overexpression in mature astrocytes simulates pivotal features of glioma pathogenesis, providing a good model for assessing the development of secondary glioblastomas.
authors: Department of Neuropathology, Philipps University of Marburg, Marburg, Germany.
authors: Josefine
authors: J
authors: Radke
authors: Ginette
authors: G
authors: Bortolussi
authors: Axel
authors: A
authors: Pagenstecher
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005910:Glioma / Q000473:pathology*; D006801:Humans; D007121:Immunocompetence; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
chemical_list: D015415:Biomarkers; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt