title: Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance.
abstract: Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Among these heterogeneous tumors, a subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IRs), then supporting the GBM rapid recurrence after radiotherapy. In the present study we demonstrated that subtoxic IR exposure of differentiated GBM cells isolated from patient resections potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an upregulation of the anti-apoptotic protein survivin and we showed that its specific downregulation led to the blockade of the IR-induced plasticity. Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to the development of some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.
authors.affiliation: INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: P
authors.initials: P
authors.lastname: Dahan
authors.affiliation: INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: J
authors.initials: J
authors.lastname: Martinez Gala
authors.affiliation: 1] INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III Paul Sabatier, Toulouse, France [2] Laboratoire d'Oncogénétique, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Delmas
authors.affiliation: 1] INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III Paul Sabatier, Toulouse, France [2] Faculté des Sciences Pharmaceutiques, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: Monferran
authors.affiliation: INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: L
authors.initials: L
authors.lastname: Malric
authors.affiliation: Faculté des Sciences Pharmaceutiques, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: D
authors.initials: D
authors.lastname: Zentkowski
authors.affiliation: 1] INSERM UMR 825, Université Toulouse III Paul Sabatier, Toulouse, France [2] Service de Neurochirurgie, Centre Hospitalier Universitaire de Rangueil, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: V
authors.initials: V
authors.lastname: Lubrano
authors.affiliation: 1] INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III Paul Sabatier, Toulouse, France [2] Laboratoire d'Oncogénétique, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Toulas
authors.affiliation: 1] INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III Paul Sabatier, Toulouse, France [2] Département de Radiothérapie et Oncologie, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.
authors.forename: E
authors.initials: E
authors.lastname: Cohen-Jonathan Moyal
authors.affiliation: 1] INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III Paul Sabatier, Toulouse, France [2] Faculté des Sciences Pharmaceutiques, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: A
authors.initials: A
authors.lastname: Lemarie
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D054337:Cell Dedifferentiation / Q000528:radiation effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D015536:Down-Regulation / Q000528:radiation effects; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D010641:Phenotype; D011836:Radiation Tolerance / Q000528:radiation effects*; D011839:Radiation, Ionizing; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin