title: Diffusible Factors Secreted by Glioblastoma and Medulloblastoma Cells Induce Oxidative Stress in Bystander Neural Stem Progenitors.
abstract: Harmful effects that alter the homeostasis of neural stem or progenitor cells (NSPs) can affect regenerative processes in the central nervous system. We investigated the effect of soluble factors secreted by control or (137)Cs-γ-irradiated glioblastoma or medulloblastoma cells on redox-modulated endpoints in recipient human NSPs. Growth medium harvested from the nonirradiated brain tumor cells, following 24 h of growth, induced prominent oxidative stress in recipient NSPs as judged by overall increases in mitochondrial superoxide radical levels (p < .001), activation of c-jun N-terminal kinase, and decrease in the active form of FoxO3a. The induced oxidative stress was associated with phosphorylation of p53 on serine 15, a marker of DNA damage, induction of the cyclin-cyclin dependent kinase inhibitors p21(Waf1) and p27(Kip1), and perturbations in cell cycle progression (p < .001). These changes were also associated with increased apoptosis as determined by enhanced annexin V staining (p < .001) and caspase 8 activation (p < .05) and altered expression of critical regulators of self-renewal, proliferation, and differentiation. Exposure of the tumor cells to radiation only slightly altered the induced oxidative changes in the bystander NSPs, except for medium from irradiated medulloblastoma cells that was more potent at inducing apoptosis in the NSPs than medium from nonirradiated cells (p < .001). The elucidation of such stressful bystander effects provides avenues to understand the biochemical events underlying the development or exacerbation of degenerative outcomes associated with brain cancers. It is also relevant to tissue culture protocols whereby growth medium conditioned by tumor cells is often used to support the growth of stem cells.
authors: Department of Radiology, New Jersey Medical School-Cancer Center, Rutgers University, NJ, USA.
authors: Neha
authors: N
authors: Sharma
authors: Department of Radiology, New Jersey Medical School-Cancer Center, Rutgers University, NJ, USA.
authors: Nicholas W
authors: NW
authors: Colangelo
authors: Department of Radiology, New Jersey Medical School-Cancer Center, Rutgers University, NJ, USA.
authors: Sonia M
authors: SM
authors: de Toledo
authors: Department of Radiology, New Jersey Medical School-Cancer Center, Rutgers University, NJ, USA edouard.azzam@rutgers.edu.
authors: Edouard I
authors: EI
authors: Azzam
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D024201:Bystander Effect / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005909:Glioblastoma / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008527:Medulloblastoma / Q000737:chemistry* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D058953:Neural Stem Cells / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D017304:Annexin A5; D017077:Culture Media, Conditioned; D017382:Reactive Oxygen Species; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D016159:Tumor Suppressor Protein p53; D048031:JNK Mitogen-Activated Protein Kinases
keywords: brain tumors; intercellular communication; ionizing radiation or bystander effect; neural stem progenitors; reactive oxygen species