title: Loss of Sparc in p53-null Astrocytes Promotes Macrophage Activation and Phagocytosis Resulting in Decreased Tumor Size and Tumor Cell Survival.
abstract: Both the induction of SPARC expression and the loss of the p53 tumor suppressor gene are changes that occur early in glioma development. Both SPARC and p53 regulate glioma cell survival by inverse effects on apoptotic signaling. Therefore, during glioma formation, the upregulation of SPARC may cooperate with the loss of p53 to enhance cell survival. This study determined whether the loss of Sparc in astrocytes that are null for p53 would result in reduced cell survival and tumor formation and increased tumor immunogenicity in an in vivo xenograft brain tumor model. In vitro, the loss of Sparc in p53-null astrocytes resulted in an increase in cell proliferation, but a loss of tumorigenicity. At 7 days after intracranial implantation, Sparc-null tumors had decreased tumor cell survival, proliferation and reduced tumor size. The loss of Sparc promoted microglia/macrophage activation and phagocytosis of tumor cells. Our results indicate that the loss of p53 by deletion/mutation in the early stages of glioma formation may cooperate with the induction of SPARC to potentiate cancer cell survival and escape from immune surveillance.
authors.affiliation: Department of Neurosurgery, Barbara Jane Levy Laboratory of Molecular Neuro-Oncology and Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI.|Department of Clinical Neurosciences, Laboratory of Molecular Neuro-Oncology, Division of Neurosurgery, Spectrum Health System, Grand Rapids, MI.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Thomas
authors.affiliation: Department of Neurosurgery, Barbara Jane Levy Laboratory of Molecular Neuro-Oncology and Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI.|Department of Clinical Neurosciences, Laboratory of Molecular Neuro-Oncology, Division of Neurosurgery, Spectrum Health System, Grand Rapids, MI.
authors.forename: Chad R
authors.initials: CR
authors.lastname: Schultz
authors.affiliation: Department of Neurosurgery, Barbara Jane Levy Laboratory of Molecular Neuro-Oncology and Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI.
authors.forename: Ezekiell
authors.initials: E
authors.lastname: Mouzon
authors.affiliation: Department of Neurosurgery, Barbara Jane Levy Laboratory of Molecular Neuro-Oncology and Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI.|Department of Clinical Neurosciences, Laboratory of Molecular Neuro-Oncology, Division of Neurosurgery, Spectrum Health System, Grand Rapids, MI.
authors.forename: William A
authors.initials: WA
authors.lastname: Golembieski
authors.affiliation: Department of Neurosurgery, Barbara Jane Levy Laboratory of Molecular Neuro-Oncology and Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI.
authors.forename: Reima
authors.initials: R
authors.lastname: El Naili
authors.affiliation: Department of Neurosurgery, Barbara Jane Levy Laboratory of Molecular Neuro-Oncology and Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI.
authors.forename: Archanna
authors.initials: A
authors.lastname: Radakrishnan
authors.affiliation: Department of Neurosurgery, Barbara Jane Levy Laboratory of Molecular Neuro-Oncology and Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI.
authors.forename: Nancy
authors.initials: N
authors.lastname: Lemke
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI.
authors.forename: Laila M
authors.initials: LM
authors.lastname: Poisson
authors.affiliation: Department of Pathology, Henry Ford Hospital, Detroit, MI.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Gutiérrez
authors.affiliation: Department of Neuropathology and Clinical Neurosciences, Spectrum Health System, Grand Rapids, MI.
authors.forename: Sandra
authors.initials: S
authors.lastname: Cottingham
authors.affiliation: Department of Neurosurgery, Barbara Jane Levy Laboratory of Molecular Neuro-Oncology and Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI.|Department of Clinical Neurosciences, Laboratory of Molecular Neuro-Oncology, Division of Neurosurgery, Spectrum Health System, Grand Rapids, MI.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Rempel
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002540:Cerebral Cortex / Q000166:cytology; D005838:Genotype; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D015676:Osteonectin / Q000172:deficiency* / Q000235:genetics; D010587:Phagocytosis / Q000235:genetics* / Q000502:physiology; D051381:Rats; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: D015676:Osteonectin; C578250:SPARC protein, mouse; D016159:Tumor Suppressor Protein p53
keywords: SPARC; Sparc-null; TP53; glioblastoma; glioma; immunosuppression; macrophage; microglia; p53; p53-null; xenograft