Abstract
Medulloblastomas are brain tumors that arise in the cerebellum of children and contain stem cells in a perivascular niche thought to give rise to recurrence following radiation. We used several mouse models of medulloblastomas in parallel to better understand how the critical cell types in these tumors respond to therapy. In our models, the proliferating cells in the tumor bulk undergo radiation-induced, p53-dependent apoptotic cell death. Activation of Akt signaling via PTEN loss transforms these cells to a nonproliferating extensive nodularity morphology. By contrast, the nestin-expressing perivascular stem cells survive radiation, activate PI3K/Akt pathway, undergo p53-dependent cell cycle arrest, and re-enter the cell cycle at 72 h. Furthermore, the ability of these cells to induce p53 is dependent on the presence of PTEN. These cellular characteristics are similar to human medulloblastomas. Finally, inhibition of Akt signaling sensitizes cells in the perivascular region to radiation-induced apoptosis.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / metabolism
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Brain / radiation effects
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Brain Neoplasms / radiotherapy*
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Cell Cycle / radiation effects
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Cell Proliferation / radiation effects
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Cell Survival
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Cells, Cultured
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Fluorescent Antibody Technique
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Hedgehog Proteins / genetics
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Hedgehog Proteins / physiology
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Humans
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Immunoenzyme Techniques
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In Situ Nick-End Labeling
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Medulloblastoma / metabolism
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Medulloblastoma / pathology
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Medulloblastoma / radiotherapy*
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Mice
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Mice, Knockout
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Neoplastic Stem Cells / pathology*
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PTEN Phosphohydrolase / physiology
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Patched Receptors
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Phosphatidylinositol 3-Kinases / physiology*
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Protein Kinases / metabolism
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Proto-Oncogene Proteins c-akt / physiology*
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / physiology
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / physiology
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Signal Transduction / radiation effects*
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TOR Serine-Threonine Kinases
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Tumor Suppressor Protein p53 / metabolism
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Whole-Body Irradiation
Substances
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Hedgehog Proteins
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Patched Receptors
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Proto-Oncogene Proteins c-myc
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Receptors, Cell Surface
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Shh protein, mouse
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Tumor Suppressor Protein p53
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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PTEN Phosphohydrolase
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Pten protein, mouse