PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo.
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.
Hambardzumyan
Dolores
D
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Becher
Oren J
OJ
Rosenblum
Marc K
MK
Pandolfi
Pier Paolo
PP
Manova-Todorova
Katia
K
Holland
Eric C
EC
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000528:radiation effects; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D002453:Cell Cycle / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D053823:Hedgehog Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000502:physiology; D000072079:Patched Receptors; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000528:radiation effects*; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014916:Whole-Body Irradiation
D053823:Hedgehog Proteins; D051059:PTEN Phosphohydrolase; D000072079:Patched Receptors; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D011956:Receptors, Cell Surface; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C465570:Shh protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C487757:Pten protein, mouse