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PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo

¹ Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA; ² Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA; ³ Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA; ⁴ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA; ⁵ Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts 02215, USA; ⁶ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA; ⁷ Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA; ⁸ Department of Surgery (Neurosurgery), Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA

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.

[Keywords: p53; PTEN; PI3K/Akt; medulloblastoma]]

Received October 17, 2007; revised version accepted December 17, 2007.

E-MAIL hollande{at}mskcc.org; FAX (646) 422-0231.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1627008

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