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

Dolores Hambardzumyan, Oren J. Becher, Marc K. Rosenblum, Pier Paolo Pandolfi, Katia Manova-Todorova, Eric C. Holland*

*Corresponding author for this work

Research output: Contribution to journalArticle

349 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)436-448
Number of pages13
JournalGenes and Development
Volume22
Issue number4
DOIs
StatePublished - Feb 15 2008

Keywords

  • Medulloblastoma
  • PI3K/Akt
  • PTEN
  • p53

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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