PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo Journal Article
| Authors: | Hambardzumyan, D.; Becher, O. J.; Rosenblum, M. K.; Pandolfi, P. P.; Manova-Todorova, K.; Holland, E. C. |
| Article Title: | PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo |
| 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. © 2008 by Cold Spring Harbor Laboratory Press. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; human tissue; protein expression; protein phosphorylation; nonhuman; brain neoplasms; cell proliferation; animal cell; mouse; animals; mice; mice, knockout; cerebellum; dna damage; cell survival; cells, cultured; cell cycle; cell structure; apoptosis; gene expression; protein kinases; animal experiment; animal model; hedgehog proteins; in vivo study; phosphatidylinositol 3 kinase; protein p53; cancer model; radiation exposure; radiation response; immunoenzyme techniques; fluorescent antibody technique; brain; neoplastic stem cells; medulloblastoma; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; cancer stem cell; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; pten phosphohydrolase; irradiation; tumor suppressor protein p53; cell cycle arrest; pten; proto-oncogene proteins c-myc; perifosine; p53; whole-body irradiation; receptors, cell surface; in situ nick-end labeling; desensitization; pi3k/akt |
| Journal Title: | Genes and Development |
| Volume: | 22 |
| Issue: | 4 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2008-02-15 |
| Start Page: | 436 |
| End Page: | 448 |
| Language: | English |
| DOI: | 10.1101/gad.1627008 |
| PUBMED: | 18281460 |
| PROVIDER: | scopus |
| PMCID: | PMC2238666 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 119" - "Export Date: 17 November 2011" - "CODEN: GEDEE" - "Source: Scopus" |
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25Becher
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