Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors Journal Article
| Authors: | Fan, X.; Matsui, W.; Khaki, L.; Stearns, D.; Chun, J.; Li, Y. M.; Eberhart, C. G. |
| Article Title: | Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors |
| Abstract: | The Notch signaling pathway is required in both nonneoplastic neural stem cells and embryonal brain tumors, such as medulloblastoma, which are derived from such cells. We investigated the effects of Notch pathway inhibition on medulloblastoma growth using pharmacologic inhibitors of γ-secretase. Notch blockade suppressed expression of the pathway target Hes1 and caused cell cycle exit, apoptosis, and differentiation in medulloblastoma cell lines. Interestingly, viable populations of better-differentiated cells continued to grow when Notch activation was inhibited but were unable to efficiently form soft-agar colonies or tumor xenografts, suggesting that a cell fraction required for tumor propagation had been depleted. It has recently been hypothesized that a small population of stem-like cells within brain tumors is required for the long-term propagation of neoplastic growth and that CD133 expression and Hoechst dye exclusion (side population) can be used to prospectively identify such tumor-forming cells. We found that Notch blockade reduced the CD133-positive cell fraction almost 5-fold and totally abolished the side population, suggesting that the loss of tumorforming capacity could be due to the depletion of stem-like cells. Notch signaling levels were higher in the stem-like cell fraction, providing a potential mechanism for their increased sensitivity to inhibition of this pathway. We also observed that apoptotic rates following Notch blockade were almost 10-fold higher in primitive nestin-positive cells as compared with nestin-negative ones. Stem-like cells in brain tumors thus seem to be selectively vulnerable to agents inhibiting the Notch pathway. ©2006 American Association for Cancer Research. |
| Keywords: | signal transduction; controlled study; protein expression; human cell; cancer growth; brain tumor; brain neoplasms; animals; mice; cell cycle; drug inhibition; apoptosis; protease inhibitors; nerve tissue proteins; notch receptor; neural stem cell; cell differentiation; neurons; cancer cell culture; tumor xenograft; cell population; cell line, tumor; carcinogenesis; stem cell; drug mechanism; receptors, notch; medulloblastoma; cell growth processes; transplantation, heterologous; cell fractionation; cd133 antigen; nestin; intermediate filament proteins; gamma secretase inhibitor; amyloid precursor protein secretases; endopeptidases; brain graft; tumor stem cells; aspartic endopeptidases |
| Journal Title: | Cancer Research |
| Volume: | 66 |
| Issue: | 15 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2006-08-01 |
| Start Page: | 7445 |
| End Page: | 7452 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-06-0858 |
| PUBMED: | 16885340 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 274" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus" |
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