Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133− cells, and the CD133+ sector is enlarged by hypoxia

Blazek, Ed Robert; Foutch, Jennifer L.; Maki, Guitta

doi:10.1016/j.ijrobp.2006.09.037

Cited by 233 publications

(196 citation statements)

References 14 publications

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“…However, recent data cast doubt on these early findings. Under hypoxic conditions, CD133 À CSCs expressed CD133 þ (38,39). Also, in vivo studies showed that CD133 À CSCs drive tumorigenesis in nude rats (24,40).…”

Section: Discussionmentioning

confidence: 98%

A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells

Lim

Roberts

Day

et al. 2012

Molecular Cancer Therapeutics

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Glioblastoma multiforme (GBM) is the most common form of brain tumor with a poor prognosis and resistance to radiotherapy. Recent evidence suggests that glioma-initiating cells play a central role in radioresistance through DNA damage checkpoint activation and enhanced DNA repair. To investigate this in more detail, we compared the DNA damage response in nontumor forming neural progenitor cells (NPC) and glioma-initiating cells isolated from GBM patient specimens. As observed for GBM tumors, initial characterization showed that gliomainitiating cells have long-term self-renewal capacity. They express markers identical to NPCs and have the ability to form tumors in an animal model. In addition, these cells are radioresistant to varying degrees, which could not be explained by enhanced nonhomologous end joining (NHEJ). Indeed, NHEJ in glioma-initiating cells was equivalent, or in some cases reduced, as compared with NPCs. However, there was evidence for more efficient homologous recombination repair in glioma-initiating cells. We did not observe a prolonged cell cycle nor enhanced basal activation of checkpoint proteins as reported previously. Rather, cell-cycle defects in the G 1 -S and S-phase checkpoints were observed by determining entry into S-phase and radioresistant DNA synthesis following irradiation. These data suggest that homologous recombination and cell-cycle checkpoint abnormalities may contribute to the radioresistance of glioma-initiating cells and that both processes may be suitable targets for therapy.

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Section: Discussionmentioning

confidence: 98%

A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells

Lim

Roberts

Day

et al. 2012

Molecular Cancer Therapeutics

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“…In this heterogeneous tumor, CD133À cells in long-term culture were found to be capable of tumor initiation in mice (Chen et al, 2010), although many recent publications maintain that not only is the CD133 þ fraction enriched in BTIC capacity Yan et al, 2011), but the features of 'stemness' marked by CD133 are associated with increasing malignancy and poor patient outcome (Bao et al, 2006;Thon et al, 2008;McCord et al, 2009;Pallini et al, 2010). In medulloblastoma, evidence more uniformly supports the application of CD133 as a BTIC marker, as CD133 þ multipotent NSCs were described in the postnatal cerebellum (Lee et al, 2005), and further studies showed that CD133 enriched for brain tumor-initiating capacity and radioresistance in primary and Daoy medulloblastoma-derived tumors (Fan et al, 2006;Blazek et al, 2007;Annabi et al, 2008Annabi et al, , 2010Pistollato et al, 2010;Yu et al, 2010). In contrast to previous experiments performed on unsorted cells, we found a differential expression of Hh pathway components between the CD133 þ stem-like cells and the CD133À late progenitors or differentiated cells.…”

Section: Shh Regulates Bmi1 In Medulloblastoma Bticsmentioning

confidence: 99%

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

et al. 2011

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Bmi1 is a key stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including medulloblastoma. Overexpression of Bmi1 promotes cell proliferation and is required for hedgehog (Hh) pathwaydriven tumorigenesis. This study aimed to determine if Sonic hedgehog (Shh) modulates the key stem cell regulatory gene Bmi1 in childhood medulloblastoma brain tumor-initiating cells (BTICs). Although current literature suggests that there is a correlation between Shh pathway genes and Bmi1 expression, it is unclear whether there is indeed a direct regulatory mechanism. To address whether Shh induces expression of Bmi1, stem cell-enriched populations from medulloblastoma cell lines and primary samples were treated with Shh ligand and KAAD-cyclopamine (Shh antagonist). Our data indicate that Bmi1 expression positively correlates with increasing Shh ligand concentrations. Chromatin immunoprecipitation reveals that Gli1 preferentially binds to the Bmi1 promoter, and Bmi1 transcript levels are increased and decreased by Gli1 overexpression and downregulation, respectively. Knockdown experiments of Bmi1 in vitro and in vivo demonstrate that Hh signaling not only drives Bmi1 expression, but a feedback mechanism exists wherein downstream effectors of Bmi1 may, in turn, activate Hh pathway genes. These findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance. Recent molecular characterization of medulloblastoma also reveals that Bmi1 is overexpressed across all subgroups of medulloblastoma, particularly in the most aggressive subtypes. Lastly, despite recent identification of BTIC markers, the molecular characterization of these cell populations remains unclear. In this work, we propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell-cell interaction between the CD133 þ Hh receptor cells and the CD133À Hh-secreting cells.

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“…CSC population is increased in hypoxic conditions, which means that HIF-1 may be stabilized in these cells. This can have a role in tumor radioresistance (Blazek et al, 2007).…”

Section: Cscs and Angiogenesismentioning

confidence: 99%

Cancer Stem Cells and Response to Therapy

Tabarestani¹,

Ghafouri‐Fard²

2012

Asian Pacific Journal of Cancer Prevention

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The cancer stem cell (CSC) model states that cancers are organized in cellular hierarchies, which explains the functional heterogeneity often seen in tumors. Like normal tissue stem cells, CSCs are capable of self-renewal, either by symmetric or asymmetric cell division, and have the exclusive ability to reproduce malignant tumors indefinitely. Current systemic cancer therapies frequently fail to eliminate advanced tumors, which may be due to their inability to effectively target CSC populations. It has been shown that embryonic pathways such as Wnt, Hedgehog, and Notch control self-renewal and cell fate decisions of stem cells and progenitor cells. These are evolutionary conserved pathways, involved in CSC maintenance. Targeting these pathways may be effective in eradicating CSCs and preventing chemotherapy or radiotherapy resistance.

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Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133− cells, and the CD133+ sector is enlarged by hypoxia

Cited by 233 publications

References 14 publications

A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells

A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

Cancer Stem Cells and Response to Therapy

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