Glioma stem cells promote radioresistance by preferential activation of the DNA damage response

  title={Glioma stem cells promote radioresistance by preferential activation of the DNA damage response},
  author={Shideng Bao and Qiulian Wu and Roger E. McLendon and Yueling Hao and Qing Shi and Anita B. Hjelmeland and Mark W. Dewhirst and Darell D. Bigner and Jeremy N. Rich},
Ionizing radiation represents the most effective therapy for glioblastoma (World Health Organization grade IV glioma), one of the most lethal human malignancies, but radiotherapy remains only palliative because of radioresistance. The mechanisms underlying tumour radioresistance have remained elusive. Here we show that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. The fraction… 

Low Dose Ionizing Radiation Responses and Knockdown of ATM Kinase Activity in Glioma Stem Cells

A benefit in low dose radiation combined with chemotherapy resulting in a reduction in malignancy of glioma stem cells is demonstrated.

Notch Promotes Radioresistance of Glioma Stem Cells

It is shown that inhibition of Notch pathway with γ‐secretase inhibitors (GSIs) renders the glioma stem cells more sensitive to radiation at clinically relevant doses, and a critical role of notch signaling to regulate radioresistance of gliomas stem cells is suggested.

DNA Repair and Resistance of Gliomas to Chemotherapy and Radiotherapy

  • G. Fròsina
  • Medicine, Biology
    Molecular Cancer Research
  • 2009
Mechanisms other than DNA repair (in particular low proliferation and activation of the DNA damage checkpoint response) are likely main players of resistance in glioma stem cells and their targeting might yield significant therapeutic gains.


Three major approaches that specifically target radioresistant cancer stem cells and their possible effects when combined with fractionated radiotherapy are evaluated as they promise to be a powerful tool in the battle against this cancer.

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

Comparisons of DNA damage response in nontumor forming neural progenitor cells and glioma-initiating cells isolated from GBM patient specimens suggest homologous recombination and cell-cycle checkpoint abnormalities may contribute to the radioresistance of gliomatic cells and that both processes may be suitable targets for therapy.

Cancer Stem Cells from Tumor Cell Lines Activate the DNA Damage Response Pathway after Ionizing Radiation More Efficiently Than Noncancer Stem Cells

Findings provide the first evidence, to the authors' knowledge, that DNA damage response sensor proteins are present and preferentially activated in CSC, as opposed to the bulk of cells in monolayer cultures, and provide the basis for biological differences in response to IR.

DNA Repair mechanisms in glioblastoma cancer stem cells

This chapter summarizes the current understanding of the DNA damage response in cancer stem cells within glioblastomas and underscores the requirement for further studies aimed at elucidation of this key cellular pathway in GSC biology.

MSI1 associates glioblastoma radioresistance via homologous recombination repair, tumor invasion and cancer stem-like cell properties.

Acute and fractionated irradiation differentially modulate glioma stem cell division kinetics.

It is hypothesize a constitutive activation of stem cell division kinetics signaling pathways during fractionated treatment, which contributes to the frequently observed accelerated repopulation after therapeutic irradiation.

Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of Glioblastoma Stem-like Cells.

Using a panel of primary patient-derived glioblastoma cell lines, data demonstrate that multiple, parallel DNA damage signaling pathways contribute to GSC radioresistance and that combined inhibition of cell-cycle checkpoint and DNA repair targets provides the most effective means to overcome radiores resistance of GSC.



Identification of human brain tumour initiating cells

The development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo gives strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.

Identification of a cancer stem cell in human brain tumors.

The identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation is reported.

DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis

It is shown that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions commonly express markers of an activated DNA damage response.

Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor.

Data indicate that stem cell-like tumor cells can be a crucial source of key angiogenic Factors in cancers and that targeting proangiogenic factors from stem cell -like tumor populations may be critical for patient therapy.

Cancerous stem cells can arise from pediatric brain tumors

It is found that tumor-derived progenitors form neurospheres that can be passaged at clonal density and are able to self-renew, which may have important implications for treatment by means of specific targeting of stem-like cells within brain tumors.

Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma

It is reported that, unlike other brain cancers, the lethal glioblastoma multiforme contains neural precursors endowed with all of the critical features expected from neural stem cells.

Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions

It is proposed that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.

Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.

The molecular mechanisms of DNA repair and the DNA damage checkpoints in mammalian cells are analyzed and apoptosis, which eliminates heavily damaged or seriously deregulated cells, is analyzed.

Direct isolation of human central nervous system stem cells.

  • N. UchidaD. Buck I. Weissman
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2000
Upon transplantation into brains of immunodeficient neonatal mice, the sorted/expanded hCNS-SC showed potent engraftment, proliferation, migration, and neural differentiation.

Cell cycle checkpoint signaling through the ATM and ATR kinases.

These checkpoints contain, as their most proximal signaling elements, sensor proteins that scan chromatin for partially replicated DNA, DNA strand breaks, or other abnormalities, and translate these DNA-derived stimuli into biochemical signals that modulate the functions of specific downstream target proteins.