Glioblastomas are aggressive brain tumours that rapidly become resistant to radiotherapy. Jeremy Rich and colleagues now show that glioma stem cells are the root of this problem.

Glioblastomas present as diffuse tumours that invade normal brain tissue, and patients who are diagnosed with this disease have a median survival of less than 12 months. Glioblastomas recur after treatment with radiation, but often as focal masses, suggesting that only a small proportion of cells are responsible for recurrence. Both normal brain stem cells and brain tumour stem cells have recently been characterized, and cells that express prominin 1 (also known as CD133) often show stem-cell-like characteristics.

Rich and colleagues asked whether the glioma subpopulation of CD133+ cells is involved in the development of radioresistance. A fourfold enrichment of the CD133+ cell population from human explants is evident after treatment with ionizing radiation in vitro, and the authors showed that radiation does not induce CD133 expression in CD133− cells. In addition, increasing the percentage of CD133+ cells in a defined number of glioblastoma tumour cells decreases the time taken for the tumours to grow in the frontal lobes of immuno-compromised mice, indicating the enrichment of tumorigenic stem cells.

So, are CD133+ glioma stem cells more resistant to radiotherapy? In vitro colony-formation assays after the irradiation of either CD133− or CD133+ cells from the same patient or xenograft confirmed that more CD133+ cells survive this treatment. Moreover, viable CD133+ cells from irradiated xenografts formed secondary tumours in mice with the same kinetics as CD133+ cells that had not been irradiated, indicating that 2 Gy of radiation does not reduce the tumour-forming capacity of these cells.

Why can these cells survive radiation treatment? The authors analysed DNA-damage checkpoints in both the CD133− and CD133+ cell populations, and found that CD133+ cells show greater activation (levels of phosphorylation) of DNA-damage checkpoint proteins such as ataxia telangiectasia mutated (ATM) and RAD17. Although both cell populations sustain the same level of DNA damage (shown by analysing DNA double-strand breaks using the comet assay) in response to irradiation, the repair of these breaks occurs 4–9 times more rapidly in CD133+ cells. The pre-treatment of CD133+ cells with an inhibitor of the DNA-damage checkpoint kinases CHK1 and CHK2 reduced the survival of these cells after irradiation in vitro.

Drugs that target the DNA-damage checkpoint are in pre-clinical and clinical trials, and these results suggest that their use might improve the outcome for patients with glioblastoma and potentially other solid tumours.