A new study has shown that although radiation therapy causes apoptosis in proliferating medulloblastoma cells, it only induces cell-cycle arrest in medulloblastoma stem cells; however, this difference can be diminished using a small-molecule inhibitor.
Radiation therapy can be followed by recurrence because a small population of cancer stem cells is resistant to the therapy. A new study shows that radiation therapy causes apoptosis in proliferating medulloblastoma cells and only cell-cycle arrest in medulloblastoma stem cells, but this difference can be diminished using a small-molecule inhibitor.
The authors chose several mouse models of medulloblastoma for study, all of which were wild-type for p53, which is known to have a role in the response to therapy. In each of the models, they used histological staining to characterize three distinct cell populations: the moderately proliferating perivascular niche, which expressed nestin, a stem cell marker, and two populations in the tumour bulk, one highly proliferating and a smaller population that was relatively quiescent. When a dose of radiation equivalent to that used in therapy was applied, only the highly proliferating tumour bulk cells underwent apoptosis. By contrast, the nestin-expressing cells went into cell-cycle arrest within 6 h of irradiation but then re-entered the cell cycle at 72 h.
To investigate the molecular basis of these effects, the authors looked at the expression of several candidate proteins. Radiation induced activation of the Akt pathway in the nestin-expressing cells that survived treatment, and subsequent analysis demonstrated that the cell-cycle arrest was dependent on a modulator of the Akt pathway, PTEN. By contrast, apoptosis was accompanied by loss of PTEN expression. Cells undergoing apoptosis and those entering cell-cycle arrest had increased p53 levels, and interestingly the induction of p53 in the two cell types happened at different times.
The stem cells that enter cell-cycle arrest are an obvious problem for radiation therapy. Therefore the authors attempted to sensitize the nestin-expressing cells by inhibiting Akt with the small molecule inhibitor perifosine. This led to a significant increase in apoptosis. These results, which implicate Akt signalling in stem cell resistance to radiation therapy, have therefore already suggested a rational intervention that could improve the efficacy of therapy.
Patrick Goymer
References
Hambardzumyan, D. et al. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medullolastoma in vivo. Genes Dev.22, 436–448 (2008) | Article | PubMed |
