It is generally accepted that ionizing radiation kills tumours by directly acting on tumour stem cells, but it now seems that this is only part of the story. Richard Kolesnick, Zvi Fuks and colleagues report in Science that radiotherapy also targets the endothelial cells in the microvasculature within growing tumours. The endothelium synthesizes 20 times more acid sphingomyelinase (ASMase) than any other cell in the body and the authors also show that the sphingomyelin apoptotic pathway is integrally involved in the response of endothelial cells to radiation.

They implanted fibrosarcoma or melanoma cells into asmase+/+ and asmase−/− mice and found that without ASMase tumours grew much faster and endothelial-cell apoptosis was decreased. So, how do these mice respond to irradiation with 10–20 Gy — doses that are equivalent in their biological effects to those given to patients in daily fractionated radiotherapy regimens? When treated with 15 Gy, 50% of fibrosarcomas in the asmase+/+ mice were cured, whereas there was no tumour control in the asmase−/− mice. The tumour response in the asmase+/+ mice was preceded by a marked increase in endothelial-cell apoptosis in the first 6 hours after irradiation. This event was lacking in asmase−/− mice.

The authors proved that the resistance of asmase−/− endothelium to radiation-induced apoptosis was due to direct loss of ASMase within the endothelium by purifying tumour endothelial cells from the mice and subjecting them to irradiation — the response of endothelial cells from asmase−/− or asmase+/+ mice mirrored the in vivo responses.

One unexpected finding was that, whereas the responses described hold true for doses of less than 20 Gy, giving doses of 20 Gy or more activated an alternative tumour response in the asmase−/− mice. Mice null for asmase lacked endothelial-cell apoptosis, even with 20 Gy, but tumours were only resistant at 15 Gy, as a tumour response resulting in 80% volume reduction was seen within one week of irradiation with 20 Gy.

So, if the endothelium remains intact following irradiation, it protects tumour cells from low-dose radiation-induced death. The authors propose that tumours might regulate the radioresponsiveness of their own microvascular endothelium and that developing a strategy to manipulate levels of ASMase might be a promising approach to sensitize tumour cells to radiotherapy.