Research ArticleCancer

Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy

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Science Translational Medicine  11 Mar 2015:
Vol. 7, Issue 278, pp. 278ra34
DOI: 10.1126/scitranslmed.aaa4214

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Not all cells are eradicated equally

Personalized cancer therapies dominate the news. But radiation therapy continues to be an essential part of the treatment regimens of nearly half of all cancer patients—sometimes achieving complete tumor regression through the safe delivery of high doses of radiation. Previous research with transplanted tumor models in mice has suggest that radiation targets, not only the tumor cells themselves, but also components of the surrounding milieu, which comprises blood vessels and various cell types that influence tumor growth. Now Moding et al. challenge the earlier findings in studies conducted with primary sarcomas in mice that carried, in either tumor or endothelial cells, genetic mutations that modulate radiation sensitivity. The authors found that it was the tumor, rather than endothelial, cells that mediate primary sarcoma shrinkage by radiation therapy and that selective small-molecule inhibition of a DNA-damage response enzyme can enhance radiosensitization of some tumors.

Abstract

Cancer clinics currently use high-dose stereotactic body radiation therapy as a curative treatment for several kinds of cancers. However, the contribution of vascular endothelial cells to tumor response to radiation remains controversial. Using dual recombinase technology, we generated primary sarcomas in mice with targeted genetic mutations specifically in tumor cells or endothelial cells. We selectively mutated the proapoptotic gene Bax or the DNA damage response gene Atm to genetically manipulate the radiosensitivity of endothelial cells in primary soft tissue sarcomas. Bax deletion from endothelial cells did not affect radiation-induced cell death in tumor endothelial cells or sarcoma response to radiation therapy. Although Atm deletion increased endothelial cell death after radiation therapy, deletion of Atm from endothelial cells failed to enhance sarcoma eradication. In contrast, deletion of Atm from tumor cells increased sarcoma eradication by radiation therapy. These results demonstrate that tumor cells, rather than endothelial cells, are critical targets that regulate sarcoma eradication by radiation therapy. Treatment with BEZ235, a small-molecule protein kinase inhibitor, radiosensitized primary sarcomas more than the heart. These results suggest that inhibiting ATM kinase during radiation therapy is a viable strategy for radiosensitization of some tumors.

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