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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Moding, EJ; Castle, KD; Perez, BA; Oh, P; Min, HD; Norris, H; Ma, Y; Cardona, DM; Lee, C-L; Kirsch, DG

Published Date

  • March 2015

Published In

Volume / Issue

  • 7 / 278

Start / End Page

  • 278ra34 -

PubMed ID

  • 25761890

Electronic International Standard Serial Number (EISSN)

  • 1946-6242

International Standard Serial Number (ISSN)

  • 1946-6234

Digital Object Identifier (DOI)

  • 10.1126/scitranslmed.aaa4214

Language

  • eng