Abstract LB-167: Tumor cells, but not endothelial cells, mediate the eradication of primary cancers by radiation therapy

Abstract

Abstract Radiation therapy is frequently utilized in the clinic as curative treatment for cancers, but the contribution of endothelial cells to tumor response to radiation remains controversial. Using the two highly efficient site-specific recombinases, Cre and FlpO, we have generated primary tumors in mice with different gene mutations specifically in tumor cells and stromal cells. With this dual recombinase technology, 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. We found that deletion of Bax in endothelial cells did not affect tumor response to radiation, but Atm deletion increased radiation-induced death of tumor endothelial cells and prolonged tumor growth delay following a non-curative dose of radiation. However, following a curative dose of radiation, Atm deletion in endothelial cells did not affect growth delay of primary tumors and failed to increase local control. In contrast, deletion of Atm in tumor cells increased local control of primary tumors by radiation therapy. These results demonstrate that tumor cells rather than endothelial cells are the critical targets that regulate tumor eradication by radiation therapy. They also emphasize the importance of using primary models of cancer to study the role of stromal cells in tumor development and response to therapy. Citation Format: Everett J. Moding, Chang-Lung Lee, Katherine D. Castle, Patrick Oh, David G. Kirsch. Tumor cells, but not endothelial cells, mediate the eradication of primary cancers by radiation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-167. doi:10.1158/1538-7445.AM2014-LB-167