Deletion of <i>Atm</i> in Tumor but not Endothelial Cells Improves Radiation Response in a Primary Mouse Model of Lung Adenocarcinoma.

Abstract

Stereotactic body radiotherapy is utilized to treat lung cancer. The mechanism of tumor response to high-dose radiotherapy (HDRT) is controversial, with competing hypotheses of increased direct tumor cell killing versus indirect effects on stroma including endothelial cells. Here we used dual recombinase technology in a primary murine lung cancer model to test whether tumor cells or endothelial cells are critical HDRT targets. Lenti-Cre deleted one or two copies of ataxia-telangiectasia mutated gene (<i>Atm</i>; KPA^FL/+ or KPA^FL/FL), whereas adeno-FlpO-infected mice expressed Cre in endothelial cells to delete one or both copies of <i>Atm</i> (KPVA^FL/+ or KPVA^FL/FL) to modify tumor cell or endothelial cell radiosensitivity, respectively. Deletion of <i>Atm</i> in either tumor cells or endothelial cells had no impact on tumor growth in the absence of radiation. Despite increased endothelial cell death in KPVA^FL/FL mice following irradiation, tumor growth delay was not significantly increased. In contrast, a prolonged tumor growth delay was apparent in KPA^FL/FL mice. Primary tumor cell lines lacking <i>Atm</i> expression also demonstrated enhanced radiosensitivity as determined via a clonogenic survival assay. These findings indicate that tumor cells, rather than endothelial cells, are critical targets of HDRT in primary murine lung cancer. SIGNIFICANCE: These findings establish radiosensitizing tumor cells rather than endothelial cells as the primary mechanism of tumor response to high-dose radiotherapy, supporting efforts to maximize local control by radiosensitizing tumors cells.<i>See related commentary by Hallahan, p. 704</i>.