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

Published

Journal Article

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 (Atm; KPAFL/+ or KPAFL/FL), whereas adeno-FlpO-infected mice expressed Cre in endothelial cells to delete one or both copies of Atm (KPVAFL/+ or KPVAFL/FL) to modify tumor cell or endothelial cell radiosensitivity, respectively. Deletion of Atm in either tumor cells or endothelial cells had no impact on tumor growth in the absence of radiation. Despite increased endothelial cell death in KPVAFL/FL mice following irradiation, tumor growth delay was not significantly increased. In contrast, a prolonged tumor growth delay was apparent in KPAFL/FL mice. Primary tumor cell lines lacking Atm 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.See related commentary by Hallahan, p. 704.

Full Text

Duke Authors

Cited Authors

  • Torok, JA; Oh, P; Castle, KD; Reinsvold, M; Ma, Y; Luo, L; Lee, C-L; Kirsch, DG

Published Date

  • February 15, 2019

Published In

Volume / Issue

  • 79 / 4

Start / End Page

  • 773 - 782

PubMed ID

  • 30315114

Pubmed Central ID

  • 30315114

Electronic International Standard Serial Number (EISSN)

  • 1538-7445

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-17-3103

Language

  • eng

Conference Location

  • United States