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

Publication ,  Journal Article
Moding, EJ; Castle, KD; Perez, BA; Oh, P; Min, HD; Norris, H; Ma, Y; Cardona, DM; Lee, C-L; Kirsch, DG
Published in: Sci Transl Med
March 11, 2015

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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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

March 11, 2015

Volume

7

Issue

278

Start / End Page

278ra34

Location

United States

Related Subject Headings

  • bcl-2-Associated X Protein
  • bcl-2 Homologous Antagonist-Killer Protein
  • Sarcoma
  • Radiosurgery
  • Radiation-Sensitizing Agents
  • Quinolines
  • Protein Kinase Inhibitors
  • Mice
  • Imidazoles
  • Endothelial Cells
 

Citation

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Moding, E. J., Castle, K. D., Perez, B. A., Oh, P., Min, H. D., Norris, H., … Kirsch, D. G. (2015). Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy. Sci Transl Med, 7(278), 278ra34. https://doi.org/10.1126/scitranslmed.aaa4214
Moding, Everett J., Katherine D. Castle, Bradford A. Perez, Patrick Oh, Hooney D. Min, Hannah Norris, Yan Ma, Diana M. Cardona, Chang-Lung Lee, and David G. Kirsch. “Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy.Sci Transl Med 7, no. 278 (March 11, 2015): 278ra34. https://doi.org/10.1126/scitranslmed.aaa4214.
Moding EJ, Castle KD, Perez BA, Oh P, Min HD, Norris H, et al. Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy. Sci Transl Med. 2015 Mar 11;7(278):278ra34.
Moding, Everett J., et al. “Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy.Sci Transl Med, vol. 7, no. 278, Mar. 2015, p. 278ra34. Pubmed, doi:10.1126/scitranslmed.aaa4214.
Moding EJ, Castle KD, Perez BA, Oh P, Min HD, Norris H, Ma Y, Cardona DM, Lee C-L, Kirsch DG. Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy. Sci Transl Med. 2015 Mar 11;7(278):278ra34.

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

March 11, 2015

Volume

7

Issue

278

Start / End Page

278ra34

Location

United States

Related Subject Headings

  • bcl-2-Associated X Protein
  • bcl-2 Homologous Antagonist-Killer Protein
  • Sarcoma
  • Radiosurgery
  • Radiation-Sensitizing Agents
  • Quinolines
  • Protein Kinase Inhibitors
  • Mice
  • Imidazoles
  • Endothelial Cells