Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury

Jeff S. Isenberg, Justin B. Maxhimer, Fuminori Hyodo, Michael L. Pendrak, Lisa A. Ridnour, William G. DeGraff, Maria Tsokos, David A. Wink, David D. Roberts

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51 Citations (Scopus)

Abstract

Radiation, a primary mode of cancer therapy, acutely damages cellular macromolecules and DNA and elicits stress responses that lead to cell death. The known cytoprotective activity of nitric oxide (NO) is blocked by thrombospondin-1, a potent antagonist of NO/cGMP signaling in ischemic soft tissues, suggesting that thrombospondin-1 signaling via its receptor CD47 could correspondingly increase radiosensitivity. We show here that soft tissues in thrombospondin-1-null mice are remarkably resistant to radiation injury. Twelve hours after 25-Gy hindlimb irradiation, thrombospondin-1-null mice showed significantly less cell death in both muscle and bone marrow. Two months after irradiation, skin and muscle units in null mice showed minimal histological evidence of radiation injury and near full retention of mitochondrial function. Additionally, both tissue perfusion and acute vascular responses to NO were preserved in irradiated thrombospondin-1-null hindlimbs. The role of thrombospondin-1 in radiosensitization is specific because thrombospondin-2-null mice were not protected. However, mice lacking CD47 showed radioresistance similar to thrombospondin-1-null mice. Both thrombospondin-1- and CD47-dependent radiosensitization is cell autonomous because vascular cells isolated from the respective null mice showed dramatically increased survival and improved proliferative capacity after irradiation in vitro. Therefore, thrombospondin-1/CD47 antagonists may have selective radioprotective activity for normal tissues.

Original languageEnglish
Pages (from-to)1100-1112
Number of pages13
JournalAmerican Journal of Pathology
Volume173
Issue number4
DOIs
Publication statusPublished - Oct 2008

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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    Isenberg, J. S., Maxhimer, J. B., Hyodo, F., Pendrak, M. L., Ridnour, L. A., DeGraff, W. G., Tsokos, M., Wink, D. A., & Roberts, D. D. (2008). Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury. American Journal of Pathology, 173(4), 1100-1112. https://doi.org/10.2353/ajpath.2008.080237