Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury.
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.
Isenberg
Jeff S
JS
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
Maxhimer
Justin B
JB
Hyodo
Fuminori
F
Pendrak
Michael L
ML
Ridnour
Lisa A
LA
DeGraff
William G
WG
Tsokos
Maria
M
Wink
David A
DA
Roberts
David D
DD
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001808:Blood Vessels / Q000473:pathology / Q000528:radiation effects; D051928:CD47 Antigen / Q000378:metabolism*; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000473:pathology / Q000528:radiation effects; D006614:Hindlimb / Q000473:pathology / Q000528:radiation effects; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology; D011833:Radiation Injuries, Experimental / Q000378:metabolism* / Q000473:pathology*; D011836:Radiation Tolerance / Q000528:radiation effects; D019700:Thrombospondin 1 / Q000378:metabolism*; D019699:Thrombospondins / Q000378:metabolism; D014022:Tissue Survival / Q000528:radiation effects*; D014965:X-Rays; D000099262:Thrombospondin 2
D051928:CD47 Antigen; D019700:Thrombospondin 1; D019699:Thrombospondins; D000099262:Thrombospondin 2
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