Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling.
Radiation-induced damage of normal tissues restricts the therapeutic doses of ionizing radiation that can be delivered to tumors and thereby limits the effectiveness of radiotherapy. Thrombospondin-1 signaling through its cell surface receptor CD47 limits recovery from several types of stress, and mice lacking either gene are profoundly resistant to radiation injury. We describe strategies to protect normal tissues from radiation damage using CD47 or thrombospondin-1 antibodies, a CD47-binding peptide, or antisense suppression of CD47. A morpholino oligonucleotide targeting CD47 confers radioresistance to human endothelial cells in vitro and protects soft tissue, bone marrow, and tumor-associated leukocytes in irradiated mice. In contrast, CD47 suppression in mice bearing melanoma or squamous lung tumors prior to irradiation result in 89% and 71% smaller tumors, respectively. Thus, inhibiting CD47 signaling maintains the viability of normal tissues following irradiation while increasing the radiosensitivity of tumors.
Maxhimer
Justin B
JB
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Soto-Pantoja
David R
DR
Ridnour
Lisa A
LA
Shih
Hubert B
HB
Degraff
William G
WG
Tsokos
Maria
M
Wink
David A
DA
Isenberg
Jeff S
JS
Roberts
David D
DD
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D017209:Apoptosis; D001853:Bone Marrow / Q000528:radiation effects; D051928:CD47 Antigen / Q000276:immunology* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000528:radiation effects; D009569:Nitric Oxide / Q000378:metabolism; D011836:Radiation Tolerance; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000276:immunology
D000906:Antibodies; D051928:CD47 Antigen; D019700:Thrombospondin 1; D009569:Nitric Oxide; D006152:Cyclic GMP