title: Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury.
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.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Isenberg
authors.forename: Justin B
authors.initials: JB
authors.lastname: Maxhimer
authors.forename: Fuminori
authors.initials: F
authors.lastname: Hyodo
authors.forename: Michael L
authors.initials: ML
authors.lastname: Pendrak
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: William G
authors.initials: WG
authors.lastname: DeGraff
authors.forename: Maria
authors.initials: M
authors.lastname: Tsokos
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: 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
chemical_list: D051928:CD47 Antigen; D019700:Thrombospondin 1; D019699:Thrombospondins; D000099262:Thrombospondin 2
references.citation: Circ Res. 2007 Mar 16;100(5):712-20
references.pmid: 17293482
references.citation: Mol Cell Biol. 2007 Oct;27(20):7073-88
references.pmid: 17682056
references.citation: J Immunol. 2007 May 1;178(9):5930-9
references.pmid: 17442977
references.citation: Cell Mol Life Sci. 2008 Mar;65(5):672-86
references.pmid: 18193164
references.citation: Neoplasia. 2008 Aug;10(8):886-96
references.pmid: 18670646
references.citation: Blood. 2007 Mar 1;109(5):1945-52
references.pmid: 17082319
references.citation: J Cell Biol. 2002 Apr 29;157(3):509-19
references.pmid: 11980922
references.citation: J Biol Chem. 1996 Jan 5;271(1):21-4
references.pmid: 8550562
references.citation: Cardiovasc Res. 2006 Sep 1;71(4):785-93
references.pmid: 16820142
references.citation: Life Sci. 2004 May 7;74(25):3055-63
references.pmid: 15081571
references.citation: Lancet Oncol. 2005 Jul;6(7):520-8
references.pmid: 15992701
references.citation: Int J Radiat Biol. 2003 Feb;79(2):71-81
references.pmid: 12569011
references.citation: J Biol Chem. 2006 Sep 8;281(36):26069-80
references.pmid: 16835222
references.citation: Am J Pathol. 2001 Nov;159(5):1949-56
references.pmid: 11696456
references.citation: J Biol Chem. 2005 Aug 19;280(33):29637-44
references.pmid: 15917238
references.citation: Semin Radiat Oncol. 2007 Apr;17(2):121-30
references.pmid: 17395042
references.citation: Oncogene. 2004 Apr 22;23(19):3265-71
references.pmid: 15064735
references.citation: Mol Cancer Res. 2007 Dec;5(12):1225-31
references.pmid: 18171979
references.citation: Cancer Res. 1994 Jul 1;54(13):3365-8
references.pmid: 7516820
references.citation: Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):59-69
references.pmid: 10708953
references.citation: Oncogene. 2006 Jun 29;25(28):3885-93
references.pmid: 16462761
references.citation: Biol Pharm Bull. 2007 Jun;30(6):1102-7
references.pmid: 17541161
references.citation: Gut. 2004 Feb;53(2):214-21
references.pmid: 14724153
references.citation: Semin Radiat Oncol. 2007 Apr;17(2):81-8
references.pmid: 17395038
references.citation: Curr Probl Cancer. 2001 Nov-Dec;25(6):334-411
references.pmid: 11740469
references.citation: Clin Cancer Res. 2007 Aug 15;13(16):4928-33
references.pmid: 17699873
references.citation: Int J Biochem Cell Biol. 2004 Jun;36(6):1115-25
references.pmid: 15094126
references.citation: Front Radiat Ther Oncol. 2007;40:18-39
references.pmid: 17641500
references.citation: Am J Pathol. 2007 Sep;171(3):777-89
references.pmid: 17640965
references.citation: Am J Pathol. 2003 Dec;163(6):2247-57
references.pmid: 14633599
references.citation: Cancer Res. 2004 Nov 1;64(21):8015-21
references.pmid: 15520210
references.citation: Exp Hematol. 2007 Jan;35(1):137-45
references.pmid: 17198882
references.citation: J Biol Chem. 2002 May 3;277(18):15400-6
references.pmid: 11856735
references.citation: Cancer Res. 1994 Dec 15;54(24):6504-11
references.pmid: 7527299
references.citation: FEBS Lett. 2004 Jul 30;571(1-3):227-32
references.pmid: 15280047
references.citation: J Invest Dermatol. 2003 Jan;120(1):14-9
references.pmid: 12535193
references.citation: Radiat Res. 2006 Jun;165(6):671-7
references.pmid: 16802867
references.citation: Am J Pathol. 2002 Mar;160(3):1057-68
references.pmid: 11891202
references.citation: Cell. 1998 Jun 26;93(7):1159-70
references.pmid: 9657149
references.citation: Cancer Res. 2003 Jul 15;63(14):4055-61
references.pmid: 12874006
references.citation: Science. 1996 Nov 1;274(5288):795-8
references.pmid: 8864123
references.citation: Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2582-8
references.pmid: 17916772
references.citation: Cell Biol Toxicol. 2003 Feb;19(1):13-27
references.pmid: 12661984
references.citation: Oncogene. 2003 Sep 1;22(37):5866-75
references.pmid: 12947393
references.citation: EMBO J. 2002 Oct 1;21(19):5195-205
references.pmid: 12356735
references.citation: J Clin Invest. 1998 Mar 1;101(5):982-92
references.pmid: 9486968
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13141-6
references.pmid: 16150726
references.citation: Dev Dyn. 2003 Dec;228(4):630-42
references.pmid: 14648840