Erythropoietin Blockade Inhibits the Induction of Tumor Angiogenesis and Progression 英文参考文献.docVIP

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Erythropoietin Blockade Inhibits the Induction of Tumor Angiogenesis and Progression 英文参考文献.doc

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Erythropoietin Blockade Inhibits the Induction of Tumor Angiogenesis and Progression 英文参考文献

ErythropoietinBlockadeInhibitstheInductionofTumor AngiogenesisandProgression MatthewE.Hardee1,YitingCao2,PingFu3,XiaohongJiang3,YulinZhao2,ZahidN.Rabbani2,ZeljkoVujaskovic2,MarkW.Dewhirst2,MuratO. Arcasoy3* 1DepartmentofPathology,DukeUniversityMedicalCenter,Durham,NorthCarolina,UnitedStatesofAmerica,2DepartmentofRadiationOncology, Duke University Medical Center, Durham, North Carolina, United States of America, 3Department of Medicine, Duke University Medical Center, Durham,NorthCarolina,UnitedStatesofAmerica Background. The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the hematopoietic cytokine erythropoietinasanangiogenicfactorthatmodulatestumorprogression.Methodology/PrincipalFindings.Fluorescently- labeledrodentmammarycarcinomacellswereinjectedintodorsalskin-foldwindowchambersinmice,anangiogenesismodel that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously using intravital microscopy and computerized image analysis during the initial stages of tumorigenesis. Erythropoietin or its antagonist proteins were co-injected with tumor cells into window chambers. In vivo growth of cells engineered to stably express a constitutively active erythropoietin receptor EPOR-R129C or the erythropoietin antagonist R103A-EPO were analyzed in window chambers and in the mammary fat pads of athymic nude mice. Co-injection of erythropoietinwithtumorcellsorexpressionofEPOR-R129Cintumorcellssignificantlystimulatedtumorneovascularization andgrowthinwindowchambers.Co-injectionoferythropoietinantagonistproteins(solubleEPORoranti-EPOantibody)with tumor cells or stable expression of antagonist R103A-EPO protein secreted from tumor cells inhibited angiogenesis and impairedtumorgrowth.Inorthotopictumorxenograftstudies,EPOR-R129Cexpressionsignificantlypromotedtumorgrowth