Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy

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dc.contributor.authorD''Amico, Gabrielako
dc.contributor.authorKorhonen, Emilia A.ko
dc.contributor.authorAnisimov, Andreyko
dc.contributor.authorZarkada, Georgiako
dc.contributor.authorHolopainen, Tanjako
dc.contributor.authorHaegerling, Reneko
dc.contributor.authorKiefer, Friedemannko
dc.contributor.authorEklund, Lauriko
dc.contributor.authorSormunen, Raijako
dc.contributor.authorElamaa, Harriko
dc.contributor.authorBrekken, Rolf A.ko
dc.contributor.authorAdams, Ralf H.ko
dc.contributor.authorKoh, Gou Youngko
dc.contributor.authorSaharinen, Pipsako
dc.contributor.authorAlitalo, Kariko
dc.date.accessioned2014-09-04T08:44:09Z-
dc.date.available2014-09-04T08:44:09Z-
dc.date.created2014-03-25-
dc.date.created2014-03-25-
dc.date.issued2014-02-
dc.identifier.citationJOURNAL OF CLINICAL INVESTIGATION, v.124, no.2, pp.824 - 834-
dc.identifier.issn0021-9738-
dc.identifier.urihttp://hdl.handle.net/10203/190177-
dc.description.abstractThe endothelial Tie1 receptor is ligand-less, but interacts with the Tie2 receptor for angiopoietins (Angpt). Angpt2 is expressed in tumor blood vessels, and its blockade inhibits tumor angiogenesis. Here we found that Tie1 deletion from the endothelium of adult mice inhibits tumor angiogenesis and growth by decreasing endothelial cell survival in tumor vessels, without affecting normal vasculature. Treatment with VEGF or VEGFR-2 blocking antibodies similarly reduced tumor angiogenesis and growth; however, no additive inhibition was obtained by targeting both Tie1 and VEGF/VEGFR-2. In contrast, treatment of Tie1-deficient mice with a soluble form of the extracellular domain of Tie2, which blocks Angpt activity, resulted in additive inhibition of tumor growth. Notably, Tie1 deletion decreased sprouting angiogenesis and increased Notch pathway activity in the postnatal retinal vasculature, while pharmacological Notch suppression in the absence of Tie1 promoted retinal hypervasularization. Moreover, substantial additive inhibition of the retinal vascular front migration was observed when Angpt2 blocking antibodies were administered to Tie1-deficient pups. Thus, Tie1 regulates tumor angiogenesis, postnatal sprouting angiogenesis, and endothelial cell survival, which are controlled by VEGF, Angpt, and Notch signals. Our results suggest that targeting Tie1 in combination with Angpt/Tie2 has the potential to improve antiangiogenic therapy.-
dc.languageEnglish-
dc.publisherAMER SOC CLINICAL INVESTIGATION INC-
dc.subjectRECEPTOR TYROSINE KINASE-
dc.subjectENDOTHELIAL CELL-CELL-
dc.subjectVASCULAR ENDOTHELIUM-
dc.subjectENHANCED EXPRESSION-
dc.subjectANTI-VEGF-
dc.subjectANGIOGENESIS-
dc.subjectMOUSE-
dc.subjectMETASTASIS-
dc.subjectNOTCH-
dc.subjectTIP-
dc.titleTie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy-
dc.typeArticle-
dc.identifier.wosid000331413300039-
dc.identifier.scopusid2-s2.0-84893859971-
dc.type.rimsART-
dc.citation.volume124-
dc.citation.issue2-
dc.citation.beginningpage824-
dc.citation.endingpage834-
dc.citation.publicationnameJOURNAL OF CLINICAL INVESTIGATION-
dc.identifier.doi10.1172/JCI68897-
dc.contributor.localauthorKoh, Gou Young-
dc.contributor.nonIdAuthorD''Amico, Gabriela-
dc.contributor.nonIdAuthorKorhonen, Emilia A.-
dc.contributor.nonIdAuthorAnisimov, Andrey-
dc.contributor.nonIdAuthorZarkada, Georgia-
dc.contributor.nonIdAuthorHolopainen, Tanja-
dc.contributor.nonIdAuthorHaegerling, Rene-
dc.contributor.nonIdAuthorKiefer, Friedemann-
dc.contributor.nonIdAuthorEklund, Lauri-
dc.contributor.nonIdAuthorSormunen, Raija-
dc.contributor.nonIdAuthorElamaa, Harri-
dc.contributor.nonIdAuthorBrekken, Rolf A.-
dc.contributor.nonIdAuthorAdams, Ralf H.-
dc.contributor.nonIdAuthorSaharinen, Pipsa-
dc.contributor.nonIdAuthorAlitalo, Kari-
dc.description.isOpenAccessY-
dc.type.journalArticleArticle-
dc.subject.keywordPlusRECEPTOR TYROSINE KINASE-
dc.subject.keywordPlusENDOTHELIAL CELL-CELL-
dc.subject.keywordPlusVASCULAR ENDOTHELIUM-
dc.subject.keywordPlusENHANCED EXPRESSION-
dc.subject.keywordPlusANTI-VEGF-
dc.subject.keywordPlusANGIOGENESIS-
dc.subject.keywordPlusMOUSE-
dc.subject.keywordPlusMETASTASIS-
dc.subject.keywordPlusNOTCH-
dc.subject.keywordPlusTIP-
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