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dc.contributor.authorBridgeman, VLen_US
dc.contributor.authorVermeulen, PBen_US
dc.contributor.authorFoo, Sen_US
dc.contributor.authorBilecz, Aen_US
dc.contributor.authorDaley, Fen_US
dc.contributor.authorKostaras, Een_US
dc.contributor.authorNathan, MRen_US
dc.contributor.authorWan, Een_US
dc.contributor.authorFrentzas, Sen_US
dc.contributor.authorSchweiger, Ten_US
dc.contributor.authorHegedus, Ben_US
dc.contributor.authorHoetzenecker, Ken_US
dc.contributor.authorRenyi-Vamos, Fen_US
dc.contributor.authorKuczynski, EAen_US
dc.contributor.authorVasudev, NSen_US
dc.contributor.authorLarkin, Jen_US
dc.contributor.authorGore, Men_US
dc.contributor.authorDvorak, HFen_US
dc.contributor.authorPaku, Sen_US
dc.contributor.authorKerbel, RSen_US
dc.contributor.authorDome, Ben_US
dc.contributor.authorReynolds, ARen_US
dc.coverage.spatialEnglanden_US
dc.date.accessioned2016-11-23T12:50:33Z
dc.date.issued2017-02en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/27859259en_US
dc.identifier.citationJ Pathol, 2017, 241 (3), pp. 362 - 374en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/245
dc.identifier.eissn1096-9896en_US
dc.identifier.doi10.1002/path.4845en_US
dc.description.abstractAnti-angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti-angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre-existing vessels from surrounding tissue (vessel co-option). As anti-angiogenic therapies were designed to target only new blood vessel growth, vessel co-option has been proposed as a mechanism that could drive resistance to anti-angiogenic therapy. However, vessel co-option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti-angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co-option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co-opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co-opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co-option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co-option mediates resistance to the anti-angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co-option in lung metastases occurs through at least three distinct mechanisms, that vessel co-option occurs frequently in lung metastases, and that vessel co-option could mediate resistance to anti-angiogenic therapy in lung metastases. Novel therapies designed to target both angiogenesis and vessel co-option are therefore warranted. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.en_US
dc.format.extent362 - 374en_US
dc.languageengen_US
dc.language.isoengen_US
dc.subjectangiogenesisen_US
dc.subjectanti-angiogenic therapyen_US
dc.subjectdrug resistanceen_US
dc.subjectlung metastasisen_US
dc.subjectsunitiniben_US
dc.subjectvessel co-optionen_US
dc.subjectAngiogenesis Inhibitorsen_US
dc.subjectCapillariesen_US
dc.subjectHumansen_US
dc.subjectImmunotherapyen_US
dc.subjectIndolesen_US
dc.subjectLung Neoplasmsen_US
dc.subjectModels, Biologicalen_US
dc.subjectNeovascularization, Pathologicen_US
dc.subjectPyrrolesen_US
dc.subjectSunitiniben_US
dc.titleVessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models.en_US
dc.typeJournal Article
dcterms.dateAccepted2016-10-18en_US
rioxxterms.versionofrecord10.1002/path.4845en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2017-02en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJ Patholen_US
pubs.issue3en_US
pubs.notes6 monthsen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer/Melanoma and Kidney Cancer (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Tumour Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublisheden_US
pubs.volume241en_US
pubs.embargo.terms6 monthsen_US
icr.researchteamMelanoma and Kidney Canceren_US
icr.researchteamTumour Biologyen_US
icr.researchteamTranslational Immunotherapyen_US
dc.contributor.icrauthorReynolds, Andrewen_US
dc.contributor.icrauthorBridgeman, Victoriaen_US
dc.contributor.icrauthorFoo, Shaneen_US
dc.contributor.icrauthorDaley, Francesen_US
dc.contributor.icrauthorNathan, Marken_US
dc.contributor.icrauthorLarkin, Jamesen_US
dc.contributor.icrauthorGore, Martinen_US
dc.contributor.icrauthorMarsden,en_US
dc.contributor.icrauthorFrentzas, Sophiaen_US


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