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dc.contributor.authorEvans, CEen
dc.contributor.authorPalazon, Aen
dc.contributor.authorSim, Jen
dc.contributor.authorTyrakis, PAen
dc.contributor.authorProdger, Aen
dc.contributor.authorLu, Xen
dc.contributor.authorChan, Sen
dc.contributor.authorBendahl, P-Oen
dc.contributor.authorBelting, Men
dc.contributor.authorVon Euler, Len
dc.contributor.authorRundqvist, Hen
dc.contributor.authorJohnson, Randallen
dc.contributor.authorMendes Branco, Cristina Brancoen
dc.date.accessioned2017-05-31T14:08:25Z
dc.date.available2017-05-31T14:08:25Z
dc.date.issued2017-05-15en
dc.identifier.issn2046-6390
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/264543
dc.description.abstractThrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular micro-occlusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic regions. To better understand the association between metastasis and thrombotic events, we generated an experimental strategy whereby we modelled the effect of microvascular occlusion in metastatic efficiency by using inert microbeads to obstruct lung microvasculature before, during and after intravenous tumour cell injection. We found that controlled induction of a specific number of these microthrombotic insults in the lungs caused an increase in expression of the hypoxia-inducible transcription factors (HIFs), a pro-angiogenic and pro-tumorigenic environment, as well as an increase in myeloid cell infiltration. Induction of pulmonary microthrombosis prior to introduction of tumour cells to the lungs had no effect on tumorigenic success, but thrombosis at the time of tumour cell seeding increased number and size of tumours in the lung, and this effect was strikingly more pronounced when the micro-occlusion occurred on the day following introduction of tumour cells. The tumorigenic effect of microbead treatment was seen even when thrombosis was induced five days after tumour cell injection. We also found positive correlations between thrombotic factors and expression of HIF2$\alpha$ in human tumours. The model system described here demonstrates the importance of thrombotic insult in metastatic success and can be used to improve understanding of thrombosis-associated tumorigenesis and its treatment.
dc.description.sponsorshipResearch was supported through a Wellcome Trust Principal Research Fellowship to R.S.J. (RG59596). C.B. is supported through a Scientific Fellowship from Breast Cancer Now (2014MaySF275). C.E.E. received a Pump-Priming Grant from the University of Cambridge British Heart Foundation Centre of Research Excellence (RG68639).
dc.languageengen
dc.language.isoenen
dc.publisherThe Company of Biologists
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectHIFen
dc.subjecthypoxiaen
dc.subjectmetastasisen
dc.subjectmicrovascularen
dc.subjectthrombosisen
dc.titleModelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesisen
dc.typeArticle
prism.endingPage697
prism.issueIdentifier5en
prism.publicationDate2017en
prism.publicationNameBiology Openen
prism.startingPage688
prism.volume6en
dc.identifier.doi10.17863/CAM.10113
dcterms.dateAccepted2017-03-15en
rioxxterms.versionofrecord10.1242/bio.024653en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-05-15en
dc.contributor.orcidJohnson, Randall [0000-0002-4084-6639]
dc.contributor.orcidMendes Branco, Cristina Branco [0000-0001-6953-4922]
dc.identifier.eissn2046-6390
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (092738/Z/10/Z)
pubs.funder-project-idBreast Cancer Campaign (2014MaySF275)
pubs.funder-project-idNational Cancer Institute (NCI) (R01CA153983)
pubs.funder-project-idEuropean Commission (331756)
pubs.funder-project-idWellcome Trust (214283/Z/18/Z)
cam.issuedOnline2017-03-16en
cam.orpheus.successThu Jan 30 12:53:57 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International