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dc.contributor.authorJones, DTen
dc.contributor.authorLechertier, Ten
dc.contributor.authorMitter, Ren
dc.contributor.authorHerbert, JMJen
dc.contributor.authorBicknell, Ren
dc.contributor.authorJones, JLen
dc.contributor.authorLi, J-Len
dc.contributor.authorBuffa, Fen
dc.contributor.authorHarris, ALen
dc.contributor.authorHodivala-Dilke, Ken

Angiogenesis is essential for solid tumour growth, whilst the molecular profiles of tumour blood vessels have been reported to be different between cancer types. Although presently available anti-angiogenic strategies are providing some promise for the treatment of some cancers it is perhaps not surprisingly that, none of the anti-angiogenic agents available work on all tumours. Thus, the discovery of novel anti-angiogenic targets, relevant to individual cancer types, is required. Using Affymetrix microarray analysis of laser-captured, CD31-positive blood vessels we have identified 63 genes that are upregulated significantly (5-72 fold) in angiogenic blood vessels associated with human invasive ductal carcinoma (IDC) of the breast as compared with blood vessels in normal human breast. We tested the angiogenic capacity of a subset of these genes. Genes were selected based on either their known cellular functions, their enriched expression in endothelial cells and/or their sensitivity to anti-VEGF treatment; all features implicating their involvement in angiogenesis. For example, RRM2, a ribonucleotide reductase involved in DNA synthesis, was upregulated 32-fold in IDC-associated blood vessels; ATF1, a nuclear activating transcription factor involved in cellular growth and survival was upregulated 23-fold in IDC-associated blood vessels and HEX-B, a hexosaminidase involved in the breakdown of GM2 gangliosides, was upregulated 8-fold in IDC-associated blood vessels. Furthermore, in silico analysis confirmed that AFT1 and HEX-B also were enriched in endothelial cells when compared with non-endothelial cells. None of these genes have been reported previously to be involved in neovascularisation. However, our data establish that siRNA depletion of Rrm2, Atf1 or Hex-B had significant anti-angiogenic effects in VEGF-stimulated ex vivo mouse aortic ring assays. Overall, our results provide proof-of-principle that our approach can identify a cohort of potentially novel anti-angiogenic targets that are likley to be, but not exclusivley, relevant to breast cancer.

dc.format.extente44294 - ?en
dc.subjectAngiogenesis Inhibitorsen
dc.subjectAntibodies, Monoclonal, Humanizeden
dc.subjectAorta, Thoracicen
dc.subjectBreast Neoplasmsen
dc.subjectCarcinoma, Ductal, Breasten
dc.subjectCell Line, Tumoren
dc.subjectGene Expression Profilingen
dc.subjectIn Vitro Techniquesen
dc.subjectMice, Inbred BALB Cen
dc.subjectMice, Inbred C57BLen
dc.subjectMice, SCIDen
dc.subjectMicroscopy, Confocalen
dc.subjectNeoplasms, Experimentalen
dc.subjectNeovascularization, Pathologicen
dc.subjectOligonucleotide Array Sequence Analysisen
dc.subjectPlatelet Endothelial Cell Adhesion Molecule-1en
dc.subjectRNA Interferenceen
dc.subjectTransplantation, Heterologousen
dc.subjectTumor Burdenen
dc.subjectVascular Endothelial Growth Factor Aen
dc.titleGene expression analysis in human breast cancer associated blood vessels.en
dc.typeJournal Article
plymouth.journalPLoS Oneen
plymouth.organisational-group/Plymouth/00 Groups by role
plymouth.organisational-group/Plymouth/00 Groups by role/Academics
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Biomedical Research Group
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Biomedical Research Group/RC Reporting Group BRG
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Collaboration for the Advancement of Medical Education Research Assessment
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
dc.publisher.placeUnited Statesen
dc.rights.embargoperiodNot knownen
rioxxterms.typeJournal Article/Reviewen

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