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dc.contributor.authorBlower, Emma
dc.contributor.authorCastle, John
dc.contributor.authorSantiago-Gomez, Angelika
dc.contributor.authorClarke, Robert B
dc.contributor.authorKirwan, Cliona C
dc.date.accessioned2021-10-28T09:26:21Z
dc.date.available2021-10-28T09:26:21Z
dc.date.issued2021en
dc.identifier.citationBlower E, Castle J, Santiago-Gomez A, Clarke R, Kirwan C. A Hypercoagulant Tumour Microenvironment Promotes Breast Cancer Progression, with Effects Inhibited by Anticoagulants. Journal of Pathology. 2021;255:S4-S.en
dc.identifier.urihttp://hdl.handle.net/10541/624745
dc.description.abstractBackground: Breast cancer patients have a four-fold increased risk of developing a venous thromboembolism (VTE). VTE is associated with increased mortality despite adjusting for cancer stage. Tissue Factor (TF) is expressed by breast cancer-associated ?broblasts as well as breast cancer epithelial cells. TF signals to promote cancer growth and metastasis. Rivaroxaban, a licensed oral anticoagulant that inhibits this TF-Factor VIIa (FVIIa)-Factor Xa (FXa) complex, could potentially be repurposed to target this procoagulant tumour microenvironment in breast cancer. Methods: Recombinant coagulation factors, lentivirally transduced TF over-expressing ?broblasts (TFF) and their control (CF) or conditioned media (TFFCM and CFCM), were cultured with oestrogen receptor positive (ER+) breast cancer cells (MCF-7) +/- Rivaroxaban or anti-TF antibody 10H10. Proliferation (sulforhodamine-B/EdU assay), migration (scratch/transwell assay) and stem cell activity (mammosphere forming e?ciency (MFE) assay) were assessed. The underlying mechanism was analysed with western blotting and quantitative PCR.Results: Recombinant TF,FVIIa and FXa versus control promoted proliferation and migration in MCF-7 cells (p<0.001), with these e?ects abrogated by Rivaroxaban (p<0.05). Recombinant TF,FVIIa and FXa increased phospho-ERK (p<0.01), CXCL8 (p<0.05) and VEGFA (p<0.0001) expression as compared to control, with CXCL8 and VEGFA inhibited by Rivaroxaban (p<0.01).TFFCM promoted proliferation, migration and stem cell activity in MCF-7 cells (p<0.05) as compared to CFCM, with these e?ects abrogated by 10H10 (proliferation, migration, MFE:p<0.05) and Rivaroxaban (migration, MFE:p<0.05). The cancer-promoting e?ects of TFFCM versus CFCM were associated with increased VEGFA (p<0.05) expression; which was reversed by 10H10 and Rivaroxaban (p<0.05). 3D co-culture of MCF-7s with TFF as compared to CF promoted cancer cell migration (p=0.04) and stem cell activity (MFE:p<0.0001), with these e?ects abrogated by 10H10 (migration:p=0.01, MFE:p=0.0028) and Rivaroxaban (migration:p= 0.0341, MFE:p=0.0003).Conclusion: A procoagulant microenvironment promotes proliferation, migration and stem cell activity in ER+ breast cancer in vitro which can be targeted by anticoagulants. Rivaroxaban could potentially be repurposed as anticancer therapy.en
dc.language.isoenen
dc.titleA hypercoagulant tumour microenvironment promotes breast cancer progression, with effects inhibited by anticoagulantsen
dc.typeOtheren
dc.contributor.departmentManchester Cancer and Thrombosis Team, The Oglesby Cancer Research Building, University of Manchester, Manchester, UKen
dc.identifier.journalJournal of Pathologyen
dc.description.noteen]


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