Tissue Factor promotes breast cancer stem cell activity in vitro
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Hudhaifah Shaker1, Hannah Harrison2, Robert Clarke3, Goran Landberg4, Nigel J. Bundred1, Henri H. Versteeg5 and Cliona C. Kirwan1
1 The University of Manchester, Manchester Academic Health Science Centre, Department of Academic Surgery, University Hospital of South Manchester, Manchester, UK
2 Faculty of Life Sciences, University of Manchester, Manchester, UK
3 Breast Biology Group, Manchester Cancer Research Centre, University of Manchester, Manchester, UK
4 Sahlgrenska Cancer Center, University of Gothenburg, Sweden
5 Department of Thrombosis and Hemostasis, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands
Cliona C. Kirwan, email:
Keywords: cancer stem cells, tissue factor, breast cancer
Received: May 23, 2016 Accepted: August 25, 2016 Published: December 13, 2016
Cancer stem cells (CSCs) are a subpopulation of cells that can self-renew and initiate tumours. The clotting-initiating protein Tissue Factor (TF) promotes metastasis and may be overexpressed in cancer cells with increased CSC activity. We sought to determine whether TF promotes breast CSC activity in vitro using human breast cancer cell lines. TF expression was compared in anoikis-resistant (CSC-enriched) and unselected cells. In cells sorted into of TF-expressing and TF-negative (FACS), and in cells transfected to knockdown TF (siRNA) and overexpress TF (cDNA), CSC activity was compared by (i) mammosphere forming efficiency (MFE) (ii) holoclone colony formation (Hc) and (iii) ALDH1 activity. TF expression was increased in anoikis-resistant and high ALDH1-activity T47D cells compared to unselected cells. FACS sorted TF-expressing T47Ds and TF-overexpressing MCF7s had increased CSC activity compared to TF-low cells. TF siRNA cells (MDAMB231,T47D) had reduced CSC activity compared to control cells. FVIIa increased MFE and ALDH1 in a dose-dependent manner (MDAMB231, T47D). The effects of FVIIa on MFE were abrogated by TF siRNA (T47D). Breast CSCs (in vitro) demonstrate increased activity when selected for high TF expression, when induced to overexpress TF, and when stimulated (with FVIIa). Targeting the TF pathway in vivo may abrogate CSC activity.
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