Abstract
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.
Highlights
Breast cancer is the most common cancer in women in the UK resulting in over 11,000 deaths per year [1]
In this study we utilised established Cancer stem cells (CSCs) activity assays to demonstrate a putative role for Tissue Factor (TF) in regulating cancer stem cells (CSCs) in vitro
Anoikis-resistant T47D and MCF7 cells have previously been demonstrated to enrich for cells with increased in vivo tumour forming ability, the gold standard for CSC activity [19, 27]
Summary
Breast cancer is the most common cancer in women in the UK resulting in over 11,000 deaths per year [1]. Cancer recurrence and subsequent death from metastasis may occur due to a subpopulation of cancer cells known as cancer stem cells (CSC), known as cancer initiating cells or cancer stem-like cells. CSC subpopulation has been demonstrated in patientderived cancers [4] and in human breast cancer cell lines [5]. Due to their relative resistance to radiotherapy and chemotherapy, CSCs are believed to be responsible for tumour relapse and represent an important therapeutic target [6]
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