Tissue Factor-Expressing Tumor Cells Can Bind to Immobilized Recombinant Tissue Factor Pathway Inhibitor under Static and Shear Conditions In Vitro

Abstract

Mammary tumors and malignant breast cancer cell lines over-express the coagulation factor, tissue factor (TF). High expression of TF is associated with a poor prognosis in breast cancer. Tissue factor pathway inhibitor (TFPI), the endogenous inhibitor of TF, is constitutively expressed on the endothelium. We hypothesized that TF-expressing tumor cells can bind to immobilized recombinant TFPI, leading to arrest of the tumor cells under shear in vitro. We evaluated the adhesion of breast cancer cells to immobilized TFPI under static and shear conditions (0.35 – 1.3 dyn/cm2). We found that high-TF-expressing breast cancer cells, MDA-MB-231 (with a TF density of 460,000/cell), but not low TF-expressing MCF-7 (with a TF density of 1,400/cell), adhered to recombinant TFPI, under static and shear conditions. Adhesion of MDA-MB-231 cells to TFPI required activated factor VII (FVIIa), but not FX, and was inhibited by a factor VIIa-blocking anti-TF antibody. Under shear, adhesion to TFPI was dependent on the TFPI-coating concentration, FVIIa concentration and shear stress, with no observed adhesion at shear stresses greater than 1.0 dyn/cm2. This is the first study showing that TF-expressing tumor cells can be captured by immobilized TFPI, a ligand constitutively expressed on the endothelium, under low shear in vitro. Based on our results, we hypothesize that TFPI could be a novel ligand mediating the arrest of TF-expressing tumor cells in high TFPI-expressing vessels under conditions of low shear during metastasis.

Comprehensive analysis of haemostatic profile depending on clinicopathological determinants in breast cancer patients

“…TF overexpression has been shown to correlate with tumour progression, poor prognosis and decreased overall survival. Hypercoagulability may influence on malignant transformation, tumour growth, tumour cell–host interactions, and metastatic potential by stimulation of new vessels formation from pre-existing ones [ 9 , 11 , 12 , 15 ]. On the other hand, a lower concentration of TFPI in BrCa patients may be due to the fact that TF inhibitor is consumed in response to the elevated TF concentration as a compensatory mechanism.…”

“…Interestingly, tumorigenesis, invasion and metastasis can indirectly be promoted via flTF by means of thrombocyte activation, fibrin deposition and thrombin generation [ 4 , 6–8 ]. flTF tightly regulates cell motility and proliferation as well as stimulating angiogenic switch, and presents anti-apoptotic properties by stimulation of anti-apoptotic proteins production [ 4 , 9 , 10 ]. However, during recent years another factor has come to light, namely flTF pathway inhibitor-1 (flTFPI-1), the most powerful regulator of TF activity.…”

“…The approach to BrCa treatment relies on the availability of clinical and pathological prognostic and predictive determinants. Immunohistochemical (IHC) evolution of the proliferation marker (Ki67), oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is clinically essential as these are markers for both prognosis and type of treatment [ 8 , 9 ]. Upon confirmation of the positive status of ER and PRs, the patient is eligible for hormone treatment, however, when positive HER2 expression is noted this predicts the response to anti-HER2 therapy [ 12 ].…”

Pre-Operative Combination of Normal BMI with Elevated YKL-40 and Leptin but Lower Adiponectin Level Is Linked to a Higher Risk of Breast Cancer Relapse: A Report of Four-Year Follow-Up Study

“…The overexpression of TF is associated with an invasive character of tumours and may be particularly related to cancer-associated thrombosis. Moreover, TF stimulates an angiogenic switch , leading to new vessel formation and further cancer cell growth [ 28 ]. Thus, elevated TF activity is associated with decreased overall survival [ 28 , 29 ].…”

“…Moreover, TF stimulates an angiogenic switch , leading to new vessel formation and further cancer cell growth [ 28 ]. Thus, elevated TF activity is associated with decreased overall survival [ 28 , 29 ]. TF activity and adiponectin levels are sensitive to the tumour’s molecular status and may serve as single biomarkers for future prognosis.…”