Tissue factor expressed by circulating cancer cell‐derived microparticles drastically increases the incidence of deep vein thrombosis in mice

Abstract

Background The risk of thrombotic complications such as deep vein thrombosis (DVT) during tumor development is well known. Tumors release into circulation procoagulant microparticles (MPs) that can participate in thrombus formation following vessel injury. The importance of this MP tissue factor (TF) in the initiation of cancer-associated DVT remains uncertain. Objective To address how pancreatic cancer MPs promote DVT in vivo. Methods We combined a DVT mouse model where thrombosis is induced by flow restriction of the inferior vena cava with one of subcutaneous pancreatic cancer in C57BL/6J mice. We infused high and low TF tumor MPs to determine the importance of TF in experimental cancer-associated DVT. Results Both tumor-bearing mice and mice infused with tumor MPs submitted to 3 hours of partial flow restriction developed an occlusive thrombus; fewer than a third of the control mice did. We observed that MPs adhered to neutrophil extracellular traps (NETs), functionally important players during DVT, whereas neither P-selectin nor GPIb were required for the MP recruitment in DVT. The thrombotic phenotype induced by MP infusion was suppressed by hirudin suggesting the importance of thrombin generation. TF carried by tumor MPs was essential to promote DVT as mice infused with low TF tumor MPs had less thrombosis than mice infused with high TF tumor MPs. Conclusions TF expressed on tumor MPs contributes to the increased incidence of cancer-associated venous thrombosis in mice in vivo. These MPs may adhere to NETs formed at the site of thrombosis.

Cross Talk Pathways Between Coagulation and Inflammation

“…The infused MPs localized to NETs and also expressed P-selectin glycoprotein ligand-1, allowing them to bind to TF and P-selectin presented by endothelial cells and platelets, thereby triggering coagulation. 124 Consistent with these findings, elevated circulating MP levels parallel D-dimers and P-selectin in deep vein thrombosis 125 and are a risk factor for coronary artery disease and atherothrombosis in humans.…”

Prostaglandin E synthase is upregulated by Gas6 during cancer-induced venous thrombosis

“…27 It was recently demonstrated that TF-bearing microvesicles derived from pancreatic cancer cells induce deep vein thrombosis (DVT) in mice. 28 Therefore, the interaction of malignant cells with surrounding cells and the coagulation system is complex and multifactorial.…”

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

“…Therefore, TF, expressed at the cell membrane on most tumors as well as on tumor vasculature and within the tumor microenvironment on stem cells, macrophages, ECs, and myofibroblasts, likely contributes to thrombin production [45][46][47][48][49][50][51]. Tumor microparticles such as exosomes may also display TF and induce thrombin generation [25], as byproducts such as these particles can enter general circulation via the abnormal, leaky blood vessels that are formed during tumor growth [52][53][54]. In addition to tumor cell-associated thrombin production, the components of the endothelium itself, including the endothelial cell protein TM, can regulate thrombin generation/activity to affect the metastatic process [26].…”