Tissue Factor Expression by Malignant Cells Contributes to Tumor Progression

Introduction

There has been a longstanding association between malignancy and coagulation. This dates back to initial reports of increased hypercoaguability in cancer patients described by Armand Trousseau in the mid-19th century [1]. Today, cancer-associated thrombosis is a clinically relevant issue. In a population-based case-control study, approximately 20% of all patients diagnosed with venous thromboembolism (VTE) were also diagnosed with a malignancy [2]. In a large cohort study, Blom and colleagues reported that the risk of VTE in cancer patients is over 10 times greater than that of the cancer-free population [3]. This risk was further increased in patients with distant metastasis or receiving chemotherapy. An independent study reported that cancer patients had a fourfold greater VTE risk in comparison to those without cancer [4]. Tissue factor (TF) is a member of the class 2 cytokine receptor family and serves as the transmembrane receptor for coagulation factor VII (FVII) [5]. Activated FVII (FVIIa) bound to TF initiates the coagulation protease cascade, which includes the proteases FXa, FVIIa, and FIIa (thrombin), resulting in the formation of a fibrin clot [6, 7].

Abstract

Tissue factor (TF) is a transmembrane protein that binds its ligand factor VII/VIIa (FVII/FVIIa) and initiates the coagulation protease cascade. The TF is essential for hemostasis. In addition, TF has been implicated in several pathological processes, including venous thromboembolism, sepsis, inflammation, and cancer. Aside from their primary roles in coagulation, FVIIa and the downstream proteases FXa and FIIa (thrombin) can also cleave and activate protease-activated receptors (PARs) on cells to induce intracellular signaling. In this review, we will summarize the proposed mechanisms by which TF contributes to tumor progression. Specifically, we will focus on how TF expression by cancer cells and host cells promotes malignancy by increasing angiogenesis, tumor growth, and metastasis.

Keywords

Tissue Factor, Cancer, Protease Activated Receptors