The prothrombotic activity of cancer cells in the circulation

Abstract

The hemostatic system is often subverted in patients with cancer, resulting in life-threatening venous thrombotic events. Despite the multifactorial and complex etiology of cancer-associated thrombosis, changes in the expression and activity of cancer-derived tissue factor (TF) - the principle initiator of the coagulation cascade - are considered key to malignant hypercoagulopathy and to the pathophysiology of thrombosis. However, many of the molecular and cellular mechanisms coupling the hemostatic degeneration to malignancy remain largely uncharacterized. In this review we discuss some of the tumor-intrinsic and tumor-extrinsic mechanisms that may contribute to the prothrombotic state of cancer, and we bring into focus the potential for circulating tumor cells (CTCs) in advancing our understanding of the field. We also summarize the current status of anti-coagulant therapy for the treatment of thrombosis in patients with cancer.

Keywords: Cancer; Circulating tumor cells; Coagulation; Platelets; Thrombosis; Tissue factor.

FIGURE 1. The procoagulant phenotype of circulating tumor cells

In CTC, the expression of the procoagulant protein TF can be enhanced by intrinsic and extrinsic cellular routes. The intrinsic route includes the mutated activity of tumor suppressors (p53 and PTEN) and/or oncogenes (kRAS and MET) that aberrantly induce the transcription and translation of the TF gene. The extrinsic route is initiated outside the cell by TGF_β paracrine signaling, thereby dependent on the EMT program. The TF cytoplasmic domain is linked to a variety of signal transduction proteins (e.g., PI3K and MAPK) that become activated following cell intravasation to prevent anoikis. At the same time, the ectodomain of TF on the CTC surface or on shed tumor-derived microparticles (MPs) initiates the extrinsic coagulation cascade leading to thrombin generation and thus, fibrin formation and platelet activation.

FIGURE 2. Coagulation and platelet activation support tumor metastasis

CTCs activate and aggregate platelets via paracrine and/or juxtacrine signals to ensure their survival in the bloodstream and to permit extravasation, proliferation and angiogenesis at the metastatic site. Aggregated platelets and fibrin surround and protect CTCs from NK-mediated lysis via physical shielding. Platelets also release TGF_β and PDGF, which function as downregulators of the NK-activating receptor NKGD. In addition, CTCs can escape the immune surveillance through molecular mimicry of platelets. Tumor cell interaction with the endothelium is thought to be mediated by platelets, specifically via P-selectin binding to PSGL-1 and integrin-fibrinogen-integrin bridges. Platelet release of growth and angiogenic factors (e.g., PDGF, TGF_β, VEGF) as well as proteases (e.g., MMPs) and adenine nucleotides (e.g., ATP) contribute to cancer cell extravasation and formation of new stable capillaries at the metastatic site. Moreover, intracellular signaling transduced via molecules downstream of TF has several benefits for tumor progression (Yellow Box).