Platelets, coagulation and fibrinolysis in breast cancer progression

Abstract

The progression of breast cancer from early-stage to metastatic disease results from a series of events during which malignant cells invade and travel within the bloodstream to distant sites, leading to a clonogenic accumulation of tumor cells in non-breast tissue. While mechanistically complex, an emerging literature supports hemostatic elements as an important patient factor that facilitates the metastatic potential of breast cancer. Hemostatic elements involved include platelets, coagulation, and fibrinolysis. Key steps in breast tumor progression, including cellular transformation, proliferation, tumor cell survival, and angiogenesis, can be mediated by components of the hemostatic system. Thus, the hemostatic system provides potential targets for novel therapeutic approaches to breast cancer therapy with drugs in current use and in development. The present article provides a comprehensive overview of the evidence and mechanisms supporting the roles played by platelets, coagulation activation, and the fibrinolytic system in breast cancer progression.

Figure 1

An overview of important interactions between hemostasis and breast cancer. (1) Hypoxia and oncogenic activation increase tissue factor expression, which increases urokinase-type plasminogen activator (uPA) expression and transcription in tumor cells, facilitating intravasation. (2) Tumor cell-induced platelet aggregation leads to platelet activation. Activated platelets subsequently shed microparticles, release various growth mediators, and protect tumor cells from immune-mediated destruction in circulation. (3) Platelets help in adhesion of tumor cells through p-selectin and integrins, aiding in extravasation from the circulation. (4) Thrombin generated through TF-FVIIa-Xa pathway upregulates growth-related oncogene-alpha (GRO-a) and leads to secretion of matrix metalloproteinase (MMP) and angiogenic molecules. (5) Tissue factor, platelets, thrombin, and the plasminogen system enhance tumor growth, invasion, and angiogenesis, leading to clonogenic accumulation of tumor cells outside breast tissue. FVIIa, activated factor VII; TF, tissue factor.

Figure 2

Tissue factor-FVIIa-PAR2 complex-related intracellular signaling. Binding of activated factor VII (FVIIa) leads to proteoyltic cleavage of protease-activated receptor-2 (PAR-2), resulting in loss of negative regulatory control of PAR-2-mediated signaling through phosphorylation of TF cytoplasmic domain. This leads to activation of mitogen-activated protein kinase (MAPK) pathways and PI3K/Akt/mTOR activation. These pathways lead to subsequent gene transcription and result in the production of various mediators like vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), colony-stimulating factor-1 (CSF-1), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor (PAI), and survivin. These mediators then play an important role in angiogenesis, tumor growth, invasion, and increased survival. mTOR, mammalian target of ripamycin; P, phosphate; PI3K, phosphatidylinositol 3 kinase.

Figure 3

TF-FVIIa-Xa complex results in thrombin generation. Thrombin is a potent platelet fibrinogen to fibrin, contributing to tumor metastasis. In breast cancer, thrombin acts through protease-activated receptor-1 (PAR-1) receptor and markedly increases growth-related oncogene-alpha (GRO-α) production. Thrombin, PAR activation peptide, and GRO-α all lead to increased production of matrix metalloproteinase (MMP), vascular endothelial growth factor (VEGF), angiopoietin-2 (ANG-2), CD31, and receptors KDR/CXCR-2 in endothelial cells, contributing to tumor growth, angiogenesis, and metastasis. Act. Plts., activated platelets; CXCR2, chemokine receptor for growth-related oncogene-alpha; KDR, kinase insert domain receptor (vascular endothelial growth factor receptor); Plts., platelets.