Tissue Factor in Cancer and Angiogenesis: The Molecular Link between Genetic Tumor Progression, Tumor Neovascularization, and Cancer Coagulopathy

Abstract

Tissue factor (TF), the primary cellular initiator of blood coagulation, is also involved in cancer-related processes such as hypercoagulability (Trousseau syndrome), tumor growth, angiogenesis, and metastasis. Indeed, elevated TF expression by cancer cells and their associated endothelial cells has been reported frequently. Oncogenic events in cancer cells (e.g., expression of mutant K- ras, EGFR, PTEN or p53) lead to an increase in TF levels and activity, and thereby promote tumor aggressiveness, angiogenesis, and hypercoagulability. Like TF, thrombin receptor (protease-activated receptor-1) is also upregulated in cancer cells expressing oncogenic K -ras. Pharmacological antagonists of some of these transforming genes (e.g., epidermal growth factor receptor inhibitors) could diminish TF expression, both locally and systemically, and hence these targeted agents could be viewed as potential indirect and cancer-specific anticoagulants, in addition to their direct antitumor effects. We postulate that levels of circulating TF may be useful in monitoring the biological activity of these agents. Although TF is essential for vascular development, its expression by tumor-associated endothelium appears to play a subtle and seemingly dispensable role. Thus, TF is a pivotal element of the tumor-vascular interface, is involved in many cancer-related processes, and may well constitute a promising new target for anticancer combination therapies in some disease settings.

Tissue Factor–Activated Coagulation Cascade in the Tumor Microenvironment Is Critical for Tumor Progression and an Effective Target for Therapy

“…This drastic upregulation may, to some extent, be caused by the existence of common tumor microenvironmental stimuli, such as those responsible for TF upregulation during inflammation and hypoxia. Recently, it was shown that TF expression is under the direct control of oncogenic pathways activated by genetic mutations sustained by cancer cells (28). This is shown experimentally by the effect of several mutant oncogenes, including K-ras, EGFR, EGFRvIII, HER-2, and PML-RARa on TF transcription, translation, halflife, and encryption.…”

Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication

“…47 The presence of MP in the tumor microenvironment may be explained by the fact that several types of cancer express TF leading to platelet activation and release of MP, which in turn may affect several aspects of tumor cell biology. 56 We studied the influence of MP on the biology/metastasis of cancer cells in more detail in experimental models of lung and breast cancers. 47 We found that MP stimulated the phosphorylation of MAPKp42/44 and serine/threonine kinase in these cells as well as the expression of membrane type 1-matrix metalloproteinase (MT1-MMP).…”

Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease

“…Factor VIIa (FVIIa) then binds to TF on the cell surface. Sequential downstream activation of haemostatic protease complexes leads to the generation of thrombin, with subsequent platelet activation and the formation of a fibrin clot, which restores vessel integrity (reviewed by Rak et al, 2006).…”