Oncogene-Driven Hemostatic Changes in Cancer

Abstract

A common feature in progression of multiple human malignancies is the protracted deregulation of the coagulation system, often referred to as cancer coagulopathy. The genesis of this syndrome can be traced to changes in the tumor vascular interface, formed through vascular invasion, angiogenesis, and metastasis. The resulting contact between cancer cells and the circulating components of the coagulation system compromise the regulatory barriers that normally control physiological hemostasis. In addition, cancer cells and their stroma often exhibit procoagulant properties. While these changes have long been thought to be unspecific in nature, evidence now exists to suggest that cancer coagulopathy and the related Trousseau syndrome are a function of the genetic tumor progression. Indeed, the expression of several effector molecules of the coagulation and fibrinolytic systems, including: tissue factor (TF), plasminogen activator inhibitor 1 (PAI-1), cyclooxygenase 2 (COX-2), or urokinase (uPA) are often direct regulatory targets of oncogenes (K-ras, EGFR, HER-2, c-MET) and tumor suppressors (p53, PTEN). Moreover, oncogenic alterations act on coagulation indirectly by driving formation of leaky vessels, metastasis, or inflammation. These procoagulant influences of oncogenic pathways are modulated by hypoxia, stress responses and cellular differentiation, the latter involving formation of cancer stem cells and their niches to which coagulation factors may contribute. It is possible that targeting cancer-related coagulopathy may require more cancer-specific measures to reduce thrombosis burden and improve overall survival.

Keywords:

• Cancer coagulopathy
• Trousseau syndrome
• Tissue factor
• Oncogenes
• Angiogenesis
• Tumor initiating cells