From Virchow's triad to metastasis: circulating hemostatic factors as predictors of risk for metastasis in solid tumors

Tumor growth is characterized by disturbances of hemostatic mechanisms towards subclinical activation of coagulation. In cancer patients there is an increased risk up to 4-6 fold for developing idiopathic thrombosis due to the tumor-associated prothrombotic status. The molecular basis for the interrelationship between malignant phenotype and hemostatic disbalance includes several specific properties of tumor cells such as production of proinflammatory and proangiogenic cytokines, exhibition of pro coagulant / fibrinolytic activities by tumor cells themselves and direct cell-to-cell interactions between tumor cells and cellular components of the hemostatic system. Aberrant tissue factor (TF) expression is a hallmark of human cancers and has been linked to their metastatic potential and neoangiogenesis. TF is a multifunctional molecule which controls the pro-/antiangiogenic balance in tumor tissue both by its procoagulant properties and via coagulation-independent mechanism inducing production of angiogenic cytokines by tumor cells. Components of the fibrinolytic system urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) facilitate targeted proteolysis of the basement matrix in order neovascularization to occur. Overexpression of these factors in tumor tissue has been identified as prognosticator for metastatic spread and overall survival in many human cancers, including breast, gastrointestinal, lung, urological and gynecological malignancies. Measurement of circulating TF and the soluble isoform of uPAR in plasma may be useful for evaluating the risk of cancer metastasis, monitoring for tumor recurrence and prediction of response to cancer therapy.