Mechanism of thrombin-induced angiogenesis

Abstract

Clinical, laboratory, histopathological and pharmacological evidence support the notion that a systemic activation of blood coagulation is often present in cancer patients. Additionally, thrombin was shown to promote tumour progression and metastasis in animals, and epidemiological studies suggest an increased risk of cancer diagnosis after primary thromboembolism. We have proposed that the aforementioned results may be related to our finding that thrombin is a potent activator of angiogenesis. This is a thrombin receptor-mediated event (the receptor is referred to as protease-activate receptor) and is independent of fibrin formation. Many cellular effects of thrombin on endothelial cells can contribute to the angiogenic action of thrombin. (i) Exposure of endothelial cells to thrombin cause a time- and dose-dependent decrease in the attachment of these cells to basement membrane components, with a concomitant increase in matrix metalloproteinase 2 activation. (ii) Thrombin upregulates the expression of integrin alphavbeta3, the marker of the angiogenic phenotype of endothelial cells. (iii) Thrombin has chemotactic and aptotactic effects on endothelial cells and upregulates the expression of the vascular endothelial growth factor (VEGF) receptors (KDR and Flt1). Thus, thrombin synergizes with the key angiogenic factor VEGF in endothelial cell proliferation. Furthermore, thrombin enhances the secretion of VEGF and matrix metalloproteinase 9 of PC3 prostate cancer cells. These results can explain the angiogenic and tumour-promoting effect of thrombin and provide the basis for development of thrombin receptor mimetics or antagonists for therapeutic application.

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

“…In fact, PARs have been suggested to play little role in the inflammatory responses in experimental endotoxemia. 74 Furthermore, the thrombininduced increase in vascular permeability and angiogenesis [75][76][77][78] may also contribute to pathophysiology in vascular lesions (Figure).…”

Fibrinogen-like protein 2/fibroleukin prothrombinase contributes to tumor hypercoagulability via IL-2 and IFN-γ

“…In addition to its primary role in homeostasis and blood coagulation, thrombin is a potent mitogen that dramatically increases the growth and metastasis potential of tumor cells. Both tissue factor (TF) and thrombin exert their influence on tumor angiogenesis and metastasis through clotting-dependent and clotting-independent pathways [6,7] . Fgl2 functions as a novel immune coagulant with the ability to generate thrombin directly.…”

Thrombohemorrhagic events in cancer surgery

“…Использование НМГ у онкологических больных также предпо-чтительно в связи с наличием сведений об их влиянии на течение опухолевого процесса и улучшением прогноза выживаемости [20][21][22][23][24][25], хотя для этого утверждения необходимо проведение дальнейших исследований у пациентов с различными типами и стадиями заболевания.…”