Mechanism of thrombin-induced angiogenesis.
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.
Maragoudakis
M E
ME
Medical School, Department of Pharmacology, University of Patras, 261 10 Rio, Patras, Greece. maragoud@med.upatras.gr
Tsopanoglou
N E
NE
Andriopoulou
P
P
D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D016228:Endothelial Growth Factors / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology; D005109:Extracellular Matrix / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008222:Lymphokines / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009369:Neoplasms / Q000097:blood / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000209:etiology*; D018179:Receptors, Thrombin / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D019030:Receptors, Vitronectin / Q000502:physiology; D013917:Thrombin / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D018179:Receptors, Thrombin; D019030:Receptors, Vitronectin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor; D013917:Thrombin; D020778:Matrix Metalloproteinase 2