Effects of thrombin/thrombosis in angiogenesis and tumour progression.
Laboratory, histopathological, pharmacological and clinical evidence support the notion that a systemic activation of blood coagulation is often present in cancer patients. On the other hand, epidemiological studies provide evidence of an increased risk of cancer diagnosis following primary thromboembolism. Moreover, the metastatic ability of human breast cancer cells is correlated with the number of thrombin receptors of these cells, and thrombin treatment of B16 melanoma cells dramatically increases the number of lung metastases in rats. We have proposed that these tumour-promoting effects of thrombin can be explained by the ability of thrombin to activate angiogenesis, an essential requirement for tumour progression. Many of the cellular events involved in the angiogenic cascade can be activated by thrombin. At the molecular level, brief exposure of endothelial cells to thrombin causes an upregulation of the receptors (KDR and Flt-1) of VEGF, the key angiogenic mediator. This results in a synergistic effect of thrombin and VEGF in the activation of angiogenesis. In addition, thrombin activates cancer cells to secrete VEGF, thus causing a mutual stimulation between EC and CA cells. Cancer cells exposed to thrombin secrete metalloproteinase 92 KD and overexpress the integrin a(v)b(3), all of which are involved in tumour metastasis.
Maragoudakis
M E
ME
University of Patras, Medical School, Department of Pharmacology, 261 10 Rio, Patras, Greece. maragoud@med.upatras.gr
Tsopanoglou
N E
NE
Andriopoulou
P
P
Maragoudakis
M M
MM
D000818:Animals; D018450:Disease Progression; D006801:Humans; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply* / Q000503:physiopathology; D009389:Neovascularization, Pathologic; D010641:Phenotype; D051381:Rats; D013917:Thrombin / Q000378:metabolism*; D013927:Thrombosis / Q000503:physiopathology*
D013917:Thrombin