Thrombin enhances tumor cell adhesive and metastatic properties via increased αIIbβ3 expression on the cell surface

Wojtukicwicz, Marek Z.; Tang, Dean G.; Nelson, Kevin; Walz, Daniel A.; Diglio, Clement A.; Honn, Kenneth V.

doi:10.1016/0049-3848(92)90081-k

Cited by 74 publications

(65 citation statements)

References 16 publications

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“…Upregulation of ␣ v ␤ 3 by thrombin has also been demonstrated previously in human colon adenocarcinoma cells (11) and in cultured smooth muscle cells (43). Furthermore, it has been shown that thrombin induces adhesion of tumor cells, neutrophils, and monocytes to endothelial cell by increasing the expression of the integrin ␣ IIb ␤ 3 in these cells (27,36,48).…”

Section: Discussionmentioning

confidence: 75%

On the mechanism of thrombin-induced angiogenesis: involvement of α_vβ₃-integrin

Tsopanoglou

Andriopoulou

Maragoudakis

2002

American Journal of Physiology-Cell Physiology

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. On the mechanism of thrombin-induced angiogenesis: involvement of ␣v␤3-integrin. Am J Physiol Cell Physiol 283: C1501-C1510, 2002. First published July 17, 2002 10.1152/ajpcell.00162.2002Thrombin has been reported to be a potent angiogenic factor both in vitro and in vivo, and many of the cellular effects of thrombin may contribute to activation of angiogenesis. In this report we show that thrombin-treatment of human endothelial cells increases mRNA and protein levels of ␣v␤3-integrin. This thrombin-mediated effect is specific, dose dependent, and requires the catalytic site of thrombin. In addition, thrombin interacts with ␣v␤3 as demonstrated by direct binding of ␣v␤3 protein to immobilized thrombin. This interaction of thrombin with ␣v␤3-integrin, which is an angiogenic marker in vascular tissue, is of functional significance. Immobilized thrombin promotes endothelial cells attachment, migration, and survival. Antibody to ␣v␤3 or a specific peptide antagonist to ␣v␤3 can abolish all these ␣v␤3-mediated effects. Furthermore, in the chick chorioallantoic membrane system, the antagonist peptide to ␣v␤3 diminishes both basal and the thrombin-induced angiogenesis. These results support the pivotal role of thrombin in activation of endothelial cells and angiogenesis and may be related to the clinical observation of neovascularization within thrombi. attachment; migration; apoptosis; reverse transcription-polymerase chain reaction THE FREQUENCY OF BLOOD COAGULATION in cancer patients, known for more than 130 years, is supported by clinical, laboratory, and histopathological evidence. This is explained at the molecular and cellular level by the thromboplastic activity of circulating tumor cells, the existence of "a cancer coagulative factor," the activation of factor X, the generation of prothrombinase by tumor cells, and the encircling of cancerous tissue by fibrin deposits (38,50). In addition, the possibility of a relation between blood clotting mechanisms and tumor progression and development of metastases was postulated as early as 1878 by Billroth (7) on the basis of the observation that cancer cells exist within thrombi. This finding was interpreted as evidence that tumor cells spread by thromboembolism. More recently, large epidemiological studies have provided evidence that the standardized incidence ratio for certain types of cancer is as high as 6.7 within a year following a thromboembolic episode (3, 41). These clinical data are in line with animal experiments where thrombin-treated B16 melanoma cells show a dramatic increase in their metastatic potential in the lung of rats (37). These observations have led to experimental use of heparin, aspirin, and warfarin for the prevention and treatment of tumors in animal models and humans (23, 50).We proposed earlier (33, 47) that the tumor-promoting effect of thrombin/thrombosis may be related to our finding that thrombin is a potent promoter of angiogenesis, a process essential for tumor growth and metastasis. The angiogenic action of thrombin was shown to b...

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Section: Discussionmentioning

confidence: 75%

On the mechanism of thrombin-induced angiogenesis: involvement of α_vβ₃-integrin

Tsopanoglou

Andriopoulou

Maragoudakis

2002

American Journal of Physiology-Cell Physiology

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“…Thrombin binds PAR-1 and mediates increased invasiveness and metastatic potential of cancer cells [33][34][35] and enhanced cancer cell adhesion to platelets [36][37][38], endothelial cells [39], fibronectin and Von Willebrand factor [12,37]. Inhibition of thrombin by Hirudin may switch off PAR-1 signalling resulting in decreased tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

Niers

Brüggemann

Klerk

et al. 2008

Clin Exp Metastasis

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Cancer progression is facilitated by blood coagulation. Anticoagulants, such as Hirudin and low molecular weight heparins (LMWHs), reduce metastasis mainly by inhibition of thrombin formation and L-and Pselectin-mediated cell-cell adhesion. It is unknown whether the effects are dependent on cancer cell type. The effects of anticoagulants on tumor development of K1735 and B16 melanoma cells and CT26 colon cancer cells were investigated in mouse lung. Tumor load was determined noninvasively each week up to day 21 in all experiments using bioluminescence imaging. Effects of anticoagulants on tumor development of the three cell lines were correlated with the fibrin/fibrinogen content in the tumors, expression of tissue factor (TF), protease activated receptor (PAR)-1 and -4 and CD24, a ligand of L-and P-selectins. Hirudin inhibited tumor development of B16 cells in lungs completely but did not affect tumor growth of K1735 and CT26 cells. Low molecular weight heparin did not have an effect on K1735 melanoma tumor growth either. TF and PAR-4 expression was similar in the three cell lines. PAR-1 and CD24 were hardly expressed by K1735, whereas CT26 cells expressed low levels and B16 high levels of PAR-1 and CD24. Fibrin content of the tumors was not affected by LMWH. It is concluded that effects of anticoagulants are dependent on cancer cell type and are correlated with their CD24 and PAR-1 expression.Keywords B16 melanoma Á CT26 colon carcinoma Á K1735 melanoma Á Hirudin Á Low molecular weight heparin Á Selectin Á PAR

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“…We and others have shown that exogenous thrombin (1 U/mL) acting through its PAR-1 receptor, is capable of enhancing tumor adhesion to platelets, [6][7][8] endothelial cells, 9 fibronectin, and von Willebrand factor 7 in vitro. Studies have also revealed that exogenous thrombin promotes tumor growth in vitro 10 and in vivo 6,7,11 as well as experimental (tail-vein injection) metastasis.…”

Section: Introductionmentioning

confidence: 99%

“…Studies have also revealed that exogenous thrombin promotes tumor growth in vitro 10 and in vivo 6,7,11 as well as experimental (tail-vein injection) metastasis. [6][7][8]12 Exogenous thrombin is also capable of inducing angiogenesis in a chorioallantoic membrane model. 13 However, the pathophysiologic relevance of thrombin in the host, that is, the end result of endogenous generation of host thrombin during tumor growth and spontaneous metastasis, has not been examined.…”

Section: Introductionmentioning

confidence: 99%

Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis

Lee

Campbell

et al. 2004

Blood

172

152

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Tumor/host-generated thrombin (endogenous thrombin) was investigated with tumor growth and metastasis experiments in mice by the use of hirudin, a highly potent specific inhibitor of thrombin. Pretreatment with hirudin inhibited tumor implantation in nude or syngeneic mice, following subcutaneous injection of 2 human and 2 murine tumors. Hirudin induced a considerable lag period in the appearance of tumor growth, compared with phosphate-buffered saline (PBS) treatment, but had no effect on established tumor nodule growth in vivo or on tumor growth in vitro. Hirudin treatment induced central necrosis of the tumor nodule compared with no effect with PBS treatment. Greater protection was noted with longer duration of treatment. Tumor seeding into blood was examined with green fluorescent protein ( IntroductionThe association of thrombosis and cancer (platelet and fibrin deposition) is well established, 1-5 but the role that activation of the coagulation pathway plays in promoting neoplastic progression is not well defined. We and others have shown that exogenous thrombin (1 U/mL) acting through its PAR-1 receptor, is capable of enhancing tumor adhesion to platelets, 6-8 endothelial cells, 9 fibronectin, and von Willebrand factor 7 in vitro. Studies have also revealed that exogenous thrombin promotes tumor growth in vitro 10 and in vivo 6,7,11 as well as experimental (tail-vein injection) metastasis. [6][7][8]12 Exogenous thrombin is also capable of inducing angiogenesis in a chorioallantoic membrane model. 13 However, the pathophysiologic relevance of thrombin in the host, that is, the end result of endogenous generation of host thrombin during tumor growth and spontaneous metastasis, has not been examined. Indeed, the concentration of thrombin generated by a developing tumor in the plasma at the interface is unknown and uncertain. In addition, the effect of thrombin on tumor growth in vitro is biplasic (activation at Ͻ 0.5 U/mL and inhibition at higher concentration). 10 Most tumor cells have constitutively active tissue factor on their surface capable of generating thrombin in vitro. However, the host has antithrombin mechanisms capable of neutralizing this activity.An approach was therefore designed to explore the mechanism of endogenously generated thrombin with its possible effect on tumor growth, seeding, and spontaneous metastasis by employing the highly potent and specific inhibitor of thrombin, hirudin. Hirudin is twice as potent as heparin in animal thrombosis models. [14][15][16] Unlike heparin, it is capable of neutralizing thrombin bound to the tumor thrombus as well as in the plasma, 17,18 with a Ki (inhibitory constant) of 0.05 pM. 19 It has other antithrombotic properties. It is able to dissociate thrombin-platelet receptor complexes (greater affinity of hirudin for thrombin than for platelets). 20 It can displace reversibly bound Factor Xa from vascular endothelium, 20 which then becomes inactivated by plasma protease inhibitors, leading to reduced prothrombin activation. It has also been reported...

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Thrombin enhances tumor cell adhesive and metastatic properties via increased αIIbβ3 expression on the cell surface

Cited by 74 publications

References 16 publications

On the mechanism of thrombin-induced angiogenesis: involvement of α_vβ₃-integrin

On the mechanism of thrombin-induced angiogenesis: involvement of α_vβ₃-integrin

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis

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Thrombin enhances tumor cell adhesive and metastatic properties via increased αIIbβ3 expression on the cell surface

Cited by 74 publications

References 16 publications

On the mechanism of thrombin-induced angiogenesis: involvement of αvβ3-integrin

On the mechanism of thrombin-induced angiogenesis: involvement of αvβ3-integrin

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis

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Product

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On the mechanism of thrombin-induced angiogenesis: involvement of α_vβ₃-integrin

On the mechanism of thrombin-induced angiogenesis: involvement of α_vβ₃-integrin