Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metastasis of tumor cells is one of the major obstacles to successful clinical therapy. A treatment strategy by incorporating a specific inhibitor of thrombin, recombinant hirudin with stealthy liposomal vinblastine, was used in this study for inhibiting the metastasis of tumor cells and enhancing the efficacy of anti-tumor agents. In vitro cytotoxicity, cell adhesion to extracellular matrix (ECM) proteins, and cell invasion and migration assays were performed on human A375 melanoma cell line. In vivo measurement of coagulation parameters, inhibition of tumor growth, and inhibition of metastasis were assessed in female BALB/c mice. In vitro, vinblastine or stealthy liposomal vinblastine alone was effective to inhibit the growth of A375 cells. On the contrary, hirudin had no influence on either cytotoxicity when treating with hirudin alone or hirudin plus vinblastine. In addition, in vitro results showed that hirudin had no impact on the adhesion of tumor cells to extracellular matrix proteins, and metastasis and invasion of tumor cells. In mice, hirudin significantly inhibited the activity of thrombin. Furthermore, administered at the initial implantation of murine B16 melanoma cells, hirudin evidently delayed the growth of tumor, and depressed the occurrence of experimental lung metastasis. A subsequent administration of stealthy liposomal vinblastine resulted in further inhibiting growth and metastasis of tumor, indicating that hirudin plus stealthy liposomal vinblastine exhibited a significant anti-metastasis effect and slightly potent effect against tumor growth as compared with stealthy liposomal vinblastine alone. In conclusion, administration of recombinant hirudin followed by giving stealthy liposomal vinblastine may be beneficial for inhibiting the growth and metastasis of melanoma in vivo. The likely mechanism could be associated with inhibition of thrombin after administration of hirudin.
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PMID:A recombinant peptide, hirudin, potentiates the inhibitory effects of stealthy liposomal vinblastine on the growth and metastasis of melanoma. 1837 65

Twist, a master regulator of embryonic morphogenesis, induces functions that are also required for tumor invasion and metastasis. Because thrombin contributes to the malignant phenotype by up-regulating tumor metastasis, we examined its effect on Twist in five different tumor cell lines and two different endothelial cell lines. Thrombin up-regulated Twist mRNA and protein in all seven cell lines. Down-regulation of Twist in B16F10 tumor cell lines led to a approximately 3-fold decrease in tumor growth on a chorioallantoic membrane assay and approximately 2-fold decrease in syngeneic mice. Angiogenesis was decreased approximately 45% and 36%, respectively. The effect of Twist on angiogenesis was further examined and compared with the effect of thrombin. In studies using a Twist-inducible plasmid, several identical vascular growth factors and receptors were up-regulated approximately 2- to 3-fold in tumor cells as well as human umbilical vascular endothelial cells by both Twist as well as thrombin (vascular endothelial growth factor, KDR, Ang-2, matrix metalloproteinase 1, GRO-alpha, and CD31). Thrombin-induced endothelial cell chemotaxis and Matrigel endothelial cell tubule formation were similarly regulated by Twist. Thus, thrombin up-regulates Twist, which is required for thrombin-induced angiogenesis as measured by endothelial cell migration, Matrigel tubule formation, and tumor angiogenesis.
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PMID:Twist is required for thrombin-induced tumor angiogenesis and growth. 1851 89

Cathepsin D (CD) up-regulation has been associated with human malignancy and poor prognosis. Thrombin up-regulated CD mRNA and protein in eight tumor cell lines as well as in human umbilical vascular endothelial cells (HUVEC). Thrombin increased the secretion of CD by 3- to 8-fold and enhanced chemotaxis ( approximately 2-fold) in 4T1 murine mammary CA cells, which was completely inhibited with the knockdown of CD. Secreted 4T1 CD induced neoangiogenesis by 2.4-fold on a chick chorioallantoic membrane, which was blocked in CD-KD cells. The addition of pure CD (2 ng) to the chick chorioallantoic membrane increased angiogenesis by 2.1-fold, which was completely inhibited by Pepstatin A (Pep A). CD enhanced human HUVEC chemotaxis and Matrigel tube formation by 2-fold, which was then blocked by Pep A. CD enhanced HUVEC matrix metalloproteinase 9 (MMP-9) activity by approximately 2-fold, which was completely inhibited by Pep A as well as a generic MMP inhibitor, GM6001. The injection of CD-KD 4T1 cells into syngeneic mice inhibited tumor growth by 3- to 4-fold compared with empty vector (EV) cells. Hirudin, a specific thrombin inhibitor, inhibited the growth of wild-type and EV cells by 2- to 3-fold, compatible with thrombin up-regulation of CD. CD and thrombin also contributed to spontaneous pulmonary metastasis; 4-fold nodule inhibition with CD versus EV and 4.6-fold inhibition with hirudin versus EV (P < 0.02). Thus, thrombin-induced CD contributes to the malignant phenotype by inducing tumor cell migration, nodule growth, metastasis, and angiogenesis. CD-induced angiogenesis requires the proteolytic activation of MMP-9.
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PMID:Thrombin up-regulates cathepsin D which enhances angiogenesis, growth, and metastasis. 1855 12

Proteinases such as thrombin and trypsin can affect tissues by activating a novel family of G protein-coupled proteinase-activated receptors (PARs 1-4) by exposing a 'tethered' receptor-triggering ligand (TL). Work with synthetic TL-derived PAR peptide sequences (PAR-APs) that stimulate PARs 1, 2 and 4 has shown that PAR activation can play a role in many tissues, including the gastrointestinal tract, kidney, muscle, nerve, lung and the central and peripheral nervous systems, and can promote tumor growth and invasion. PARs may play roles in many settings, including cancer, arthritis, asthma, inflammatory bowel disease, neurodegeneration and cardiovascular disease, as well as in pathogen-induced inflammation. In addition to activating or disarming PARs, proteinases can also cause hormone-like effects via PAR-independent mechanisms, such as activation of the insulin receptor. In addition to proteinases of the coagulation cascade, recent data suggest that members of the family of kallikrein-related peptidases (KLKs) represent endogenous PAR regulators. In summary: (1) proteinases are like hormones, signaling in a paracrine and endocrine manner via PARs or other mechanisms; (2) KLKs must now be seen as potential hormone-like PAR regulators in vivo; and (3) PAR-regulating proteinases, their target PARs, and their associated signaling pathways appear to be novel therapeutic targets.
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PMID:Kallikreins and proteinase-mediated signaling: proteinase-activated receptors (PARs) and the pathophysiology of inflammatory diseases and cancer. 1862 96

Venous thromboembolism (VTE) is a well-recognized problem in malignancy. Patients with cancer who have VTE have a worse prognosis than other patients with cancer. Hypercoagulability in patients with cancer is related to malignancy itself and its treatment. These patients have multiple risk factors for thromboembolism, such as being immobilized, having central venous catheters, and receiving chemoradiation therapy. Cancer procoagulant, tissue factor, factor VIII, and thrombin have important roles in causing cancer-associated thromboembolism. Tumors require neovascularization for delivering oxygen and other nutrients. Therefore, angiogenesis facilitates tumor growth, invasion, and metastasis. New blood vessels formed by angiogenesis are thrombogenic. Hypercoagulability and tumor growth are closely related. Vascular endothelial growth factor (VEGF) is a proangiogenic factor that may also cause VTE in patients with cancer. The relationship between cancer, angiogenesis, VEGF, and thrombosis is reviewed herein. Studies are ongoing to enhance our understanding of this complex interaction.
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PMID:Venous thromboembolism in patients with cancer and its relationship to the coagulation cascade and vascular endothelial growth factor. 1863 33

Oncogenic upregulation of tissue factor (TF) and release of TF-containing microvesicles play an important role in cancer-related coagulopathy (Trousseau's syndrome), angiogenesis, and disease progression. In addition, certain types of host cells (stromal cells, inflammatory cells, activated endothelium) may also express TF. Although the relative contribution of host-related versus tumor-related TF to tumor progression is not known, our recent studies indicate that the role of both sources of TF in tumor formation is complex and context-dependent. Disruption of TF expression/activity in cancer cells leads to tumor growth inhibition in immunodeficient mice, even in cases where TF overexpression is driven by potent oncogenes ( K-RAS or EGFR). Interestingly, TF expression in vivo appears to be influenced by many factors, including the level of oncogenic transformation, tumor microenvironment, and differentiation from cancer stem-like cells. We postulate that activation of TF signaling and coagulation may deliver growth-promoting stimuli (e.g., fibrin, thrombin, platelets) to dormant cancer stem cells (CSCs). Functionally, these influences may be tantamount to formation of a provisional (TF-dependent) cancer stem cell niche. As such, these changes may contribute to the involvement of CSCs in tumor growth, angiogenesis, and metastasis.
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PMID:Diverse roles of tissue factor-expressing cell subsets in tumor progression. 1864 22

Factor VIIa (FVIIa)-induced signal transduction is strongly dependent on cellular surface expression of Tissue Factor (TF) and Protease Activated Receptors (PARs). FVIIa signals primarily through PAR2. This contrasts to thrombin which signals primarily via PAR1 and does so without the assistance of a co-receptor, but by binding to an exosite on PAR1. Various TF:FVII-mediated cellular activities are now well documented and have indicated possible links to inflammation, atherosclerosis, angiogenesis, tissue repair, tumor growth and metastasis. Further knowledge about cellular responses induced by coagulation factors has been obtained by gene-expression profiling of MDA-MB-231 cells stimulated with FVIIa or alternatively with PAR1 or PAR2 agonist peptides. These studies and qPCR measurements of the transcription of selected genes in these and other carcinoma cell lines have provided new information about gene expression induced by PAR activation, the gene repertoire induced by TF:FVIIa via PAR2, and how it differs from that induced via PAR1 by thrombin.
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PMID:Microarray studies of factor VIIa-activated cancer cells. 1869 91

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 P-selectin-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.
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PMID:Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung. 1906 86

Blood coagulation appears to play an important role in the occurrence of cancer and its effects may be twofold. First, in patients with cancer, blood coagulation is activated in the direction of a prothrombotic state. Second, a procoagulant environment may promote cancer in different ways. In this chapter we discuss some of the mechanisms that may be involved in this interplay between coagulation and cancer. Blood coagulation proteins interact with cells in the vasculature to maintain hemostasis. However, many proteins that are involved in coagulation and anticoagulation, as well as fibrinolysis, are also found in extravascular tissues. In different organs, these proteins may be involved in cell-signaling mechanisms, through interaction with cell receptors like protease-activated receptors (PARs). Such interactions may drive inflammation, angiogenesis and cell proliferation. The potential procarcinogenic actions of proteases like thrombin may be counteracted by the anticoagulant and anti-inflammatory actions of the protein C-thrombomodulin mechanism. In the blood of cancer patients, the balance is usually shifted towards a procoagulant direction. The resulting excess thrombin- and fibrin-forming activity promotes venous thrombosis and may in the extravascular compartment stimulate cancer progression. The activation of platelets and their interaction with leukocytes may propagate this process. In addition to the therapeutic modulation of the prothrombotic environment, the induction of specific anticoagulant proteins including thrombomodulin may have effects on tumor growth or dissemination, but the nature of these effects still remains hard to predict. The interplay between cancer and blood coagulation merits further experimental and clinical research.
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PMID:Overview of the postulated mechanisms linking cancer and thrombosis. 1917 85

Both women and men with cancer are at increased risk for developing venous thromboembolism (VTE), a propensity that has been known for many years. Until recently it was assumed, however, that the association between cancer and thrombosis is an epiphenomenon - not causally related to the transforming malignant events. The pathophysiology of thrombosis in patients with cancer is complex involving multiple tumor-related and host-related factors. Several recent studies have provided strong evidence that activation of blood coagulation, perhaps most often mediated by tissue factor (TF)-rich microparticles (MPs), is linked directly to oncogene-induced malignant transformation. In addition, the development of VTE, either before or concurrent with the diagnosis of cancer, appears to predict an aggressive behavior of a tumor, and correlates with increased tumor angiogenesis and early onset of distant metastasis. The regulation of expression of TF in tumor cells is controlled at the molecular level by several oncogenes, as appears to be true for cyclooxygenase-2 (COX-2), an important regulator of platelet function and plasminogen activator inhibitor type 1 (PAI-1), an inhibitor of fibrinolysis. In addition, engagement of protease-activated receptors (PARs) by the TF-factor VIIa complex, factor Xa and/or thrombin, have now been shown to be important for tumor growth, angiogenesis and metastasis. Targeting blood clotting reactions in cancer, therefore, may provide a unique approach to cancer treatment.
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PMID:Cancer and thrombosis in women - molecular mechanisms. 1921 69


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