Journal Article•
The role of thrombin in tumor cell metastasis.
TL;DR: Thrombin, at concentrations which precede fibrin formation, is a potent inducer of tumor cell expression of various integrin receptors and tumor cell adhesion to the matrix and other activated cells.
Abstract: The relationship between malignancy and thrombosis and hemostasis has long been recognized but is poorly understood. The interaction of tumor cells and the proteins and cells of coagulation is symbiotic and complex. Selected cancers have been known to respond to antithrombotic and anticoagulant therapies such as warfarin, heparin and most recently, hirudin. The identification of the functional 'tethered ligand' thrombin receptor on platelets, other cells and recently tumor cells has provided additional opportunities to examine and control the course of tumor proliferation. Thrombin, at concentrations which precede fibrin formation, is a potent inducer of tumor cell expression of various integrin receptors and tumor cell adhesion to the matrix and other activated cells. New strategies based on specifically controlling the action of thrombin may be beneficial in arresting the proliferation of these cells.
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TL;DR: It is concluded that fibrin(ogen) is a critical determinant of the metastatic potential of circulating tumor cells and thrombin appears to facilitate tumor dissemination through at least one fibrIn(ogen)-independent mechanism.
553 citations
TL;DR: Thrombin receptor, a member of the protease-activated receptor family, is preferentially expressed in highly metastatic human breast carcinomas cell lines and breast carcinoma biopsy specimens and introduction of thrombin receptors antisense cDNA considerably inhibited the invasion of metastatic breast carcin cancer cells in culture through a reconstituted basement membrane.
Abstract: Although the involvement of soluble and matrix-immobilized proteases in tumor cell invasion and metastasis is well recognized, the role of proteolytically activated cell surface receptors has not been elucidated. We report here that thrombin receptor, a member of the protease-activated receptor family, is preferentially expressed in highly metastatic human breast carcinoma cell lines and breast carcinoma biopsy specimens. Introduction of thrombin receptor antisense cDNA considerably inhibited the invasion of metastatic breast carcinoma cells in culture through a reconstituted basement membrane. During placental implantation of the human embryo, thrombin receptor is transiently expressed in the invading cytotrophoblasts. These results emphasize the involvement of thrombin receptor in cell invasion associated with tumor progression and normal embryonic development.
425 citations
Journal Article•
TL;DR: It is concluded that the ultimate effect of heparin treatment on cancer progression is uncertain and mechanisms by which heparins potentially exert their activity on various steps in cancer progression and malignancy related processes are discussed.
Abstract: Patients with cancer are frequently treated with anticoagulants, including heparins, to treat or to prevent thrombosis. Recent randomized trials that compared low molecular weight heparin to unfractionated heparin for the treatment of deep vein thrombosis have indicated that heparins affect survival of patients with cancer. Experimental studies support the hypothesis that cancer progression can be influenced by heparins, but results of these studies are not conclusive. Heparins are negatively charged polysaccharides that can bind to a wide range of proteins and molecules and affect their activity. As a consequence, heparins have a wide variety of biological activities other than their anticoagulant effects, which may interfere with the malignant process. In the present systematic review, we critically evaluate experimental studies in which heparins have been tested as anti-cancer drugs. All animal studies, published between 1960 and 1999, that report effects of heparins on growth of subcutaneously implanted tumors, spontaneous metastasis or experimentally induced metastasis are reviewed. In addition, we discuss mechanisms by which heparins potentially exert their activity on various steps in cancer progression and malignancy related processes. It is shown that heparins can affect proliferation, migration, and invasion of cancer cells in various ways and that heparins can interfere with adherence of cancer cells to vascular endothelium. Moreover, heparins can affect the immune system and have both inhibitory and stimulatory effects on angiogenesis. Because of the wide variety of activities of heparins, it is concluded that the ultimate effect of heparin treatment on cancer progression is uncertain.
287 citations
Cites background from "The role of thrombin in tumor cell ..."
...In summary, the importance of platelets, thrombin and clot formation for intravascular arrest and survival of cancer cells has been demonstrated in vitro and in vivo (Honn et al., 1992b; Walz and Fenton, 1994; Nierodzik et al., 1995)....
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...Production of thrombin and induction of platelet aggregation by cancer cells is positively correlated with cancer progression and metastatic potential (Nierodzik et al., 1991; Honn et al., 1992b; Walz and Fenton, 1994)....
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Journal Article•
TL;DR: In situ techniques were used to determine the cellular localization of XLF, TF, VEGF, and an alternative tumor procoagulant, so-called cancer procoAGulant (CP), a cysteine protease that activates clotting factor X, consistent with a highly complex interaction between tumor cells, macrophages, and endothelial cells in the TME leading to fibrin formation and tumor angiogenesis.
Abstract: Thrombin-catalyzed, cross-linked fibrin (XLF) formation is a characteristic histopathological finding in many human and experimental tumors and is thought to be of importance in the local host defense response. Although the pathogenesis of tumor-associated fibrin deposition is not entirely clear, several tumor procoagulants have been described as likely primary stimuli for the generation of thrombin (and XLF) in the tumor microenvironment (TME). In a previous study of a variety of human tumors we have shown that tissue factor (TF) is the major procoagulant. However, the relative contribution to fibrin deposition in the TME of tumor cell TF and host cell TF (eg, macrophage-derived) was not established. In addition, recent evidence has implicated TF in the regulation of the synthesis of the pro-angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells. In the current study we used in situ techniques to determine the cellular localization of XLF, TF, VEGF, and an alternative tumor procoagulant, so-called cancer procoagulant (CP), a cysteine protease that activates clotting factor X. In lung cancer we have found XLF localized predominantly to the surface of tumor-associated macrophages, as well as to some endothelial cells and perivascular fibroblasts in the stromal area of the tumors co-distributed with TF at the interface of the tumor and host cells. Cancer pro-coagulant was localized to tumor cells in several cases but not in conjunction with the deposition of XLF. TF and VEGF were co-localized in both lung cancer and breast cancer cells by in situ hybridization and immunohistochemical staining. Furthermore, a strong relationship was found between the synthesis of TF and VEGF levels in human breast cancer cell lines (r2 = 0.84; P < 0.0001). Taken together, these data are consistent with a highly complex interaction between tumor cells, macrophages, and endothelial cells in the TME leading to fibrin formation and tumor angiogenesis.
264 citations
Journal Article•
TL;DR: It is demonstrated here that PAR1 activation has a role in experimental metastasis using the anti-PAR1 antibodies ATAP2 and WEDE15, which block PAR1 cleavage and activation and confirm a role for PAR1 in migration and metastasis and demonstrate an unexpected role forPAR2 in thrombin-dependent tumor cell migration and in metastasis.
Abstract: The effects of the pleiotropic serine protease thrombin on tumor cells are commonly thought to be mediated by the thrombin receptor protease-activated receptor 1 (PAR1). We demonstrate here that PAR1 activation has a role in experimental metastasis using the anti-PAR1 antibodies ATAP2 and WEDE15, which block PAR1 cleavage and activation. Thrombin also stimulates chemokinesis of human melanoma cells toward fibroblast conditioned media and soluble matrix proteins. Thrombin-enhanced migration is abolished by anti-PAR1 antibodies, demonstrating that PAR1 cleavage and activation are required. The PAR1-specific agonist peptide TFLLRNPNDK, however, does not stimulate migration, indicating that PAR1 activation is not sufficient. In contrast, a combination of TFLLRNPNDK and the PAR2 agonist peptide SLIGRL mimics the thrombin effect on migration, whereas PAR2 agonist alone has no effect. Agonist peptides for the thrombin receptors PAR3 and PAR4 used alone or with PAR1 agonist also have no effect. Similarly, activation of PAR1 and PAR2 also enhances chemokinesis of prostate cancer cells. Desensitization with PAR2 agonist abolishes thrombin-enhanced cell motility, demonstrating that thrombin acts through PAR2. PAR2 is cleaved by proteases with trypsin-like specificity but not by thrombin. Thrombin enhances migration in the presence of a cleavage-blocking anti-PAR2 antibody, suggesting that thrombin activates PAR2 indirectly and independent of receptor cleavage. Treatment of melanoma cells with trypsin or PAR2 agonist peptide enhances experimental metastasis. Together, these data confirm a role for PAR1 in migration and metastasis and demonstrate an unexpected role for PAR2 in thrombin-dependent tumor cell migration and in metastasis.
236 citations