Role of the Coagulation System in Tumor-Cell-Induced Platelet Aggregation and Metastasis

Cavanaugh, Philip G.; Sloane, Bonnie F.; Honn, Kenneth V.

doi:10.1159/000215781

Cited by 33 publications

(26 citation statements)

References 16 publications

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“…Both molecules are ultimately responsible for the activation of factor X, which in turn leads to the generation of active thrombin from plasma prothrombin (15). All these observations would suggest that thrombin generation caused by tumor procoagulant activities might be responsible for in vivo platelet activation (16) and the release of biologically active substances, as demonstrated recently for vascular endothelial growth factor (12).…”

Section: Introductionmentioning

confidence: 71%

“…Preclinical and clinical studies suggested that activation of the hemostatic system may play an important role in tumor growth and metastasis. Indeed, it is well known that many human tumors possess a procoagulant activity that can be responsible for the generation of active thrombin from plasma prothrombin (15), leading to in vivo platelet activation (16) and release of various factors, including growth factors and cytokines, most of which may have important biological functions in the development and progression of human tumors (12,23).…”

Section: Discussionmentioning

confidence: 99%

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Soluble CD40 Ligand Plasma Levels in Lung Cancer

Roselli¹,

Mineo

Basili³

et al. 2004

Clinical Cancer Research

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Purpose: Tumor-induced platelet activation may cause the release of various cytokines, including CD40 ligand (CD40L). Activation of the CD40/CD40L pathway in human tumors may result in thrombin generation, which is known to be involved in angiogenesis. Thus, we investigated whether soluble (s)CD40L levels are increased in patients with lung cancer as a result of platelet and/or coagulation activation.Experimental Design: Citrated plasma samples were obtained from 120 patients with different stages and histotypes of lung cancer and 60 age-and sex-matched control subjects. sCD40L, sP-selectin (marker of platelet activation), prothrombin fragment 1 ؉ 2, and thrombin-antithrombin III complex levels (both markers of coagulative activation) were measured in all samples.Results: Patients with lung cancer had median sCD40L levels higher than in control subjects (0.46 versus 0.13 ng/ml; P < 0.0001), although correlation with the stage of disease was not evident. Nonetheless, sCD40L levels were significantly higher in squamous cancer compared with adenocarcinoma (0.75 versus 0.27 ng/ml; P < 0.05). Moreover, median sCD40L levels were higher in stage IV compared with nonmetastatic squamous lung cancer (1.02 versus 0.61 ng/ ml; P < 0.05). sCD40L levels significantly correlated with sP-selectin (P < 0.001), prothrombin fragment 1 ؉ 2 (P < 0.001), or thrombin-antithrombin III complex (P < 0.05) in squamous lung cancer, but only sP-selectin (P ‫؍‬ 0.011) was independently related to sCD40L.Conclusions: These findings indicate that elevated sCD40L levels can be preferentially found in patients with advanced squamous cancer and provide evidence that increased levels of this cytokine are associated to the occurrence of in vivo platelet activation.

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Section: Introductionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Soluble CD40 Ligand Plasma Levels in Lung Cancer

Roselli¹,

Mineo

Basili³

et al. 2004

Clinical Cancer Research

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“…Tumor cells are unique because they have constitutively active tissue factor on the surface. 37,38) The tissue factor could induce thrombin generation, which in turn could stimulate tumor cell growth, adhesion, and invasion. In the presence of hirudin, thrombin activity could be inhibited hence resulting in a decreased trend in ability of tumor cell adhesion, growth, invasion, and metastasis.…”

Section: Effect On Tumor Cell Proliferation In Vivomentioning

confidence: 99%

A Recombinant Peptide, Hirudin, Potentiates the Inhibitory Effects of Stealthy Liposomal Vinblastine on the Growth and Metastasis of Melanoma

Guo

Liu

et al. 2008

Biological & Pharmaceutical Bulletin

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The metastasis of tumor cells is one of the major obstacles to successful clinical chemotherapy, surgery, and radiotherapy. Accordingly, new therapeutic strategies are needed for overcoming the occurrence of invasion and metastasis of tumor to improve patients' prognosis and survival.The anticoagulants low-molecular weight heparin (LMWH) and recombinant hirudin have shown anti-invasion and antimetastasis effects in experimental models.1,2) However, recombinant hirudin was found ineffective at preventing metastasis of HT168-M1 human melanoma cells in preclinical study, 1) suggesting that the anti-invasion and anti-metastasis effects of anticoagulants may vary by tumor cells. Most likely, each anticoagulant agent has its own mechanisms for application.The association of thrombosis and cancers as evidenced by platelet and fibrin deposition is well established.3-6) Previous studies indicate that exogenous thrombin (1 U/ml) acting through its protease-activated receptor (PAR-1) is capable of enhancing tumor adhesion to platelets, 7-9) endothelial cells, 10) fibronectin, and von Willebrand factor 8) in vitro. Studies have also revealed that exogenous thrombin promotes tumor growth in vitro 11) and in vivo 7,8,12) as well as metastasis in experimental animals (via tail-vein injection of cancer cells). 9,13) The endogenous generation of host thrombin plays a significant role during tumor growth and spontaneous metastasis.2) Recent investigation demonstrated that advanced cancer is associated with a hypercoagulable state triggered by tissue factor (TF).14) TF-initiated thrombin generation is a critical step for metastasis through fibrin, platelet deposition, and PAR-1 signaling responses. In addition, PAR-2, which was not cleaved by thrombin, appears to be a cosignal with PAR-1 to elicit thrombin effects in metastatic tumor cells. 14)Hirudin is a highly potent and specific inhibitor of thrombin. It has shown an inhibitory effects against tumor growth and metastasis in experimental tumor models. [15][16][17] Hirudin induced a pronounced lag time in the appearance of tumor growth, as compared with phosphate-buffered saline (PBS) as control, but had no effect on existing tumor cells. We postulated that hirudin may have different effects on tumor growth depending on its administrations, because hirudin resulted in central necrosis of the tumor nodule, and inhibited spontaneous metastases from subcutaneously implanted tumor by reducing the number of tumor nodules in the lungs following administration at early stage of tumor cell inoculation in experimental animals. 2)Heparins are negatively charged polysaccharides that are able to bind to a number of proteins and molecules, thus probably influencing their biological activity. LMWH is composed of low-molecular weight fragments of heparin manufactured by controlled enzymatic or chemical depolymerization. LMWH may affect the progression of tumor in many ways. For example, it may potentially inhibit intravascular arrest and metastasis due to its anticoagulant role. [18][19][20] I...

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“…In an experimental metastasis model, tumor cell-associated TF stimulates the formation of tumor cell/platelet/fibrin complexes, which greatly enhance tumor cell seeding in the lungs. 4,6,7 The major physiologic inhibitor of the TF/fVIIa complex is the tissue factor pathway inhibitor (TFPI). 1 TFPI is a multidomain protein consisting of 3 independently folded kunitz proteinase inhibitor (KPI) domains, and a highly basic carboxy-terminal tail.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of a very low density lipoprotein receptor-binding peptide from tissue factor pathway inhibitor that has antitumor and antiangiogenic activity

Hembrough

Ruiz

Swerdlow

et al. 2004

Blood

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Tissue factor pathway inhibitor (TFPI) is the major physiologic inhibitor of the extrinsic coagulation pathway. We have previously shown that TFPI is also a potent inhibitor of endothelial proliferation in vitro and of primary and metastatic tumor growth in vivo. Surprisingly, the antitumor activity of TFPI was demonstrated to be independent of its anticoagulant activity, suggesting a possible nonhemostatic mechanism of action for TFPI in these models. This antitumor mechanism may involve the very low density lipoprotein (VLDL) receptor because the in vitro antiproliferative activity of TFPI is mediated through interaction with the VLDL receptor. In the current study, we identify a 23-amino acid fragment of TFPI (TFPIc23) localized to the C-terminus, which mediates binding to the VLDL receptor. The TFPIc23 peptide inhibits endothelial cell proliferation through an apoptotic mechanism and blocks vessel outgrowth in the in vitro assays, and this activity is mediated through interaction with the VLDL receptor. In vivo, this peptide potently inhibits angiogenesis in Matrigel and chick chorioallantoic membrane models and also inhibits metastatic tumor growth. Our data demonstrate that this VLDL receptor-binding fragment of the TFPI molecule has apoptotic, antiangiogenic, and antitumor activity and suggests a possible mechanism whereby TFPI can regulate angiogenesis and tumor growth independently of its anticoagulant activity. (Blood. 2004;103: 3374-3380)

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Role of the Coagulation System in Tumor-Cell-Induced Platelet Aggregation and Metastasis

Cited by 33 publications

References 16 publications

Soluble CD40 Ligand Plasma Levels in Lung Cancer

Soluble CD40 Ligand Plasma Levels in Lung Cancer

A Recombinant Peptide, Hirudin, Potentiates the Inhibitory Effects of Stealthy Liposomal Vinblastine on the Growth and Metastasis of Melanoma

Identification and characterization of a very low density lipoprotein receptor-binding peptide from tissue factor pathway inhibitor that has antitumor and antiangiogenic activity

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