Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue factor (TF) is a transmembrane glycoprotein that initiates blood coagulation when complexed with activated factor VII (FVIIa). TF is constitutively expressed in a variety of tumor cells and has been implicated in cellular signaling, angiogenesis, and tumor progression. Formation of TF-FVIIa complex and generation of downstream coagulation proteases, including activated factor X (FXa) and thrombin, initiate signaling by activation of protease-activated receptors (PARs). We have previously shown that TF-FVIIa-Xa complex formation promotes phosphorylation of p44/42 mitogen-activated protein kinase and Akt/protein kinase B in human breast cancer cells. In the present study, we show that formation of TF-FVIIa-FXa complex induces phosphorylation of mammalian target of rapamycin (mTOR) and p70 S6 kinase in a human breast cancer cell line, Adr-MCF-7. Activation of the mTOR pathway, which is probably mediated by PAR1 and/or PAR2, was associated with enhanced cell migration, a key step in the metastatic cascade. Inhibition of this pathway with the specific mTOR inhibitor, rapamycin, markedly decreased cell migration induced by formation of TF-FVIIa-FXa complex. These studies suggest that TF-FVIIa-mediated signaling modulates mTOR pathway activation, which regulates in part breast cancer cell migration. Targeting the TF-mediated cell signaling pathway might represent a novel strategy for the treatment of breast cancer.
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PMID:Formation of tissue factor-factor VIIa-factor Xa complex induces activation of the mTOR pathway which regulates migration of human breast cancer cells. 1861 47

There is a persuasive body of evidence suggesting that tissue factor (TF) is a major determinant of tumor progression. In addition to its "traditional" function as the initiator of hemostasis, TF may support tumor progression through signaling mechanisms involving either direct signal transduction through the TF cytoplasmic domain or TF:F VIIa-mediated and TF/F VIIa/F Xa-mediated activation of protease-activated receptors. Whereas TF-mediated signaling events uncoupled from hemostasis may play an important role in tumor dissemination in some contexts, TF-mediated thrombin generation appears to be the major mechanism linking tumor cell-associated TF to metastasis. At least one mechanism coupling thrombin generation to metastatic potential involves the most distal components of the hemostatic system (i.e., platelets, fibrinogen, and factor XIII) and leads to a restriction in natural killer cell-mediated lysis of newly formed micrometastases. A detailed understanding of the mechanisms linking TF and circulating hemostatic system components to tumor progression may lead to novel therapeutic targets for cancer treatment.
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PMID:Mechanisms linking tumor cell-associated procoagulant function to tumor dissemination. 1864 20

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

The G protein-coupled protease-activated receptors (PAR) are key signaling components for proteases in vascular biology and tumor progression. To address the contributions of PAR1 and PAR2 to breast cancer development, we established cohorts of mouse mammary tumor virus-polyoma middle T (PyMT) PAR1(-/-) and PAR2(-/-) mice, considering that the PyMT model recapitulates aspects of human disease. Appearance of palpable tumors, tumor expansion, and metastasis was indistinguishable between wild-type and PAR1(-/-) mice. PAR1(-/-) breast cancer cells were no longer responsive to thrombin in vitro, excluding compensatory up-regulation of alternative thrombin receptors and indicating that thrombin-PAR1 signaling is dispensable in breast tumor microenvironments. In contrast, palpable tumors and multifocal disease developed slower in PAR2(-/-) mice, and as a consequence of delayed tumor onset, metastasis was reduced. Analysis of early tumors showed persistence of adenomas with delayed appearance of vascularized adenocarcinomas in PAR2(-/-) mice. Furthermore, CXCL1 production by early PAR2(-/-) tumors was reduced. These results are consistent with previous xenograft data that implicated breast cancer PAR2 signaling in the induction of proangiogenic growth factors and chemokines. This study establishes that protease signaling contributes to mammary tumor development and that PAR2, rather than the thrombin receptor PAR1, plays a crucial role in the angiogenic switch.
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PMID:Protease-activated receptor (PAR) 2, but not PAR1, signaling promotes the development of mammary adenocarcinoma in polyoma middle T mice. 1875 38

Human protease-activated receptor 1 (hPar1) is a bona fide receptor of the hemostatic protease thrombin, and has a central function in tumor progression. Inactivation of the tumor suppressor gene p53 is one of the most common genomic alterations occurring in cancer. Here, we address the interrelations between p53 and hPar1 in cancer. We demonstrate an inverse correlation between hPar1 gene expression and wild-type (wt) p53 levels, and a direct correlation with levels of the mutant (mt) p53. Bioinformatic search revealed the presence of at least two p53 motifs in the hPar1 promoter. Indeed, temperature-sensitive (ts) p53 forms reduced hPar1 promoter activity on wt p53 expression. Ectopic introduction of the p53R175H mutant into cells lacking p53 caused a moderate two-fold induction of hPar1 promoter activity. Chromatin immunoprecipitation (ChIP) analyses confirmed a physical association between the p53 protein and hPar1 chromatin fragments. In parallel, PAR1 function is attenuated by p53, as shown by inhibition of pFAK levels and a Matrigel invasion assay. Ectopic reinforcement of hPar1 rescued the inhibition conferred by p53, confirming that p53 directly affects hPar1 expression and function. Altogether, we provide evidence for a direct binding between p53 and hPar1 chromatin, and assign hPar1 as a target of p53.
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PMID:p53 controls hPar1 function and expression. 1882 Jul 8

Many tumor types express matrix metalloproteinase-1 (MMP-1); its collagenase activity facilitates both tumor cell invasion and metastasis. MMP-1 expression is also associated with increased angiogenesis; however, the exact mechanism by which this occurs is not clear. MMP-1 proteolytically activates protease activated receptor-1 (PAR-1), a thrombin receptor that is highly expressed in endothelial cells. Thrombin is also present in the tumor microenvironment, and its activation of PAR-1 is pro-angiogenic. It is currently unknown whether MMP-1 activation of PAR-1 induces angiogenesis in a similar or different manner compared with thrombin. We sought to determine the mechanism by which MMP-1 promotes angiogenesis and to compare the effects of MMP-1 with those of thrombin. Our results demonstrate that via PAR-1, MMP-1 activates mitogen-activated protein kinase signaling cascades in microvessel endothelial cells. Although thrombin activation of PAR-1 also induces signaling through these pathways, the time-course of activation appears to vary. Gene expression analysis revealed a possible consequence of these signaling differences as MMP-1 and thrombin induce expression of different subsets of pro-angiogenic genes. Furthermore, the combination of thrombin and MMP-1 is more angiogenic than either protease alone. These data demonstrate that MMP-1 acts directly on endothelial cells as a pro-angiogenic signaling molecule and also suggest that the effects of MMP-1 may complement the activity of thrombin to better facilitate angiogenesis and promote tumor progression.
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PMID:Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis. 1898 1

The supporting role of proteases in tumor progression and invasion is well known; however, the use of proteases as therapeutic agents has also been demonstrated. In this article, the authors report on the differential effects of exogenous serine proteases on the motility of tumor and normal cells. The treatment of normal and tumor cells with a single dose of pancreatic serine proteases, trypsin (TR) and chymotrypsin (CH), leads to a concentration-dependent response by cells, first accelerating and then slowing mobility. Tumor cells are 10 to 20 times more sensitive to exogenous TR/CH, suggesting that a single dose of proteases may cause discordant movements of normal and tumor cells within the tumor environment. The inhibitory effects of TR on cell motility are contradicted by thrombin (TH), particularly in the regulation of normal cells' migration. The purpose of this investigation was to ascertain the role of protease-activated receptors (PARs) in terms of normal and tumor cell motility. Duplicate treatments with proteases resulted in diminished mobility of both normal and tumor cells. Repeated application of TR and TH in 1-hour treatment intervals initially desensitizes cell surface PARs. However, cell surface PARs reappear regardless of subsequent protease treatments in both normal and tumor cells. The resensitization process is retarded in tumor cells when compared with normal cells. This is evidenced by lower expression of PARs as well as by their relocalization at the tumor cell surfaces. Under these conditions, normal cells remain responsive to exogenous proteases in terms of cell motility. Exogenous proteases do not modulate motility of repeatedly stimulated tumor cells, and consequently, the migration of tumor cells appears disconnected from the PAR signaling pathways. The use of activating peptides in lieu of the cognate proteases for a given PAR system indicated that proteases may act through additional targets not regulated by PAR signaling. We hypothesize that the divergent migration patterns of normal and tumor cells due to exposure to proteases is in part mediated by PARs. Thus, treatment with exogenous proteases may cause rearrangement of the tumor and stromal cells within the tumor microenvironment. Such topographical effects may lead to the inhibition of tumor progression and metastasis development.
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PMID:Differential effects of serine proteases on the migration of normal and tumor cells: implications for tumor microenvironment. 1911 24

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

Perillyl alcohol (POH) is a naturally occurring monoterpene with antiangiogenic and anti-tumoral properties. This chemotherapeutic agent has proven effectiveness in several clinical trials, including an ongoing phase I, comprising patients with recurrent glioblastoma multiform (GBM) under treatment with POH by intranasal administration. Proteomics offers tools to distinguish states of biological systems according to protein expression differences and therefore, can be used to gain pathological insights and to search for disease follow-up biomarkers. In this work, a differential gel electrophoresis (DIGE) proteomic approach was used to search for plasma proteins that correlated with the disease progression in 10 of these patients. Our results pointed antithrombin (down) and fibrinogen (up) regulated after a four months treatment deserving to be further verified as prognostic markers for this treatment. Possible links between tumor progression and anti-thrombin expression level are also discussed.
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PMID:Anti-thrombin as a prognostic biomarker candidate for patients with recurrent glioblastoma multiform under treatment with perillyl alcohol. 1922 8

Tissue factor (TF) plays a critical role in tumour growth and metastasis, and its enhanced release into plasma in association with cellular microparticles (MPs) has recently been associated with pathological cancer progression. We have previously demonstrated significantly elevated levels of plasma TF antigen as well as systemic coagulation and platelet activation in patients with localised prostate cancer. In this prospective study, we used a highly sensitive one-stage clotting assay to measure preoperative TF-specific procoagulant activity (PCA) of plasma MPs in 68 consecutive patients with early-stage prostate cancer to further explore the relevance of circulating TF in this tumour entity. Automated calibrated thrombography was used to monitor thrombin generation in cell-free plasma samples in the absence of exogenous TF or phospholipids. Compared to healthy male controls (n=20), patients had significantly increased levels of both D-dimer and TF-specific PCA of plasma MPs (p<0.001). Furthermore, MP-associated TF PCA was higher in patients with (n=29) than in those without (n=39) laboratory evidence of an acute-phase reaction (p=0.004) and decreased to normal levels within one week after radical prostatectomy. Overall, we found a significant correlation between TF-specific PCA of plasma MPs and plasma D-dimer (p=0.002), suggesting that plasma MPs contributed to in-vivo coagulation activation in a TF-dependent manner. Thrombin generation in plasma was also significantly increased in patients compared to controls (p<0.01). Collectively, our findings suggest that TF-specific PCA of plasma MPs contributes to intravascular coagulation activation in patients with early-stage prostate cancer and may represent a potential link between hypercoagulability, inflammation, and disease progression.
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PMID:Tissue factor procoagulant activity of plasma microparticles is increased in patients with early-stage prostate cancer. 1949 60


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