Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PDGF-B released from colon tumor cells regulated tumor growth in athymic mice in a paracrine manner by inducing blood vessel formation. A positive correlation was found between expression of PDGF B-chain in cells grown in vitro and the number of factor VIII-positive blood vessels in tumors induced by three classes of colon carcinoma cell lines. Elevated expression of PDGF-B was also correlated with tumor size. Each cell line had the same mutations in the colon cancer genes APC, DCC, and p53 and had wild type c-K-ras genes (Huang et al. [1994] Oncogene, 9:3701-3706.) eliminating the possibility that any differences in tumor blood vessel formation were due to mutations and/or deletions in these genes. Colon carcinoma cells released biologically active PDGF capable of stimulating the growth of NIH3T3 cells, which was inhibited by neutralizing antisera to PDGF-AB chains. An inverse correlation was found between induction of factor VIII-positive blood vessels and expression of vascular endothelial growth factor (VEGF), while no correlation was seen with expression of either TGF alpha or k-FGF. Basic fibroblast growth factor (FGF) expression was not detected in these tumor cells. TGF beta 1 was capable of inducing PDGF-B expression in the undifferentiated U9 colon carcinoma cell line, but this sensitivity was not seen in differentiated cells. In contrast, TGF beta 1 inhibited VEGF expression in both undifferentiated cells and differentiated colon cancer cells. Thus, TGF beta 1 has two roles in the growth of undifferentiated U9 colon carcinoma cells in vivo: direct stimulation of cell proliferation as we have showed in earlier studies, and an increase in angiogenesis by inducing PDGF-B.
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PMID:Platelet-derived growth factor-B increases colon cancer cell growth in vivo by a paracrine effect. 759 1

Thrombomodulin (TM) is a cell-surface receptor that plays a critical role in endothelial cell anticoagulant activity through its cofactor role in the thrombin-catalyzed activation of human protein C. In this study, we examined the effect of vascular endothelial growth factor (VEGF), a potent angiogenic factor, on surface anticoagulant activity and thrombomodulin expression. We show that thrombin-dependent activation of human protein C, measured on the endothelial cell surface, increased from 50 to 80% following exposure of cells to VEGF for 24 h. The effect was concentration dependent with the half-maximal stimulatory effect at approximately 100 pM. This increase in thrombin-dependent aPC generation correlated with a proportional and concentration-dependent increase in the level of cell-surface TM antigen. Both the total cellular TM antigen and the total cellular TM mRNA levels increased approximately 2.5-fold in VEGF-treated cells suggesting that most if not all of the regulation was at the message level. We further show that VEGF blocked IL-1 beta-induced suppression of both TM surface antigen and mRNA and was similarly capable of antagonizing the down-regulation of TM by TGF-beta and from cell activation by LPS. Our data suggest that VEGF regulation of TM may contribute to mechanisms that would maintain local hemostasis during angiogenesis and revascularization and could play a role in minimizing loss of vessel anticoagulant function during inflammatory processes.
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PMID:Thrombomodulin-dependent anticoagulant activity is regulated by vascular endothelial growth factor. 945 83

Tumors produce a number of immunosuppressive factors that block the maturation of CD34+ stem cells into dendritic cells (DC). We hypothesized that tumors might also interfere with the maturation and/or function of human monocyte-derived DC. In contrast to stem cells, we found that CD14+ cells responded to tumor culture supernatant (TSN) by increasing expression of APC surface markers, up-regulating nuclear translocation of RelB, and developing allostimulatory activity. Although displaying these characteristics of mature DC, TSN-exposed DC lacked the capacity to produce IL-12, did not acquire full allostimulatory activity, and rapidly underwent apoptosis. The effects of TSN appeared to be specific for maturing DC, and were not reversed by Abs against known DC regulatory factors including IL-10, vascular endothelial growth factor, TGF-beta, or PGE2. Supernatants collected from nonmalignant cell sources had no effect on DC maturation. The altered maturation and early apoptosis of monocyte-derived DC may represent another mechanism by which tumors evade immune detection.
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PMID:Tumors promote altered maturation and early apoptosis of monocyte-derived dendritic cells. 1064 Jul 40

An increased number of circulating endothelial cells (CECs) was demonstrated in alpha- and beta-thalassemic patients, beta-thalassemia/hemoglobin E (BE), both splenectomized (BE[S]) and non-splenectomized (BE[NS]), had higher numbers of CECs than alpha-thalassemia, both HbH (alpha-thal l/alpha-thal 2; H) and HbH with hemoglobin Constant Spring (alpha-thal 1/CS; H/CS). CECs were also increased in heterozygous HbE (EA) and homozygous HbE (EE). The highest level of tumor necrosis factor-alpha (TNF-alpha) was found in HbH/CS patients, whereas the highest levels of vascular endothelial growth factor (VEGF) was observed in BE[S] patients. Significant decreases, in protein C and protein S levels were found in both alpha- and beta-thalassemia compared with normal. Good correlations between the numbers of CEC and TNF-alpha, VEGF, protein C, and protein S levels were demonstrated in this study. In addition, markers for endothelial cell activation and injury (intercellular adhesion molecule-1, ICAM-1/CD54; vascular cell adhesion molecule-1, VCAM-1/CD106; and E-selectin, ELAM-1/CD62E) were detected on the surface of isolated CECs using immunofluorescence technique. Appearance of CECs with markers for endothelial cell activation, together with increased levels of TNF-alpha and VEGF and decreased levels of protein C and protein S in the circulation, may account for the propensity of vascular perturbation in thalassemic subjects.
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PMID:Increased circulating activated endothelial cells, vascular endothelial growth factor, and tumor necrosis factor in thalassemia. 1211 82

Thromboembolic complications are often seen in patients with nephrotic syndrome. Markers of endothelial cell injury [thrombomodulin, intracellular adhesion molecule, vascular cell adhesion molecule, thrombin activatable fibrinolysis inhibitor (TAFI), protein Z, vascular endothelial growth factor, markers of thrombin and plasmin generation] were studied in 22 patients with nephrotic syndrome. All these parameters studied, except protein Z and D-dimers, were significantly higher in patients with nephrotic syndrome, whereas protein Z was significantly lower when compared with the healthy volunteers. None of the endothelial cell markers (thrombomodulin, P-selectin, E-selectin, intracellular adhesion molecule, vascular cell adhesion molecule), thrombin and plasmin generation markers (thrombin-antithrombin complexes, prothrombin fragments 1 + 2, plasmin-antiplasmin complexes, D-dimers), protein C, protein Z, vascular endothelial growth factor, and TAFI concentration and activity were directly correlated with the level of proteinuria, albumin, cholesterol, triglycerides or creatinine, except significant positive correlations between TAFI activity and serum creatinine, E-selectin and albumin as well as negative correlations between plasmin-antiplasmin complexes and proteinuria. In these patients, there is evidence of endothelial cell injury and probably secondary activation of the coagulation cascade. Elevated circulating TAFI antigen and activity might be a new link in the pathogenesis of impaired fibrinolysis and the progression of atherosclerosis in nephrotic syndrome. Protein Z deficiency might also contribute to the enhanced risk of thromboembolic complications in nephrotic syndrome.
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PMID:Markers of endothelial cell injury and thrombin activatable fibrinolysis inhibitor in nephrotic syndrome. 1243 47

Cyclooxygenase and its derived prostaglandin E2 (PGE2) have been shown to stimulate the growth of cancer cells and promote tumor angiogenesis. Here, we show that PGE2 activated the beta-catenin/T cell factor-dependent transcription in colon cancer cells through the cAMP/protein kinase A pathway. The expression of cyclin D1 and vascular endothelial growth factor was induced by PGE2 in LS-174T cells. Moreover, PGE2 and mutated beta-catenin stimulated the transcription of cyclin D1 and vascular endothelial growth factor in a synergistic fashion. Mechanistically, PGE2 increased the phosphorylation of glycogen synthase kinase-3 and consequently accumulated beta-catenin. In addition, PGE2 induced the expression of T cell factor-4 transcription factor, which formed transcriptionally active complex with beta-catenin. In animal experiments, administration of 16,16-dimethyl PGE2 strongly increased the expression of cyclin D1 and vascular endothelial growth factor in APC(min/+) mouse polyps. Thus, our results provide a novel mechanism, suggesting that cyclooxygenase-2/PGE2 may exert pro-oncogenic actions through stimulating the beta-catenin/T cell factor-mediated transcription, which plays critical roles in colorectal carcinogenesis.
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PMID:Prostaglandin E2 Stimulates the beta-catenin/T cell factor-dependent transcription in colon cancer. 1589 4

Activated protein C (APC) is a serine protease that plays a central role in physiological anticoagulation, and has more recently been shown to be a potent anti-inflammatory mediator. Using cultured human cells, we show here that APC up-regulates the angiogenic promoters matrix metalloproteinase-2 in skin fibroblasts and umbilical vein endothelial cells, vascular endothelial growth factor in keratinocytes and fibroblasts, and monocyte chemoattractant protein-1 in fibroblasts. In the chick embryo chorioallantoic membrane assay, APC promoted the granulation/remodeling phases of wound healing by markedly stimulating angiogenesis as well as promoting reepithelialization. In a full-thickness rat skin-healing model, a single topical application of APC enhanced wound healing compared to saline control. APC-treated wounds had markedly more blood vessels on day 7 and a significantly lower infiltration of neutrophils at days 4 and 7. The broad spectrum matrix metallo-proteinase, GM6001, prevented the ability of APC to promote wound healing. In summary, our results show that APC promotes cutaneous wound healing via a complex mechanism involving stimulation of angiogenesis and inhibition of inflammation. These unique properties of APC make it an attractive therapeutic agent to promote the healing of chronic wounds.
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PMID:Activated protein C prevents inflammation yet stimulates angiogenesis to promote cutaneous wound healing. 1595 48

Angiogenesis, a complex, coordinated process resulting in the assembly and maturation of new blood vessels, is critical for the growth of tumors. Several lines of evidence argue for angiogenesis inhibition in the treatment of colorectal cancer (CRC) : 1) angiogenesis (as measured by microvessel count), and the expression of pro-angiogenesis factors, such as vascular endothelial growth factor (VEGF), the key regulator of normal and pathological angiogenesis, have been reported to correlate with advanced disease and a worse prognosis ; 2) the expression of VEGF has been shown to correlate with RAS mutations, alterations in the APC-WNT signaling pathway, and overexpression of cyclo-oxygenase-2, which all are frequent in CRC ; 3) bevacizumab, a humanized anti-VEGF monoclonal antibody, is a potent inhibitor of tumor growth of various CRC cell lines in murine xenografts ; 4) the addition of bevacizumab to systemic chemotherapy has been shown to be significantly superior to chemotherapy alone in terms of objective tumor response rate, progression-free survival, and overall survival in patients with metastatic CRC, in the frontline, and more recently in the second-line setting, without worsening of chemotherapy-related toxicity. However, several potential specific adverse events, such as thrombosis, hemorrhages, proteinuria, arterial hypertension, and bowel perforations have been described. Whether the antitumoral efficacy of bevacizumab could be increased when combined to low-dose (metronomic) chemotherapy, or radiotherapy (in rectal cancer), is under development, as well other VEGF-targeted approaches (e.g., dominantnegative mutants, antisense oligonucleotides, antibodies directed against VEGF receptors (VEGFR), VEGFR tyrosine kinase inhibitors, soluble VEGFR,...), or other anti-angiogenesis agents (e.g., thalidomide, celecoxib, angiozyme...).
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PMID:[Therapeutic strategies using VEGF inhibitors in colorectal cancer]. 1638 67

Activated protein C (APC) is a serine protease that plays a central role in physiological anticoagulation, and has more recently been shown to be a potent anti-inflammatory mediator. We show here that APC upregulates the angiogenic promoters, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8) or matrix metalloproteinase-2 (MMP-2) in cultured human skin fibroblasts (HF), keratinocytes (HK) or umbilical vein endothelial cells (HUVE). In the chick embryo chorio-allantoic membrane assay, APC promoted angiogenesis. In a full-thickness rat skin healing model, a single topical application of APC enhanced wound healing compared to saline control. In summary, our results demonstrate that APC promotes cutaneous wound healing at least partly by stimulation of angiogenesis.
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PMID:Activated protein C stimulates expression of angiogenic factors in human skin cells, angiogenesis in the chick embryo and cutaneous wound healing in rodents. 1654 31

Neuropilin-1 (NRP1) is a transmembrane protein expressed on neuronal and endothelial cells where it plays a crucial role in guiding axons and regulating angiogenesis. We have recently shown that NRP1 also is expressed on dendritic cells (DC) in the human immune system and have proposed a role for NRP1 in the first stages of the immune response. In these studies, we show that NRP1 can be transferred with a high efficiency from human DC to T lymphocytes by trogocytosis. The NRP1 transfer can occur independently of T lymphocyte activation; the amount of NRP1 transferred depends on the NRP1 expression level on APC and is enhanced when T cells are activated through the TCR. Moreover, the NRP1 transfer occurs between specific donor and recipient cells, because no NRP1 transfer is observed between endothelial cells and T lymphocytes or between APCs and CD34(+) hemopoietic cells. Finally, we show that a major NRP1 ligand, vascular endothelial growth factor (VEGF)(165), is secreted by mature human DCs and binds to NRP1 captured by T lymphocytes. These results show that NRP1 transfer to T lymphocytes during the immune synapse can convert T lymphocytes into VEGF(165)-carrying cells. Together with the enhanced signaling of VEGF-R2 on endothelial cells in the presence, in trans, of the NRP1-VEGF(165) complex, our results suggest that the intercellular transfer of NRP1 might participate in the Ag-independent remodelling of the endothelial vessels in secondary lymphoid organs during inflammation.
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PMID:Dendritic cells can turn CD4+ T lymphocytes into vascular endothelial growth factor-carrying cells by intercellular neuropilin-1 transfer. 1684 52


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