Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor angiogenesis progresses by a dynamic balance between tumor vascular regression and growth. Angiopoietin (Ang)-2 (the natural antagonist for the angiogenic Tie-2 receptor) and vascular endothelial growth factor (VEGF) are thought to be critical regulators in this process; therefore, these may play a critical role in cancer aggressiveness. The aim of this study was to clarify the clinical and biological significance of the expression of Ang-2 in human gastric cancers and to investigate the relationship between Ang-2 together with VEGF and the induction of proteases such as matrix metalloproteinases (MMPs) in the process of tumor development. Eighty-five individuals with gastric cancer, who had undergone surgery without preoperative treatment, were studied. A stable transfectant of the human MKN-7 gastric cancer cell lines with an Ang-2 expression vector was used for the experimental study. First, we examined the relationship between the mRNA expression of Angs by Northern blot analysis and clinicopathological features. High Ang-2-expression cases showed more frequent vascular involvement and more advanced stages of disease compared with low Ang-2-expression cases (P < 0.05). With regard to prognosis, the survival time for patients in the high-Ang-2 mRNA group was significantly shorter (P < 0.05). When we examined the localization of Ang-2 in human gastric cancers, immunohistochemical analysis revealed that this protein was expressed predominantly in cancer tissues when compared with normal tissues. Interestingly it was expressed not only in endothelia cells (ECs) but also in cancer cells. Second, Ang-2-transfected cells were implanted in vivo into the gastric walls of nude mice. Ang-2-transfectant mice developed highly metastatic tumors with hypervascularity as compared with MKN-7 or control vector-transfectant tumors. There was a significant correlation between Ang-2 mRNA expression and lower grade of vessel maturation. Third, on the basis of the in vivo data, we focused on production of proteases such as MMPs to investigate possible mechanisms in these processes. MMP-1, MMP-9, and urokinase-type plasminogen activator in ECs were strongly up-regulated by Ang-2 in the presence of VEGF in vitro. These data suggest that production of Ang-2 is implicated in tumor development in human gastric cancers. Its production may contribute to tumor angiogenesis by induction of proteases in ECs, which may be enhanced in the presence of VEGF.
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PMID:Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. 1128 Jul 79

From collagenase digests of human thyroid, endothelial cells were separated from follicular cells by their greater adherence to gelatin-coated plates. Endothelial cells were further purified using fluorescence-activated cell sorting, selecting for cells expressing factor VIII-related antigen. Isolated cells were negative for thyroglobulin and calcitonin when examined by immunostaining. The receptor for the angiopoietins, Tie-2, was expressed by the cells, and expression was increased by agents that elevate cAMP. Nitric oxide synthase (NOS) 3, the endothelial form of NOS, was expressed by the cells and similarly regulated. Cells responded strongly to the mitogen fibroblast growth factor (FGF)-2 in growth assays but only weakly to vascular endothelial growth factor (VEGF). VEGF was, however, able to stimulate nitric oxide release from the cells consistent with their endothelial origin. The FGF receptor (FGFR1) was full length (120 kDa) and immunolocalized to the cytosol and nucleus. Thyrotropin (TSH) did not regulate FGFR1, but its expression was increased by VEGF. Thrombospondin, a product of follicular cells, was a growth inhibitor, but neither TSH nor 3,5,3'-triiodothyronine had direct mitogenic effects. Thyroid follicular cell conditioned medium contained plasminogen activator activity and stimulated the growth of the endothelial cells, but when treated with plasminogen to produce the endothelial-specific inhibitor, angiostatin, growth was inhibited. Human thyroid endothelial cell cultures will be invaluable in determining the cross talk between endothelial and follicular cells during goitrogenesis.
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PMID:Isolation and characterization of human thyroid endothelial cells. 1962 78

We hypothesized that human smoking and its deleterious effects on endothelial function can be modeled by exposure of mice to tobacco smoke, and further that these changes would be reflected in gene regulation in vascular endothelium. We used for these studies a mouse strain that expresses green fluorescent protein under the control of an endothelial-specific promoter, Tie-2. Mice were exposed to sidestream smoke from reference cigarettes at 34 mg total suspended particulates/m3. After exposure for 5 days/wk for 1 and 6 wk, aortas were pooled from treatment and control groups. Endothelial cells were rapidly isolated by collagenase treatment followed by fluorescent activated cell sorting to yield populations of >95% purity. RNA isolated from >500 endothelial cells was amplified and analyzed on deeply representative long oligo microarrays. Transcripts dysregulated by >2.5-fold were confirmed by real-time PCR and selected proteins by immunofluorescent localization. In the endothelial cells, the observed more than threefold upregulation of complement factor H (Cfh), calcitonin receptor-like (Calcr1), and soluble epoxide hydrolase (Epxh2) may play a role in hypertensive responses of the vasculature to smoking. We have identified gene regulation in vivo in vascular endothelium that potentially underlies hypertensive responses to tobacco smoke.
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PMID:Tobacco smoke dysregulates endothelial vasoregulatory transcripts in vivo. 1572 32

Vascular endothelial cells play a critical role in the maintenance of endometrial homeostasis. Indeed many pathological conditions causing abnormal endometrial bleeding including progestin only contraception, hormone replacement therapy, endometrial polyps, myomas, hyperplasia and cancer are associated with aberrant angiogenesis. Critical to the process of angiogenesis is the breakdown of the surrounding tissues by matrix metalloproteases (MMPs). In addition to the cells surrounding the endometrial endothelial cells, the endothelial cells themselves produce their own panel of MMPs. We now characterize the specific MMPs that are expressed by endothelial cells derived from human endometrium. These include MMP-1, MMP-2 and MMP-10 but not MMP-3. In addition, in order to successfully carry out consistent, homogeneous and sufficient numbers of studies we investigated the in vitro expression of the MMPs with both freshly isolated, early passaged endometrial endothelial cells (HEECs) as well as with newly telomerase immortalized HEECs (T-HEECs). The latter were karyotypically normal and expressed classic endothelial cell endpoints such as tubulogenesis on matrigel and expression of the endothelial cell markers CD-31 (PECAM), von Willebrand's factor, and the Tie-2 receptors. The levels of MMP expression as well as that of the metalloprotease inhibitors TIMP-1 and TIMP-2 were similar in parent and immortalized endothelial cells.
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PMID:Metalloproteinase expression by control and telomerase immortalized human endometrial endothelial cells. 1594 20

Wnts are lipid-modified secreted glycoproteins that regulate diverse biological processes. We report that Wnt5a, which functions in noncanonical Wnt signaling, has activity on endothelial cells. Wnt5a is endogenously expressed in human primary endothelial cells and is expressed in murine vasculature at several sites in mouse embryos and tissues. Expression of exogenous Wnt5a in human endothelial cells promoted angiogenesis. Wnt5a induced noncanonical Wnt signaling in endothelial cells, as measured by Dishevelled and ERK1/2 phosphorylation, and inhibition of canonical Wnt signaling, a known property of Wnt5a. Wnt5a induced endothelial cell proliferation and enhanced cell survival under serum-deprived conditions. The Wnt5a-mediated proliferation was blocked by Frizzled-4 extracellular domain. Wnt5a expression enhanced capillary-like network formation, whereas reduction of Wnt5a expression decreased network formation. Reduced Wnt5a expression inhibited endothelial cell migration. Screening for Wnt5a-regulated genes in cultured endothelial cells identified several encoding angiogenic regulators, including matrix metalloproteinase-1, an interstitial collagenase, and Tie-2, a receptor for angiopoietins. Thus, Wnt5a acts through noncanonical Wnt signaling to promote angiogenesis.
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PMID:Wnt5a signaling induces proliferation and survival of endothelial cells in vitro and expression of MMP-1 and Tie-2. 1703 33

Angiopoietin-1 (Ang-1) belongs to a novel family of endothelial growth factors that function as ligands for an endothelialspecific receptor tyrosine kinase (Tie-2). The Ang-/Tie-2 system may contribute to angiogenesis and vascular remodeling by mediating interactions of endothelial cells with smooth muscle cells and pericytes. The spatial distribution and temporal expression of Ang-1 and Tie-2 in the rat brain were studied following collagenase-induced intracerebral hemorrhage (ICH) by immunohistochemistry and reverse transcription-polymerase chain (RT-PCR) analysis, respectively. Immunohistochemical analysis revealed that some Ang-1 or Tie-2-positive dilated vessels resided around the hematoma and extended into the clot. RT-PCR analysis showed that Ang-1 and Tie-2 mRNA signal was detected at 2 days and persisted for 28 days after ICH. These findings suggest that ICH could lead to upregulation of Ang-1 and the receptor Tie-2 mRNA.
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PMID:Expression of Angiopoietin-1 and the receptor Tie-2 mRNA in rat brains following intracerebral hemorrhage. 1851 51

The latency period for lung tumor progression offers a window of opportunity for therapeutic intervention. Herein, we studied the effect of oral silibinin (742 mg/kg body weight, 5 d/wk for 10 weeks) on the growth and progression of established lung adenocarcinomas in A/J mice. Silibinin strongly decreased both tumor number and tumor size, an antitumor effect that correlates with reduced antiangiogenic activity. Silibinin reduced microvessel size (50%, P < 0.01) with no change in the number of tumor microvessels and reduced (by 30%, P < 0.05) the formation of nestin-positive microvessels in tumors. Analysis of several proteins involved in new blood vessel formation showed that silibinin decreased the tumor expression of interleukin-13 (47%) and tumor necrosis factor-alpha (47%), and increased tissue inhibitor of metalloproteinase-1 (2-fold) and tissue inhibitor of metalloproteinase-2 (7-fold) expression, without significant changes in vascular endothelial growth factor levels. Hypoxia- inducible factor-1 alpha expression and nuclear localization were also decreased by silibinin treatment. Cytokines secreted by tumor cells and tumor-associated macrophages regulate angiogenesis by activating nuclear factor-kappaB (NF-kappaB) and signal transducers and activators of transcription (STAT). Silibinin decreased the phosphorylation of p65NF-kappaB (ser276, 38%; P < 0.01) and STAT-3 (ser727, 16%; P < 0.01) in tumor cells and decreased the lung macrophage population. Angiopoietin-2 (Ang-2) and Ang-receptor tyrosine kinase (Tie-2) expression were increased by silibinin. Therapeutic efficacy of silibinin in lung tumor growth inhibition and regression by antiangiogenic mechanisms seem to be mediated by decreased tumor-associated macrophages and cytokines, inhibition of hypoxia-inducible factor-1 alpha, NF-kappaB, and STAT-3 activation, and up-regulation of the angiogenic inhibitors, Ang-2 and Tie-2.
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PMID:Growth inhibition and regression of lung tumors by silibinin: modulation of angiogenesis by macrophage-associated cytokines and nuclear factor-kappaB and signal transducers and activators of transcription 3. 1913 21

Preterm infants exposed to oxygen and mechanical ventilation are at risk for bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disorder characterized by arrested alveolar development and nonsprouting, dysmorphic microvascular angiogenesis. The molecular regulation of this BPD-associated pathological angiogenesis remains incompletely understood. In this study, the authors used focused microarray technology to characterize the angiogenic gene expression profile in postmortem lung samples from short-term ventilated preterm infants (born at 24 to 27 weeks' gestation) and age-matched control infants. Microarray analysis identified differential expression of 13 of 112 angiogenesis-related genes. Genes significantly up-regulated in ventilated lungs included the antiangiogenic genes thrombospondin-1, collagen XVIII alpha-1, and tissue inhibitor of metalloproteinase-1 (TIMP1), as well as endoglin, transforming growth factor-alpha, and monocyte chemoattractant protein-1 (CCL2). Increased expression of thrombospondin-1 in ventilated lungs was verified by real-time polymerase chain reaction (PCR) and immunolocalized primarily to intravascular platelets and fibrin aggregates. Down-regulated genes included proangiogenic angiogenin and midkine, as well as vascular endothelial growth factor (VEGF)-B, VEGF receptor-2, and the angiopoietin receptor TEK/Tie-2. In conclusion, short-term ventilated lungs show a shift from traditional angiogenic growth factors to alternative, often antisprouting regulators. This angiogenic shift may be implicated in the regulation of dysmorphic angiogenesis and, consequently, deficient alveolarization characteristic of infants with BPD.
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PMID:Angiogenesis-related gene expression profiling in ventilated preterm human lungs. 2071 99