Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endostatin is a potent endogenous angiogenesis inhibitor that induces regression of tumors in mice. Neither an extracellular receptor for endostatin nor intracellular signals that result in the regression of tumor vascular beds have been identified. We demonstrate that endostatin, but not angiostatin, at comparable concentrations to those used in in vivo animal trials, rapidly down-regulates many genes in exponentially growing endothelial cells. These include immediate early response genes, cell cycle-related genes, and genes regulating apoptosis inhibitors, mitogen-activated protein kinases, focal adhesion kinase, G-protein-coupled receptors mediating endothelial growth, a mitogenic factor, adhesion molecules, and cell structure components. Suppression of both apoptosis inhibitors and cell proliferation genes may have a limited contribution to the antiangiogenesis process because endostatin induces neither apoptosis nor growth inhibition, unless studied under reduced serum conditions. In contrast, the antimigratory effect of endostatin was rapid and potent even under serum-supplemented conditions. Endostatin caused gene suppression and migration arrest exclusively in endothelial cells, most profoundly in microvascular endothelial cells. The c-myc null fibroblasts obtained by targeted homologous recombination showed an attenuated migration rate compared with isogenic parental cells, whereas the introduction of the c-myc gene into endothelial cells abrogated the antimigratory effect of endostatin. Inhibition of E-box-driven transcription by overexpressing max or mad suppressed endothelial migration. Thus, rapid down-regulation of genes by endostatin neither restores proliferating endothelial cells to their resting states nor induces apoptosis; rather, it potently inhibits endothelial cell migration partly via suppression of c-myc expression.
 ...
PMID:Antiangiogenesis signals by endostatin. 1129 66

Endostatin, an endogenous angiogenesis inhibitor, attenuates endothelial cell migration through an unknown mechanism. We show that endostatin induced tyrosine phosphorylation of focal adhesion kinase and paxillin, and promoted formation of focal adhesions and actin stress fibers, similar to fibroblast growth factor-2 (FGF-2). In cells cotreated with endostatin and FGF-2, focal adhesions and actin stress fibers were decreased, indicating that endostatin disturbs cell-matrix adhesion. Reduced tyrosine phosphorylation and cytoplasmic relocalization of beta-catenin in cells treated with FGF-2 and endostatin indicates that loosening of cell-cell adhesion is also disturbed by endostatin. These data provide a molecular basis both for the lack of effect of endostatin on the normal, quiescent vasculature, and its antagonistic effects on stimulated tumor vessels.
 ...
PMID:Endostatin regulates endothelial cell adhesion and cytoskeletal organization. 1192 7

Endostatin is a 20-kDa endogenous angiogenesis inhibitor that has recently been shown to inhibit the expression of vascular endothelial growth factor (VEGF), an angiogenic growth factor that is up-regulated by hypoxia via the HIF-1 transcription factor complex. To determine if the anti-angiogenic activity of endostatin involves a modulation of the HIF-1/VEGF pathway in cancer cells, experiments were conducted to establish what effect endostatin has on HIF-1 activity, HIF-1alpha protein production, and cellular localization in prostate cancer cells and endothelial cells. Endothelial cell tube formation was inhibited by endostatin purchased from Calbiochem (San Diego, CA) but not endostatin obtained from EntreMed (Rockville, MD). Subsequent experiments using Calbiochem endostatin showed that it did not alter HIF-1alpha protein production or cellular localization in any of the cell lines tested, nor did it alter HIF-1 transactivational activity in hypoxia. Whether or not this is also true in vivo remains to be determined. Nevertheless, these data suggest that the anti-angiogenic activity of endostatin is independent of the HIF-1/VEGF pathway. Immunocytochemical staining results do not indicate a decreased production of VEGF in Calbiochem endostatin-treated LNCaP or human umbilical vein endothelial cells (HUVEC). Treatment of rat aortic cross sections with human endostatin from Calbiochem resulted in a dose-dependent inhibition of microvessel outgrowth. Importantly, inhibition of vessel outgrowth by Calbiochem endostatin in a human saphenous vein angiogenesis assay required early treatment. In view of this in vitro data, we suggest that clinical trials involving endostatin treatment of late-stage disease may not adequately represent the efficacy of this drug in early-stage cancer.
 ...
PMID:Anti-angiogenic activity of human endostatin is HIF-1-independent in vitro and sensitive to timing of treatment in a human saphenous vein assay. 1455 3

Angiogenesis is controlled by anti-angiogenic factors as well as by angiogenic factors, such as VEGF (vascular endothelial growth factor) and HGF (hepatocyte growth factor). Endostatin, a potent endogenous angiogenesis inhibitor, is known to inhibit endothelial proliferation and suppress tumour growth. However, to date, little is known about the pathophysiology of endostatin in ischaemia/reperfusion. To investigate the mechanisms of angiogenesis induced by myocardial ischaemia/reperfusion in more detail, we studied the circulating levels of endostatin, VEGF and HGF in 17 patients with acute myocardial infarction, who underwent early reperfusion therapy. In all patients, serum endostatin, VEGF and HGF levels before reperfusion were increased significantly compared with those in 17 control subjects (endostatin, 49.2+/-11.7 ng/ml, but not detectable in controls; VEGF, 685.6+/-150.3 pg/ml compared with 173.7+/-33.6 pg/ml; HGF, 3638+/-1285 pg/ml compared with 59+/-13 pg/ml; values are means+/-S.E.M.). After reperfusion, the serum endostatin and VEGF levels decreased significantly, but still remained higher than those in control subjects (endostatin, 19.6+/-7.0 ng/ml; VEGF, 284.2+/-90.2 pg/ml). In contrast, serum HGF levels increased significantly (15 146+/-2230 pg/ml) after reperfusion. These data indicated that serum levels of endostatin changed in parallel with those of VEGF in response to myocardial ischaemia/reperfusion, and the marked increase in serum HGF levels after reperfusion seemed to be, at least in part, due to heparin administration. Our data offer a possible anti-endostatin therapy in patients with acute myocardial infarction to facilitate collateral vessel formation.
 ...
PMID:Serum levels of endostatin, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in patients with acute myocardial infarction undergoing early reperfusion therapy. 1523 Jun 92

It is here demonstrated that the set of gene expressions underlying the angiogenic balance in tissues can be molecularly reset en masse by a single protein. Using genome-wide expression profiling, coupled with RT-PCR and phosphorylation analysis, we show that the endogenous angiogenesis inhibitor endostatin downregulates many signaling pathways in human microvascular endothelium associated with proangiogenic activity. Simultaneously, endostatin is found to upregulate many antiangiogenic genes. The result is a unique alignment between the direction of gene regulation and angiogenic status. Profiling further reveals the regulation of genes not heretofore associated with angiogenesis. Our analysis of coregulated genes shows complex interpathway communications in an intricate signaling network that both recapitulates and extends on current understanding of the angiogenic process. More generally, insights into the nature of genetic networking from the cell biologic and therapeutic perspectives are revealed.
 ...
PMID:Endostatin's antiangiogenic signaling network. 1502 36

The hypothesis that tumor growth and metastasis is angiogenesis-dependent was proposed by Judah Folkman in 1971. Its major implication is that blocking angiogenesis could be a strategy for arresting tumor growth. This hypothesis is now supported by extensive experimental evidence, and hence the angiogenic switch and microvascular endothelial cells recruited by the tumor have emerged as important targets in cancer therapy. A large number of proangiogenic and antiangiogenic factors have been discovered. At least three angiogenesis inhibitors have received FDA approval in the US, with Avastin (anti-VEGF-antibody) also approved in 26 other countries. The recognition that antiangiogenic therapy is becoming the fourth therapeutic modality in addition to surgery, chemotherapy and radiotherapy underlines the urgent need to understand the systems biology of the antiangiogenic response. A particularly important question for cancer therapy is whether antiangiogenic therapy will also face the same drug resistance as one sees with other treatment modalities. Recently, the cellular signaling induced by the endogenous angiogenesis inhibitor - endostatin - was dissected revealing that the antiangiogenic response is characterized by a large number of individual genetic signals, which are highly coordinated and interdependent. The objective of this review is to elucidate the multifaceted nature of tumor angiogenesis, and to discuss the subtle but important distinctions that exist between variations in tumor responsiveness that evolve with antiangiogenic therapy and the classic resistance that frequently develops with conventional therapy. Furthermore, this review discusses the implications of current findings for cancer treatment and potential ways of overcoming or predicting tumor resistance to these agents.
 ...
PMID:Endostatin: the logic of antiangiogenic therapy. 1593 43

Endostatin, a cleaved fragment of collagen XVIII, is a potent endogenous angiogenesis inhibitor. Elevated serum endostatin levels have been recently reported in patients with various types of neoplasms. The purpose of our study was to evaluate serum concentrations of endostatin in patients harbouring various pituitary adenoma types and to examine the relationship of serum endostatin levels to circulating vascular endothelial growth factor (VEGF) levels. Preoperative serum endostatin and VEGF concentrations were measured using competitive enzyme immunoassays in 71 patients with pituitary adenomas (20 somatotropinomas, 3 corticotropinomas, 6 prolactinomas and 42 clinically nonfunctioning pituitary adenomas - CNFPAs) and compared with levels from age-matched controls. In 35 patients postoperative immunohistochemical investigations were performed. Serum endostatin concentrations were significantly higher in all pituitary adenoma types, except for prolactinomas (somatotropinomas: 124 +/- 16; p < 0.02, corticotropinomas: 157 +/- 42; p < 0.02, prolactinomas: 141 +/- 37; p > 0.05, CNFPAs: 169 +/- 11 ng/ml; p < 0.000005 vs 73 +/- 10 ng/ml in controls). There was a significant positive correlation between endostatin and VEGF serum levels in patients with pituitary adenomas (r = +0.322; p = 0.006). In the control group a significant negative correlation xbetween circulating endostatin and VEGF was found (r = -0.653; p = 0.00975). The simultaneous elevation of endostatin and VEGF may attenuate the pro-angiogenic action of VEGF and be responsible for rather weak neovascularization of pituitary adenomas. Prospective studies are required to assess the usefulness of circulating endostatin and VEGF as markers of progression or recurrence of pituitary tumors.
 ...
PMID:Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with pituitary adenomas. 1637 29

Antiangiogenic therapy is nowadays one of the most active fields in cancer research. The first strategies, aimed at inhibiting tumor vascularization, included upregulation of endogenous inhibitors and blocking of the signals delivered by angiogenic factors. But interaction between endothelial cells and their surrounding extracellular matrix also plays a critical role in the modulation of the angiogenic process. This study introduces a new concept to enhance the efficacy of antibody-based antiangiogenic cancer therapy strategies, taking advantage of a key molecular event occurring in the tumor context: the proteolysis of collagen XVIII, which releases the endogenous angiogenesis inhibitor endostatin. By fusing the collagen XVIII NC1 domain to an antiangiogenic single-chain antibody, a multispecific agent was generated, which was efficiently processed by tumor-associated proteinases to produce monomeric endostatin and fully functional trimeric antibody fragments. It was demonstrated that the combined production in the tumor area of complementary antiangiogenic agents from a single molecular entity secreted by gene-modified cells resulted in enhanced antitumor effects. These results indicate that tailoring recombinant antibodies with extracellular matrix-derived scaffolds is an effective approach to convert tumor progression associated processes into molecular clues for improving antibody-based therapies.
 ...
PMID:Enhanced antiangiogenic therapy with antibody-collagen XVIII NC1 domain fusion proteins engineered to exploit matrix remodeling events. 1647 26

Endostatin is an endogenous angiogenesis inhibitor which requires E-selectin for its antiangiogenic activity. The aim of this study was to investigate the expression of endostatin in human choroidal neovascular membranes (CNV) secondary to age-related macular degeneration (AMD) with regard to vascularization and proliferative activity. An interventional case series of 36 patients who underwent removal of CNV were retrospectively investigated. Thirty-six CNV were analyzed by light microscopic immunohistochemistry for the expression of CD34 (endothelial cells, EC), CD105 (activated EC), Ki-67 (cell proliferation), Cytokeratin 18 (epithelial cells), VEGF (vascular endothelial growth factor), E-selectin and endostatin. Donor eyes (n=7) including one with AMD were used as controls. Endostatin immunoreactivity was present in choroidal vessels of five as well as in the retinal pigment epithelium (RPE)-Bruch's membrane complex of two donor eyes without AMD. In one eye with AMD, endostatin was detected in RPE, Bruch's membrane and choroidal vessels. Ninety-two percent (33/36) of CNV disclosed endostatin staining. RPE-Bruch's membrane complex, choroidal vessels and stroma were positive in 50% (18/36), 72% (26/36), and 78% (28/36) of the membranes, respectively. Both control eyes and CNV expressed all the investigated markers except E-selectin being positive only in membranes. Endostatin, an endogenous angiogenesis inhibitor, is expressed in CNV and its therapeutic up-regulation may be a new strategy in the treatment of neovascular AMD.
 ...
PMID:Expression of endostatin in human choroidal neovascular membranes secondary to age-related macular degeneration. 1658 30

Many previous reports have demonstrated that systemic administration of endostatin (ES), a proteolytic cleavage product of collagen type XVIII and an endogenous angiogenesis inhibitor, represses tumor angiogenesis in different preclinical tumor models with varying efficacy. For example, systemic delivery of recombinant ES to rat insulin promoter 1 (Rip1)T-antigen 2 (Tag2)-transgenic mice, a mouse model of pancreatic beta-cell carcinogenesis, has repressed tumor angiogenesis efficiently and with it, tumor growth. Here, we report that the transgenic expression of ES in Rip1ES-transgenic mice only interferes moderately with tumor growth in Rip1Tag2;Rip1ES double-transgenic mice. Tumor incidence is not reduced by the local expression of ES, and tumor outgrowth and progression to tumor malignancy are only retarded slightly. A significant effect of local ES expression on tumor angiogenesis is only apparent during the early stages of tumor development, where less angiogenic hyperplastic lesions are observed. Although efficiently produced and secreted by transgenic beta cells, locally expressed ES appears to be sequestered in the microenvironment, and its systemic levels are not increased. The results indicate that the antiangiogenic functions of ES critically depend on the mode of delivery and the site of expression: although its systemic application represses tumor angiogenesis and tumor growth efficiently, locally expressed ES appears to be less effective, and hence, additional mechanisms of solubilization or activation of latent ES seem to be required. These results have important implications about the modes of delivery used in antiangiogenic, therapeutic strategies, which are based on the antiangiogenic activities of ES.
 ...
PMID:Moderate antiangiogenic activity by local, transgenic expression of endostatin in Rip1Tag2 transgenic mice. 1679 8


1 2 3 Next >>