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

Pigment epithelium-derived factor (PEDF) inhibits the formation of blood vessels in the eye by inducing apotosis in actively dividing endothelial cells. The activity of PEDF equals or supersedes that of other anti-angiogenic factors, including angiostatin, endostatin and thrombospondin-1. In addition, PEDF has the potential to promote the survival of neurons and affect their differentiation. Here we show that PEDF is present in plasma at a concentration of approx. 100 nM (5 microg/ml) or twice the level required to inhibit aberrant blood-vessel growth in the eye. Thus the systemic delivery of PEDF has the potential to affect angiogenesis or neurotrophic processes throughout the body, significantly expanding the putative physiological role of the protein. A complete map of all post-translational modifications revealed that authentic plasma PEDF carries an N-terminal pyroglutamate blocking group and an N-linked glycan at position Asn266. The pyroglutamate residue may regulate the activity of PEDF analogously to the manner in which it regulates thyrotropin-releasing hormone.
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PMID:Pigment-epithelium-derived factor (PEDF) occurs at a physiologically relevant concentration in human blood: purification and characterization. 1273 24

A catalogue of proteins in the human vitreous humor may contribute to elucidating the pathogenesis of various diseases in ophthalmology. To improve the recovery of proteins in vitreous, we applied one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (1D-PAGE). Proteins were extracted from unstained gel strips and digested in gel with trypsin and the peptides were analyzed by capillary-column reversed-phase high-performance liquid chromatography coupled with electrospray ionization-ion trap-mass spectrometry. From a patient with diabetic retinopathy, 84 different proteins were identified. Most of the proteins which we identified in vitreous previously using 2D-PAGE were also identified in the present study. In total, we identified 121 different proteins including five proteins seen at the genomic level only. Four angiogenic factors, insulin-like growth factor, vascular endothelial growth factor, fibroblast growth factor, and placental endothelial cell growth factor, and three anti-angiogenic factors, pigment epithelium-derived factor, endostatin, and thrombospondin, were found, and this may contribute to elucidating the pathological changes in the concentration and the modified structures of these proteins, in diseases of the retina, especially, diabetic retinopathy.
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PMID:Catalogue of soluble proteins in human vitreous humor by one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electrospray ionization mass spectrometry including seven angiogenesis-regulating factors. 1282 93

The vascular system that ensures an adequate blood flow is required to provide the cells with sufficient supply of nutrients and oxygen. Two different mechanisms of the formation of new vessels can be distinguished: vasculogenesis, the formation of the first primitive vascular plexus de novo and angiogenesis, the formation of new vessels from preexisting ones. Both processes are regulated by a delicate balance of pro- and anti-angiogenic factors. Physiologically, angiostatic mediators outweigh the angiogenic molecules and angiogenesis does not occur. Under certain conditions such as tumor formation or wound healing, the positive regulators of angiogenesis predominate and the endothelium becomes activated. Angiogenesis is initiated by vasodilatation and an increased permeability. After destabilization of the vessel wall, endothelial cells proliferate, migrate and form a tube, which is finally stabilized by pericytes and smooth muscle cells. Numerous soluble growth factors and inhibitors, cytokines and proteases as well as extracellular matrix proteins and adhesion molecules strictly control this multi-step process. The properties and interactions of angiogenic molecules such as VEGFs, FGFs, angiopoietins, PDGF, angiogenin, angiotropin, HGF, CXC chemokines with ELR motif, PECAM-1, integrins and VE-cadherin as well as angiostatic key players such as angiostatin, endostatin, thrombospondin, CXC chemokines without ELR motif, PEDF are discussed in this review with respect to their molecular impact on angiogenesis.
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PMID:Angiogenic and angiostatic factors in the molecular control of angiogenesis. 1289 7

Chemotherapy for the treatment of advanced or metastatic colon cancer, utilizing agents such as 5-fluorouracil (5-FU) and irinotecan (CPT-11), produce a 5-year survival of about 10%. Thus, the identification of new, effective, therapeutic regimens to treat this disease remains critically important. To this end, selected antiangiogenic agents, compounds that inhibit neovascularization, have been shown to produce a modest tumor growth-inhibitory effect with little systemic toxicity. Thus these agents are attractive candidates for use with conventional chemotherapeutic agents to treat this disease. To evaluate this approach, experiments were undertaken to assess the cytotoxic and antineoplastic activity of CPT-11 and the antiangiogenic agent thrombospondin-1 (TSP-1) in the HT-29 model of human colon cancer. These agents were chosen since CPT-11 is a camptothecin analogue efficacious in the treatment of colon cancer and TSP-1 is a human glycoprotein that possess antiangiogenic activity. As expected, in vitro studies revealed that a 5-day exposure to TSP-1 at concentrations up to 130 microg/ml was not cytotoxic alone and did not affect the cytotoxicity of CPT-11, or of its active metabolite SN38, in HT-29 cells. Similarly, in human umbilical vein endothelial cells, TSP-1 alone induced only a slight cell growth-inhibitory effect and did not significantly increase the cytotoxicity of either CPT-11 or SN38. The antineoplastic activities of TSP-1 and CPT-11 were assessed in athymic (nude) female mice bearing advanced subcutaneous xenografts of HT-29 cells. Mice received TSP-1 alone (5-40 mg/kg per day) intraperitoneally (i.p.), CPT-11 alone (100-300 mg/kg, i.p.), TSP-1 (10 mg/kg per day) plus CPT-11 (125 mg/kg), or TSP-1 (20 mg/kg per day) plus CPT-11 (150 mg/kg). TSP-1 was injected daily (Monday through Friday) for 4 weeks (20 injections in total) whereas CPT-11 was administered once weekly on days 0, 7, 14 and 21. By day 28, treatment with TSP-1 alone (5, 10 or 20 mg/kg per day) induced a dose-dependent inhibition of xenograft growth. Further, treatment with 10 or 20 mg/kg per day resulted in an average treated tumor size/control tumor size (T/C) on day 28 of 0.68 (range 0.64-0.71) or 0.58 (range 0.54-0.60), respectively. CPT-11 at all doses significantly inhibited tumor growth with an average T/C value of 0.21 (range 0.15-0.27). However, the 250 and 300 mg/kg regimens induced significant toxicity and mortality. When TSP-1 was combined with CPT-11, a significant ( P< or = 0.05) inhibition of tumor growth also was observed (T/C < or = 0.17, range 0.11-0.20). Importantly, this enhanced tumor growth inhibition was obtained without significant toxicity. The therapeutic implications of these findings are discussed.
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PMID:Thrombospondin-1 plus irinotecan: a novel antiangiogenic-chemotherapeutic combination that inhibits the growth of advanced human colon tumor xenografts in mice. 1465 7

During angiogenesis, endothelial cell growth, migration, and tube formation are regulated by pro- and anti-angiogenic factors, matrix-degrading proteases, and cell-extracellular matrix interactions. Temporal and spatial regulation of extracellular matrix remodeling events allows for local changes in net matrix deposition or degradation, which in turn contributes to control of cell growth, migration, and differentiation during different stages of angiogenesis. Remodeling of the extracellular matrix can have either pro- or anti-angiogenic effects. Extracellular matrix remodeling by proteases promotes cell migration, a critical event in the formation of new vessels. Matrix-bound growth factors released by proteases and/or by angiogenic factors promote angiogenesis by enhancing endothelial migration and growth. Extracellular matrix molecules, such as thrombospondin-1 and -2, and proteolytic fragments of matrix molecules, such as endostatin, can exert anti-angiogenic effects by inhibiting endothelial cell proliferation, migration and tube formation. In contrast, other matrix molecules promote endothelial cell growth and morphogenesis, and/or stabilize nascent blood vessels. Hence, extracellular matrix molecules and extracellular matrix remodelling events play a key role in regulating angiogenesis.
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PMID:Regulation of angiogenesis by extracellular matrix. 1498 64

Low-dose cyclophosphamide (LDC) induces selective apoptosis of endothelial cells within the vascular bed of tumors. Here, we investigated a hypothesis that the effect of LDC is mediated by the pro-apoptotic action of endogenous inhibitors of angiogenesis. Tumors treated with LDC demonstrate similar expression of matrix metalloproteinases and also basement membrane-derived angiogenesis inhibitors when compared with wild-type tumors, whereas the expression of thrombospondin-1 (TSP-1) is significantly elevated in LDC-treated tumors. We used mice with an absence of type XVIII collagen (endostatin) or type IV collagen alpha3 chain (tumstatin) or TSP-1 to assess the contribution of these endogenous inhibitors of angiogenesis on LDC-mediated tumor suppression. Lack of TSP-1 in the host in addition to tumor cells leads to diminished capacity of LDC to suppress tumor growth, whereas the absence of endostatin and tumstatin did not alter the effect of LDC. LDC treatment predominantly induces selective expression of TSP-1 in tumor cells and peri-vascular cells and facilitates apoptosis of proliferating endothelial cells, with minimal direct effect on tumor cells and peri-vascular cells. These studies indicate that TSP-1 contributes to tumor growth suppression induced by LDC and suggest that tumors that express high basal level of TSP-1 may be more susceptible to tumor suppression by such a regimen. This study also makes a strong case for TSP-1 expression levels as a potential predictive marker for the successful use of LDC in cancer patients.
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PMID:Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. 1499 10

Angiogenesis, the development of new vessels from a pre-existing vasculature, accompanies the growth and malignant transformation of astrocytic brain tumors. Neovascularization is essential for sustained tumor growth, and with increasing grade, astrocytic tumors undergo an, angiogenic switch, manifested by marked increases in vessel density and changes in vascular morphology. In the quiescent state, endogenous anti-angiogenic factors including endostatin, thrombospondin, and soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) balance the actions of pro-angiogenic stimuli and restrain the angiogenic switch. Once activated, pro-angiogenic factors including most notably basic fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF-A), and platelet-derived growth factor (PDGF) incite robust astrocytoma neovascularization. Recent studies have also explored the expression patterns and functional importance of the angiopoietins, Tie2 and neuropilin receptors, and hepatocyte growth factor/scatter factor (HGF). Together these angiogenic factors have diverse actions on endothelium and perivascular supporting cells that engender tumor neovessels with a unique phenotype, distinct from normal vessels. Properties of the astrocytoma neovasculature contribute to tumor growth, malignant progression, invasion, hemorrhage, and edema formation. Thus, the mechanistic actions of angiogenic factors on cerebral microvessels and the nature of the resultant tumor neovasculature establish a framework for understanding many of the characteristic behaviors of astrocytoma tumors.
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PMID:Angiogenesis and its role in the behavior of astrocytic brain tumors. 1535 41

Genistein has been reported to be a natural chemopreventive in several types of human cancer. In our prior study, soy isoflavones were shown to induce cell cycle arrest and apoptosis of bladder cancer cells in the range of human urine excretion. This study was designed to identify the novel molecular basis underlying anti-angiogenic activities of soy isoflavones. An immortalized E6 and five human bladder cancer cell lines were studied by immunoassay, flow cytometry, functional activity, reverse transcription-polymerase chain reaction, immunoblotting, and transwell co-culture in vitro. The efficacy of soy isoflavones on angiogenesis inhibition in vivo was examined by nude mice xenograft and chick chorioallantoic membrane bioassay. Factors analyzed included angiogenic factors, matrix-degrading enzymes, and angiogenesis inhibitors. Genistein was the most potent inhibitor of angiogenesis in vitro and in vivo among the isoflavone compounds tested. It may also account for most of the reduced microvessel density of xenografts observed and the suppressed endothelial migration by soy isoflavones. Genistein exhibited a dose-dependent inhibition of expression/excretion of vascular endothelial growth factor165, platelet-derived growth factor, tissue factor, urokinase plasminogen activator, and matrix metalloprotease-2 and 9, respectively. On the other hand, there was an up-regulation of angiogenesis inhibitors-plasminogen activator inhibitor-1, endostatin, angiostatin, and thrombospondin-1. In addition, a differential inhibitory effect between immortalized uroepithelial cells and most cancer cell lines was also observed. Altogether, we discovered that tissue factor, endostatin, and angiostatin are novel molecular targets of genistein. The current investigation provides further evidence in support of soy-based foods as natural dietary inhibitors of tumor angiogenesis.
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PMID:The novel targets for anti-angiogenesis of genistein on human cancer cells. 1562 83

Disruption of the systemic angiogenesis balance to favor enhanced angiogenesis is speculated to represent a key step in the growth of tumors. Although a major emphasis has been placed on the increase of angiogenesis stimulators, such as VEGF, on the disruption of the angiogenic balance, the potential role of the physiological levels of endogenous inhibitors of angiogenesis on tumor growth is poorly understood. Here, we use three independent lines of mice deficient in tumstatin, endostatin, or thrombospondin-1 (TSP-1), to address the role that these endogenous angiogenesis inhibitors play in tumor growth. Our experiments demonstrate that normal physiological levels of these inhibitors serve to retard the growth of tumors, and that their absence leads to enhanced angiogenesis and a 2- to 3-fold increase in tumor growth. The tumor-suppressive action of TSP-1, endostatin, and tumstatin correlates with expression of CD36 receptor, alpha5beta1 integrin, and alphavbeta3 integrin on proliferating endothelial cells, respectively. Moreover, tumors grow 2-fold faster in the tumstatin/TSP-1 double-knockout mice, compared with either the tumstatin- or the TSP-1-deficient mice, strongly suggesting that ceiling rate of cancer growth is not completely dependent on the genetic defects of cancer cells but also depends on the host-derived tumor microenvironment. Additionally, tumor growth in transgenic mice overproducing endostatin specifically in the endothelial cells (a 1.6-fold increase in the circulating levels; mimicking Down's syndrome condition) is 3-fold slower than the tumor growth in wild-type mice. Collectively, our data suggest that physiological levels of endogenous inhibitors of angiogenesis can serve as endothelium-specific tumor suppressors.
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PMID:Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors. 1571 Aug 85

Angiogenesis is necessary for tumor growth beyond a volume of approximately 2 mm(3). This observation, along with the accessibility of tumor vessels to therapeutic targeting, has resulted in a research focus on inhibitors of angiogenesis. A number of endogenous inhibitors of angiogenesis are found in the body. Some of these are synthesized by specific cells in different organs, and others are created by extracellular proteolytic cleavage of plasma-derived or extracellular matrix-localized proteins. In this review, we focus on angiostatin, endostatin, PEX, pigment epithelial-derived factor, and thrombospondin (TSP)-1 and -2, either because these molecules are expressed in malignant glioma biopsies or because animal studies in malignant glioma models have suggested that their therapeutic administration could be efficacious. We review the known mechanisms of action, potential receptors, expression in glioma biopsy samples, and studies testing their potential therapeutic efficacy in animal models of malignant glioma. Two conclusions can be made regarding the mechanisms of action of these inhibitors: (1) Several of these inhibitors appear to mediate their antiangiogenic effect through multiple protein-protein interactions that inhibit the function of proangiogenic molecules rather than through a specific receptor-mediated signaling event, and (2) TSP-1 and TSP-2 appear to mediate their antiangiogenic effect, at least in part, through a specific receptor, CD36, which initiates the antiangiogenic signal. Although not proven in gliomas, evidence suggests that expression of specific endogenous inhibitors of angiogenesis in certain organs may be part of a host antitumor response. The studies reviewed here suggest that new antiangiogenic therapies for malignant gliomas offer exciting promise as nontoxic, growth-inhibitory agents.
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PMID:Endogenous inhibitors of angiogenesis in malignant gliomas: nature's antiangiogenic therapy. 1583 Dec 30


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