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)

Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)alpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPARalpha would promote tumor growth. Surprisingly, the PPARalpha agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPARalpha-deficient tumors were still susceptible to fenofibrate, absence of PPARalpha in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPARalpha as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPARalpha agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPARalpha agonists in cancer treatment, alone and in combination with other therapies.
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PMID:PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. 1819 35

The promising but still limited efficacy of angiogenesis inhibitors as monotherapies for cancer treatment indicates a need to integrate these agents into existing therapeutic regimens. Presently, we investigate the antitumor activity of the small-molecule angiogenesis inhibitor axitinib (AG-013736) and its potential for combination with metronomic cyclophosphamide. Axitinib significantly inhibited angiogenesis in rat 9L tumors grown s.c. in scid mice but only moderately delayed tumor growth. Combination of axitinib with metronomic cyclophosphamide fully blocked 9L tumor growth on initiation of drug treatment. In contrast, metronomic cyclophosphamide alone required multiple treatment cycles to halt tumor growth. However, in contrast to the substantial tumor regression that is ultimately induced by metronomic cyclophosphamide, the axitinib/cyclophosphamide combination was tumor growth static. Axitinib did not inhibit hepatic activation of cyclophosphamide or export of its activated metabolite, 4-hydroxy-cyclophosphamide (4-OH-CPA), to extrahepatic tissues; rather, axitinib selectively decreased 9L tumor uptake of 4-OH-CPA by 30% to 40%. The reduced tumor penetration of 4-OH-CPA was associated with a decrease in cyclophosphamide-induced tumor cell apoptosis and a block in the induction of the endogenous angiogenesis inhibitor thrombospondin-1 in tumor-associated host cells, which may contribute to the absence of tumor regression with the axitinib/cyclophosphamide combination. Finally, axitinib transiently increased 9L tumor cell apoptosis, indicating that its effects are not limited to the endothelial cell population. These findings highlight the multiple effects that may characterize antiangiogenic agent/metronomic chemotherapy combinations and suggest that careful optimization of drug scheduling and dosages will be required to maximize antitumor responses.
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PMID:Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib. 1820 11

Angiogenesis is essential for tumor growth and progression. It has been demonstrated that the expression of angiogenesis stimulators (e.g. basic fibroblast growth factor and vascular endothelial growth factor) correlates to tumor progression in various human tumor types. Furthermore, endogenous angiogenesis inhibitors (e.g. angiostatin and endostatin) have been isolated from human tumor models and have been successfully used to treat tumors in mice and humans. In the present study, the expression of angiostatin, endostatin and thrombospondin-1 in four different human bladder cancer cell lines with different tumorigenic potential (MGH-U4, RT-4, RT-112 and UMUC-3) were investigated. A subset of bladder carcinoma patients demonstrates rapid metastatic progression after removal of the primary tumor, although no evidence of metastasis is diagnosed before the surgical procedure. A potential mechanism to explain this phenomenon is suggested. Angiostatin, endostatin and thrombospondin-1 was detected in the conditioned media of four human bladder cancer cell lines using Western blotting. Angiostatin was purified and amino acid sequenced via mass spectrometry. The biological activity of angiostatin was determined by proliferation assays using endothelial cells, smooth muscle cells and fibroblasts. Tumor characteristics of the four human bladder carcinoma models were investigated in vitro and in vivo. All the bladder carcinoma cell lines employed in this study produced two biologically active variants of the angiostatin molecule (38 and 49 kDa). Endostatin and thrombospondin-1 were only produced by the low malignancy MGH-U4 and RT-4 bladder carcinoma models. This study identified the expression of different antiangiogenic molecules in human bladder carcinoma. The expression of antiangiogenic molecules seems to be a characteristic of low malignancy bladder carcinomas. The sudden lack of expression of antiangiogenic molecules as a consequence of surgical removal of highly malignant bladder carcinomas may explain the rapid metastatic progression of a subset of bladder carcinomas.
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PMID:Expression of angiogenesis inhibitors in human bladder cancer may explain rapid metastatic progression after radical cystectomy. 1914 51

There is a growing interest in the role that cancer biomarkers, metastasis-related molecules, and chemokines may play in the development and progression of various cancers. However, few studies have addressed the reliability of such biomarkers in healthy individuals over time. The objective of this study was to investigate the temporal reliability of multiple proteins in serum samples from healthy women who donated blood over successive years. Thirty five, postmenopausal women with two, repeated annual visits, and thirty, premenopausal women with three, repeated annual visits were randomly selected among eligible subjects from an existing, prospective cohort. Multiplexing Luminex xMAPTM technology was used to measure the levels of 55 serum proteins representing cancer antigens, chemokines, angiogenic and anti-angiogenic factors, proteases, adipokines, apoptotic molecules, and other markers in these women. The biomarkers with high detection rates (> 60%) and acceptable reliability (intraclass correlation coefficient, ICCs > or = 0.55) using xMAPTM method were: cancer antigens: AFP, CA 15-3, CEA, CA-125, SCC, SAA; growth factors/related molecules: ErbB2, IGFBP-1; proteases and adhesion molecules: MMP-1, 8, 9, sE-selectin, human kallikreins (KLK) 8,10, ICAM-1, VCAM-1, chemokines: fractalkine, MCP-1,2, RANTES, MIP-1alpha, MIP-1beta, Eotaxin, GRO-alpha, IP-10; inhibitors of angiogenesis: angiostatin and endostatin; adipokines leptin and resistin; apoptotic factor: Fas, and other proteins mesothelin, myeloperoxidase (MPO), and PAI-1. The rest of the biomarkers under investigation either had ICCs less than 0.55 or had low levels of detection (< 60%). These included cancer antigens: CA 19-9, CA 72-4, MICA, S100, TTR, ULBP1, ULBP2, ULBP3; proteases: MMP 2, 3, 7, 12, 13; chemokines: MCP-3, MIF, MIG; adipokines: leptin and resistin; apoptotic factors: FasL, DR5, Cyfra 21-1; and inhibitors of angiogenesis and other markers: thrombospondin and heat shock protein (HSP) 27. In conclusion, 34 out of the 55 biomarkers investigated were present in detectable levels in > 60% of the samples, and with an ICC > or = 0.55, indicating that a single serum measurement can be used in prospective epidemiological studies using the xMAPTM method.
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PMID:Reliability of tumor markers, chemokines, and metastasis-related molecules in serum. 1931 17

Low-dose metronomic (LDM) chemotherapy represents a new strategy to treat solid tumors by stronger antiangiogenic activity and lower side effects, especially in combination with other antiangiogenic agents. This study aims to investigate whether LDM chemotherapy of paclitaxel could synergize with cetuximab, an antiangiogenic agent to suppress HT-29 human colon tumors in BALB/c nude mice. To explore its possible mechanism, the tumor vascular status was detected by staining with anti-CD31 Ab and the tumoral expression of thrombospondin-1 was examined by immunohistochemistry, western blot analysis, and real-time PCR. Our results showed that empirical metronomic paclitaxel regimens in combination with cetuximab induces significant and durable antitumor responses without overt toxicity. Paclitaxel LDM chemotherapy displayed stronger antiangiogenic activity than maximum tolerable dose (MTD) chemotherapy, whereas MTD chemotherapy induced more apoptotic cells. The combinational therapy with LDM and cetuximab showed the strongest antiangiogenic activity among all the groups. Paclitaxel LDM chemotherapy also dramatically upregulated the expression of thrombospondin-1, but MTD chemotherapy did not. These results suggest that the combination of paclitaxel LDM chemotherapy and cetuximab represents a potent strategy to combat colon cancers.
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PMID:Low-dose metronomic chemotherapy of paclitaxel synergizes with cetuximab to suppress human colon cancer xenografts. 1931 12

Angiostatin, a proteolytic fragment of plasminogen, is a potent endogenous antiangiogenic agent. The molecular mechanisms governing angiostatin's antiangiogenic and antitumor effects are not well understood. Here, we report the identification of mitochondrial compartment as the ultimate target of angiostatin. After internalization of angiostatin into the cell, at least 2 proteins within the mitochondria bind this molecule: malate dehydrogenase, a member of Krebs cycle, and adenosine triphosphate synthase. In vitro and in vivo studies revealed differential regulation of key prosurvival and angiogenesis-related proteins in angiostatin-treated tumors and tumor-endothelium. Angiostatin induced apoptosis via down-regulation of mitochondrial BCL-2. Angiostatin treatment led to down-regulation of c-Myc and elevated levels of another key antiangiogenic protein, thrombospondin-1, reinforcing its antitumor and antiangiogenic effects. Further evidence is provided for reduced recruitment and infiltration of bone marrow-derived macrophages in angiostatin-treated tumors. The observed effects of angiostatin were restricted to the tumor site and were not observed in other major organs of the mice, indicating unique tumor specific bioavailability. Together, our data suggest mitochondria as a novel target for antiangiogenic therapy and provide mechanistic insights to the antiangiogenic and antitumor effects of angiostatin.
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PMID:Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins. 1971 80

Multiplexins are multidomain collagens typically composed of an N-terminal thrombospondin-related domain, an interrupted triple helix and a C-terminal endostatin domain. They feature a clear regulatory function in the development of different tissues, which is chiefly conveyed by the endostatin domain. This domain can be found in proteolytically released monomeric and trimeric versions, and their diverse and opposed effects on the migratory behavior of epithelial and endothelial cell types have been demonstrated in cell culture experiments. The only Drosophila multiplexin displays specific features of both vertebrate multiplexins, collagens XV and XVIII. We characterized the Drosophila multiplexin (dmp) gene and found that three main isoforms are expressed from it, one of which is the monomeric endostatin version. Generation of dmp deletion alleles revealed that Dmp plays a role in motor axon pathfinding, as the mutants exhibit ventral bypass defects of the intersegmental nerve b (ISNb) similar to other motor axon guidance mutants. Transgenic overexpression of monomeric endostatin as well as of full-length Dmp, but not trimeric endostatin, were able to rescue these defects. In contrast, trimeric endostatin increased axon pathfinding accuracy in wild type background. We conclude that Dmp plays a modulating role in motor axon pathfinding and may be part of a buffering system that functions to avoid innervation errors.
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PMID:Drosophila multiplexin (Dmp) modulates motor axon pathfinding accuracy. 1946 89

Endostatin is a C-terminal proteolytic fragment of collagen XVIII that is localized in vascular basement membrane zones in various organs. It binds to heparin/heparan sulfate and to a number of proteins, but its molecular mechanisms of action are not fully elucidated. We have used surface plasmon resonance (SPR) arrays to identify new partners of endostatin, and to give further insights on its molecular mechanism of action. New partners of endostatin include glycosaminoglycans (chondroitin and dermatan sulfate), matricellular proteins (thrombospondin-1 and SPARC), collagens (I, IV, and VI), the amyloid peptide Abeta-(1-42), and transglutaminase-2. The biological functions of the endostatin network involve a number of extracellular proteins containing epidermal growth factor and epidermal growth factor-like domains, and able to bind calcium. Depending on the trigger event, and on the availability of its members in a given tissue at a given time, the endostatin network might be involved either in the control of angiogenesis, and tumor growth, or in neurogenesis and neurodegenerative diseases.
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PMID:The first draft of the endostatin interaction network. 1954 24

Corneal neovascularization (CNV) associated with severe limbal stem cell (LSC) deficiency remains a challenging ocular surface disease in that corneal inflammation may persist and progress, and the condition will not improve without LSC transplantation. A prominent feature after successful LSC transplantation is the suppression of corneal inflammation and CNV, which is generally attributed to the endogenous anti-angiogenic/anti-inflammatory factors secreted by corneal epithelial cells. In addition, corneal epithelial basement membrane (EBM) plays a unique role in the regulation of angiogenesis; several potent anti-angiogenic factors are derived from the matrix component of EBM, such as endostatin (from collagen XVIII) and restin (from collagen XV). Also, angio-inhibitory thrombospondin and tissue inhibitor of metalloproteinase-3 are deposited in EBM. Moreover, the heparan sulphate proteoglycan in EBM can bind and sequester VEGF and FGF-2 from activation. Recently, cultivated corneal epithelial transplantation (CCET) and cultivated oral mucosal epithelial transplantation (COMET) have emerged as promising techniques for the treatment of LSC deficiency. When human limbo-corneal epithelial (HLE) cells are cultivated on cryopreserved amniotic membrane, production of endostatin, restin, and IL-1ra is enhanced. This highlights the significance of delicate epithelial-matrix interactions in the generation of anti-angiogenic/anti-inflammatory factors by HLE cells, and this may, in part, explain the rapid restoration of corneal avascularity following CCET. In addition, whether epithelial stem cells can persist after transplantation is the key for CCET and COMET. Emerging evidence of long-term survival of cultivated epithelial cells after transplantation suggest that epithelial stem cells can be isolated and cultivated in vitro, and can re-establish the epithelial phenotype in vivo. Taken together, the merits of enhanced anti-angiogenic activity and the preservation of corneal epithelial stem cells encourage further application of this tissue engineering technique for ocular surface reconstruction.
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PMID:Matrix revolution: molecular mechanism for inflammatory corneal neovascularization and restoration of corneal avascularity by epithelial stem cell transplantation. 1963 46

Angiogenesis is a multistep process that depends on the balance of proangiogenic factors and inhibitors as well as on interactions with the extracellular matrix. We examined the immunohistochemical expression of the defining angiogenic agents, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), and the antiangiogenic agent thrombospondin-1 (TSP-1) in 131 patients with urothelial carcinoma and correlated their expression levels with clinicopathological parameters. VEGF and MMP-9 expression was higher in high-grade tumors than in low-grade tumors (p=0.000 and p=0.001, respectively), whereas the reverse was true for TSP-1 (p=0.000). VEGF and MMP-9 expression was higher in deeper tumors compared to superficial tumors and in invasive tumors compared to non-invasive tumors (p=0.001 and p=0.001, respectively), while TSP-1 was lower (p=0.000). We could differentiate 22 of 41 muscle-invasive (T2) cases as superficial (T2a; n=7) or deep (T2b; n=15), but no difference was found between them regarding VEGF, MMP-9, or TSP-1 expression (p=0.783, p=0.289, and p=0.783, respectively). There was a positive correlation between VEGF and MMP-9 expression (p=0.008, r=0.23) but a negative correlation between MMP-9 and TSP-1 expression (p=0.014, r=-0.21). Increased VEGF and MMP-9 expression as well as decreased TSP-1 expression may play considerable roles in the invasion and differentiation of urothelial carcinoma.
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PMID:Vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and thrombospondin-1 (TSP-1) expression in urothelial carcinomas. 1976 63


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