UMLS:C1519670 - FACTA Search

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Query: UMLS:C1519670 (tumor angiogenesis)
6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which DL-alpha-difluoromethylornithine (DFMO) inhibits angiogenesis is generally thought to involve the inhibition of the rate-limiting enzyme, ornithine decarboxylase (ODC), leading to polyamine depletion in cells and the ultimate cytostatic effect on proliferating endothelial cells. Another mechanism for inhibiting tumor growth involves pentosan polysulfate (PPS) which binds heparin-binding growth factors, known to be crucial for tumor angiogenesis. To quantitate the combined anti-angiogenic effect of DFMO and PPS on tumors, blood vessels were stained using monoclonal antibodies against the platelet endothelial cell adhesion molecule (PECAM). When compared to untreated mice, DFMO/PPS-treated mice exhibited significantly lower (6-fold) blood vessel counts. Furthermore, mice receiving the combination drug treatment had prolonged life compared to untreated tumor-bearing mice, but less than normal tumor-free mice. The prolonged life span of drug treated tumor-bearing mice also correlated with reduced tumor burden in these mice. The use of single drug treatment results in rapid tumor growth and eventual death of tumor-bearing mice. We have demonstrated that there was significant difference in survival time which correlated to less tumor burden in treated groups of mice as compared to the controls. Inhibition of tumor angiogenesis by the drug combinations suggest that these compounds are anti-angiogenic agents for potential use in clinical trial.
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PMID:Inhibition of breast cancer in nude mouse model by anti-angiogenesis. 976 82

Angiogenesis plays a fundamental role in tumor growth and metastasis. What is needed is a quantitative, noninvasive, and repeatable assay to estimate functional angiogenic activity of the entire tumor. The aims of the present study were to: (a) examine the relationship between functional magnetic resonance imaging (MRI)-based parameters with established histomorphological markers of tumor angiogenesis [histological microvessel density (HMVD) and vascular endothelial growth factor expression (VEGF)]; and (b) determine the ultimate value of both approaches to assess functional angiogenic active hotspots as markers of disease outcome in patients with cancer of the uterine cervix. Pharmacokinetic parameters (amplitude A, tissue exchange rate constant k21) were calculated from contrast-enhanced dynamic MRI series in 57 patients (mean age, 49 +/- 14 years) with biopsy proven uterine cervical cancer. Both pharmacokinetic parameters were correlated to histomorphologically determined areas of high HMVD and VEGF expression obtained from the operative specimens after radical surgery. In addition, the functional MRI and histomorphological data were used to assess disease outcome. A significant association was found between HMVD and the amplitude A (P < 0.001) and a less pronounced association with k21, (P < 0.05), respectively. No significant associations were found between the pharmacokinetic parameters (A, k21) and VEGF expression. When stratified into high and low median k21 groups, median k21 values >5.4 min(-1) were the only significant (P < 0.05) factors in predicting poor patient survival. None of the histomorphological markers of angiogenesis (HMVD or VEGF expression) showed any predictive power. We have found that: (a) focal hotspots of HMVD are the pathophysiological basis for differences in functional MRI; (b) areas of high microvessel density and microvessel permeability do not necessarily coincide, as demonstrated by the histomorphological and functional MRI findings; (c) the functional angiogenic activity of a tumor may not be sufficiently characterized by a histomorphological approach but rather by a functional MRI-based approach; and (d) functional MRI-based analysis may assess tumor angiogenic activity in terms of disease outcome more comprehensively than the histomorphological approach.
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PMID:Angiogenic activity of cervical carcinoma: assessment by functional magnetic resonance imaging-based parameters and a histomorphological approach in correlation with disease outcome. 979 59

Angiogenesis is essential for tumor proliferation and metastasis. The extent of angiogenesis is measured by microvessel density (MVD) which has been identified as an independent prognostic factor for relapse-free survival in cancer patients. Existing methods of MVD assessment measure the microvessel count in the most active area of neovascularization ("hot spots") using antibodies against vascular endothelial antigens. This may produce unreliable results because of tissue volume loss and misshapening during the fixation and dehydration procedures. We report here a genetically engineered 9L cell line constitutively expressing green fluorescent protein that can be visualized using fluorescence microscopy without additional histological staining. The model developed in this study allows for the performance of simple and easy MVD counting, assuming that nonfluorescent "black spots" visible by fluorescence microscopy within the borders of the tumor tissue represent blood vessels. This assumption was confirmed by a comparative study utilizing conventional histological methods, anti-CD31 immunohistology, and Hoechst 33258 dye exclusion. This model is also useful for delineation of the true borders between tumor and normal brain tissue, including microscopic tumor extensions, without multiple histological staining. The suggested model allows quantification of tumor angiogenesis in tissue specimens, thus providing independent prognostic information about tumor growth and regression. It is expected to be most valuable in evaluating the efficacy of anti-angiogenic therapy.
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PMID:Novel gliosarcoma cell line expressing green fluorescent protein: A model for quantitative assessment of angiogenesis. 982 52

Extravascular fibrin deposition is frequently observed within and around neoplastic tissue and has been implicated in various aspects of tumor growth. The distribution of fibrin deposits was investigated in squamous cell carcinomas representing different stages of tumor progression of the larynx (n = 25) and hypopharynx (n = 9) by immunofluorescent techniques. Double and treble labelings were used to detect fibrinogen and fibrin in combination with marker antigens for tumor cells (cytokeratin), endothelial cells (von Willebrand factor), macrophages (recognized by KiM7), as well as factor XIII subunit A (FXIIIA) and tenascin (an embryonic extracellular matrix protein newly expressed during tumorigenesis). All tissue samples showed specific staining for fibrinogen/fibrin. Fibrin deposition was localized almost exclusively in the connective tissue compartment of tumors with characteristic accumulation at the interface of connective tissue and the tumorous parenchyma. In certain tumor samples showing highly invasive characteristics, fibrin deposits were observed in close association with tumor blood vessels in the tumor cell nodules. The overlapping reactions with polyclonal antibody to fibrinogen/fibrin and monoclonal antibody to fibrin indicate the activation of the coagulation cascade resulting in in situ thrombin activation and fibrin formation. Fibrin was crosslinked and stabilized by FXIIIA as revealed by urea insolubility test. Accumulation of phagocytozing macrophages detected by Ki M7 monoclonal antibody could be seen in areas of fibrin deposition. The blood coagulation factor XIIIA was detected in and around the cells labeled with Ki M7 antibody. Tenascin and fibrin deposits were found in the same localization in the tumor stroma and in association with tumor blood vessels within the tumor cell nodules. Neither fibrin nor tenascin were detected in the histologically normal tissue adjacent to tumors. The close association between fibrin deposits and macrophage accumulation strongly suggests the active participation of tumor-associated macrophages in the formation of stabilized intratumoral fibrin that facilitates tumor matrix generation and tumor angiogenesis.
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PMID:Fibrin deposition in squamous cell carcinomas of the larynx and hypopharynx. 984 69

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy in which multiple independent lesions develop over time throughout the mucosa of the upper aerodigestive tract. Therefore, the comprehensive treatment of this neoplasm must include a chemopreventive arm to hold premalignant lesions in check, a role well-suited to antiangiogenic agents. Retinoic acid (RA) and interferon alpha (IFN-alpha), drugs with known biological activity against HNSCC when used individually, are also inhibitors of angiogenesis. Here we show that they are remarkably synergistic antiangiogenic agents able to inhibit both the growth and the neovascularization of HNSCC injected into the floor of the mouth of nude mice. The mechanism of action of these drugs as antiangiogenic agents was 2-fold. They decreased the angiogenic activity of the tumor cells, and they caused the endothelial cells to become refractory to inducers of angiogenesis. When tumor cells were treated in vitro with IFN-alpha A/D, there was a dramatic drop in their secretion of interleukin-8, the major angiogenic factor produced by these tumors. When combined with RA, which causes tumor cells to secrete an inhibitor of angiogenesis, there was a synergistic inhibition of both tumor cell growth and secreted angiogenic activity. The combination of RA and IFN-alpha also acted synergistically on endothelial cells by reducing their responsiveness to both interleukin-8 and tumor conditioned media. Doses of each drug could be reduced by two logs without loss of activity. When animals bearing human HNSCC tumor cells were treated systemically with a combination of RA and IFN-alpha A/D at doses that were ineffective when used alone, dramatic decreases in both tumor growth and tumor angiogenesis were seen. These data suggest that the use of antiangiogenic mixtures may be a particularly effective way to design future chemoprevention protocols against HNSCC.
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PMID:Retinoic acid and interferon alpha act synergistically as antiangiogenic and antitumor agents against human head and neck squamous cell carcinoma. 985 93

Vascular endothelial growth factor (VEGF), a very important in the process of tumor angiogenesis, was chosen as a target in a study to determine whether manipulation of angiogenesis with antibody against VEGF may interrupt tumor growth and metastasis. Anti-VEGF antibody was obtained from immunized rabbits, purified on an affinity column, and identified as neutralized antibody by Mile's assay. IVTA2MA891, a murine spontaneous breast cancer with a high rate of metastasis in lung in TA2 x 615 F1 mice, was chosen as an animal model in this study, because of the high expression of VEGF in the primary tumor as well as in the lung metastatic tumor. The anti-VEGF antibody could inhibit growth of S180 sarcoma in a dose-dependent manner, and the inhibition rate could reach 41.0% with a dose of 200 microg mouse(-1) day(-1). Anti-VEGF antibody could inhibit tumor growth by 76.2% in nude mice bearing human gastric cancer (MGC 803). When anti-VEGF antibody was combined with 131I-3H11, a murine monoclonal antibody conjugated with 131I, only one of five nude mice developed tumor and 84.0% more inhibition of tumor growth was obtained in comparison with treatment by 131I-3H11 alone. The growth of the primary tumor was inhibited by 44.0% and the number and size of the metastatic foci in the lungs were reduced by 73.0% and 83.7% respectively in the animal model, with a high rate of metastasis in lung. The anti-VEGF antibody may be potentially useful for clinical treatment of cancer and metastasis.
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PMID:The effect of antibody against vascular endothelial growth factor on tumor growth and metastasis. 986 Feb 90

The heparin-binding polypeptide homologs pleiotrophin and midkine are the only known members of a family of secreted growth/differentiation cytokines. Pleiotrophin and midkine are both developmentally regulated and highly conserved among species. They signal a number of physiological functions involved with angiogenesis, neuorogenesis, cell migration, and mesoderm-epithelial interactions. Constitutive expression of pleiotrophin and midkine in responsive cells support their role as "tumor growth factors" and positive regulators of tumor angiogenesis. Widespread deregulation of pleiotrophin and midkine is found in many known human cancers or their derived cell lines, and the molecular targeting of pleiotrophin to block its signaling in tumor cells has limited tumor growth and metastasis in animal models. Elucidating the molecular mechanisms of pleiotrophin and midkine action in tumorgenesis and tumor angiogenesis may lead to the identification of novel targets for tumor therapy.
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PMID:Pleiotrophin and midkine, a family of mitogenic and angiogenic heparin-binding growth and differentiation factors. 991 53

Thrombospondin (TSP) is a Mr 450,000 multifunctional matrix glycoprotein that interferes with tumor growth, angiogenesis, and metastasis. It has recently been shown that TSP expression is enhanced by the product of the p53 gene and that a down-regulation of TSP may be observed when alterations of the p53 protein occur. Moreover, a number of studies have demonstrated a regulatory activity of p53 on human vascular endothelial growth factor (VEGF), although additional investigations will be necessary to understand their relationship. In non-small cell lung carcinoma (NSCLC), neoangiogenesis, p53 alterations, and VEGF expression seem to have meaningful implications in the development and progression of this type of cancer. The aim of this study is to identify and quantitate TSP I and TSP II mRNA in NSCLCs with respect to p53 alterations, angiogenic growth factor expression, and microvascular density. A series of 24 cases of NSCLC were analyzed. Eleven of 24 of the cases were positive for TSP II mRNA, whereas 8 of 24 showed TSP I mRNA expression. A significant inverse association was found between TSP I mRNA and fibroblast growth factor (FGF) protein expression (P = 0.00001). Tumors with low FGF protein expression (< or = 40% of positive cells) presented a number of TSP I cDNA molecules, significantly higher than tumors expressing high levels of FGF protein. No association was found between TSP mRNA expression and other angiogenic growth factors (i.e., VEGF) or tumoral neovascularization. On the contrary, tumors with high levels of FGF showed a higher number of microvessels (P = 0.05). By PCR-single-strand conformational polymorphism analysis, we observed aberrations of the p53 gene in 19 of the 24 tumor samples. No association was found between p53 alterations and TSP mRNA expression. Instead, an interestingly significant association was found between the presence of p53 mutations and high VEGF protein expression (P = 0.01) and neovascularization (P = 0.03). Highly vascularized tumors showed higher VEGF protein expression (r = 0.45; P = 0.02). These data support the concept that in NSCLC, p53 exerts an important role in the control of neoangiogenesis. This influence is probably mediated by VEGF. The inverse association we found between TSP I and basic FGF suggests a different role of TSP I and TSP II in the angiogenic "switch," supporting the hypothesis that especially TSP I may have a significant function in tumor angiogenesis.
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PMID:Thrombospondins I and II messenger RNA expression in lung carcinoma: relationship with p53 alterations, angiogenic growth factors, and vascular density. 991 14

Endothelial receptor tyrosine kinases (RTKs) and their signaling mechanisms are of interest because they may control tumor angiogenesis and thereby tumor growth. In this report we have examined activation of the signal transducers and activators of transcription (STATs) by the three known vascular endothelial growth factor receptors (VEGFR1-3), as well as by the endothelial Tie-1 and -2 receptors. We also studied signaling by the R849W mutant of Tie-2 (MTie-2), which has been shown to cause venous malformations. When overexpressed in 293T cells, MTie-2 activated STAT1 while the other endothelial RTKs failed to do so. In contrast, the three VEGFRs were strong activators of STAT3 and STAT5, suggesting that they activate only a specific subset of these signal transducers. STAT3 and STAT5 were also activated by Tie-2 and, more so, by MTie-2. Tyrosine phosphorylation and DNA binding of STATs correlated with their ability to activate transcription as judged by luciferase assays. When co-expressed with STAT5, VEGFR-1 as well as both the Tie-2 receptor forms increased expression of the cell cycle inhibitor p21. Interestingly, co-expression of the Tie-2 receptors with STAT1 resulted in appearance of a novel, p21 related transcript. Taken together, these findings identify STAT proteins as novel targets for signal transduction by the endothelial RTKs, suggesting that they may be involved in the regulation of endothelial function.
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PMID:Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. 992 14

We report here that tumor angiogenesis-mediated endothelial cell (EC) anergy can be overcome by inhibitors of angiogenesis. We found previously that tumor growth, known to be dependent on angiogenesis, results in down-regulation of endothelial adhesion molecules and tumor EC anergy to inflammatory signals. We hypothesized that counteracting angiogenesis induces re-expression of adhesion molecules and normalizes responses to inflammatory cytokines. Here, we present data to show that the angiogenesis inhibitor platelet factor-4 (PF4) is able to prevent basic fibroblast growth factor (bFGF)-induced down-regulation of intercellular adhesion molecule-1 (ICAM-1). Furthermore, PF4 restores ICAM-1 expression following bFGF-induced down-regulation of ICAM-1. This PF4 effect occurs at the protein level and the RNA level and it has functional impact on leukocyte adhesion. In addition, PF4 overcomes the tumor-induced EC anergy to inflammatory signals such as tumor necrosis factor alpha (TNF alpha). Our findings may be the basis of new cancer therapies by combining anti-angiogenic therapy and immunotherapy to decrease blood vessel formation and to increase the effectiveness of inflammatory reactions against tumors.
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PMID:Angiogenesis inhibitors overcome tumor induced endothelial cell anergy. 993 16

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