Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that linomide, a quinoline-3-carboxamide, has antitumor effects against prostatic cancers in vivo through its ability to inhibit tumor angiogenesis. Subsequently, we reported that linomide inhibits several steps in the process of angiogenesis, including direct effects on endothelial cell proliferation and their chemotactic migration and invasion. Besides these direct effects, linomide's antiangiogenic activity also involves indirect effects secondary to inhibition of tumor infiltration of macrophages and their ability to secrete the angiogenic factor tumor necrosis factor-alpha (TNF-alpha). The current studies were conducted to gain insight into the mechanism by which linomide inhibits macrophage TNF-alpha secretion. The virally transformed RAW 264.7 mouse macrophage cell line was used as a model system. Chronic in vitro exposure (7 days) to 81-650 microM linomide is cytostatic to RAW cells. Such chronic exposure to linomide significantly decreased (P < 0.05) RAW cells' baseline ability to secrete TNF-alpha and also their ability to up-regulate TNF-alpha secretion in response to lipopolysaccharide (LPS) challenge. Ribonuclease protection assays demonstrated that linomide's ability to inhibit baseline and LPS-challenged TNF-alpha secretion is not functioning at the mRNA level, because steady-state levels of TNF-alpha mRNA do not change in response to linomide. Linomide's ability to inhibit TNF-alpha secretion is not associated with an increase in cell-associated TNF-alpha levels. Immunoprecipitation experiments demonstrated that linomide did not inhibit the normal proteolytic processing of the initial 26 kDa plasma membrane-bound TNF-alpha to the secreted 17 kDa soluble form. These results demonstrate that linomide inhibits TNF-alpha secretion by inhibition of the synthesis of the TNF-alpha protein. Linomide's ability to inhibit TNF-alpha protein synthesis is not due to an inhibition of general protein synthesis or secretion and is not mediated via a change in cyclic adenosine monophosphate levels.
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PMID:The antiangiogenic agent linomide inhibits tumor necrosis factor-alpha secretion via inhibition of its synthesis. 882 87

Using a murine breast cancer model, we earlier found a positive correlation between the expression of nitric oxide synthase (NOS) and tumor progression; treatment with inhibitors of NOS, N(G)-methyl-L-arginine (NMMA) and N(G)-nitro-L-arginine methyl ester (L-NAME), had antitumor and antimetastatic effects that were partly attributed to reduced tumor cell invasiveness. In the present study, we used a novel in vivo model of tumor angiogenesis using subcutaneous implants of tumor cells suspended in growth factor-reduced Matrigel to examine the angiogenic role of NO in a highly metastatic murine mammary adenocarcinoma cell line. This cell line, C3L5, expresses endothelial (e) NOS in vitro and in vivo, and inducible (i) NOS in vitro on stimulation with lipopolysaccharide and interferon-gamma. Female C3H/HeJ mice received subcutaneous implants of growth factor-reduced Matrigel inclusive of C3L5 cells on one side, and on the contralateral side, Matrigel alone; L-NAME and D-NAME (inactive enantiomer) were subsequently administered for 14 days using osmotic minipumps. Immediately after sacrifice, implants were removed and processed for immunolocalization of eNOS and iNOS proteins, and measurement of angiogenesis. Neovascularization was quantified in sections stained with Masson's trichrome or immunostained for the endothelial cell specific CD31 antigen. While most tumor cells and endothelial cells expressed immunoreactive eNOS protein, iNOS was localized in endothelial cells and some macrophages within the tumor-inclusive implants. Measurable angiogenesis occurred only in implants containing tumor cells. Irrespective of the method of quantification used, tumor-induced neovascularization was significantly reduced in L-NAME-treated mice relative to those treated with D-NAME. The quantity of stromal tissue was lower, but the quantity of necrotic tissue higher in L-NAME relative to D-NAME-treated animals. The total mass of viable tissue (ie, stroma and tumor cells) was lower in L-NAME relative to D-NAME-treated animals. These data suggest that NO is a key mediator of C3L5 tumor-induced angiogenesis, and that the antitumor effects of L-NAME are partly mediated by reduced tumor angiogenesis.
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PMID:Nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester inhibits tumor-induced angiogenesis in mammary tumors. 1051 20

We evaluated the role of COX-2 pathway in 35 head and neck cancers (HNCs) by analyzing COX-2 expression and prostaglandin E2 (PGE2) production in relation to tumor angiogenesis and lymph node metastasis. COX-2 activity was also correlated to vascular endothelial growth factor (VEGF) mRNA and protein expression. COX-2 mRNA and protein expression was higher in tumor samples than in normal mucosa. PGE2 levels were higher in the tumor front zone in comparison with tumor core and normal mucosa (P<.0001). Specimens from patients with lymph node metastasis exhibited higher COX-2 protein expression (P=.0074), PGE2 levels (P=.0011) and microvessel density (P<.0001) than specimens from patients without metastasis. A significant correlation between COX-2 and tumor vascularization (r(s)=0.450, P=.007) as well as between COX-2 and microvessel density with VEGF expression in tumor tissues was found (r(s)=0.450, P=.007; r(s)=0.620, P=.0001, respectively). The induction of COX-2 mRNA and PGE2 synthesis by EGF and Escherichia coli lipopolysaccharide (LPS) in A-431 and SCC-9 cell lines, resulted in an increase in VEGF mRNA and protein production. Indomethacin and celecoxib reversed the EGF- and LPS-dependent COX-2, VEGF, and PGE2 increases. This study suggests a central role of COX-2 pathway in HNC angiogenesis by modulating VEGF production and indicates that COX-2 inhibitors may be useful in HNC treatment.
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PMID:Cyclooxygenase-2 pathway correlates with VEGF expression in head and neck cancer. Implications for tumor angiogenesis and metastasis. 1132 16

In murine macrophages, the anti-tumor agent, paclitaxel, induces expression of a wide variety of inflammatory and anti-inflammatory genes, and causes cytokine secretion via signaling pathways that overlap with those engaged by lipopolysaccharide (LPS), the endotoxic component of Gram-negative bacteria. Using semi-quantitative RT-PCR for detection of gene expression, coupled with ELISA for the detection of secreted gene products, we analyzed the responsiveness of an extensive panel of cytokine and non-cytokine genes to induction by paclitaxel and LPS in the murine DA-3 breast cancer line. A subset of the genes examined (e.g., G-CSF, MIP-2, iNOS, and IL-1 beta, and GM-CSF) was upregulated >3-20-fold by both LPS and paclitaxel in the DA-3 cell line, while IP-10 mRNA was induced by paclitaxel, but not by LPS. In the human MDA-MB-231 breast cancer cell line, LPS also increased mRNA levels for both GM-CSF and IP-10 significantly, while, paclitaxel increased IP-10 mRNA levels with delayed kinetics and failed to induce GM-CSF mRNA. Co-cultures of murine breast cancer cells and macrophages, stimulated with IFN-gamma plus either paclitaxel or LPS, resulted in augmented release of nitric oxide. As both GM-CSF and IP-10 have been implicated in tumor rejection in vivo through either indirect actions on the host immune system or by inhibiting tumor angiogenesis, our data strengthen the hypothesis that tumor cell-derived inflammatory mediators may, in part, underlie the anti-tumor efficacy of paclitaxel in breast cancer.
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PMID:Induction of proinflammatory and chemokine genes by lipopolysaccharide and paclitaxel (Taxol) in murine and human breast cancer cell lines. 1155 85

Angiostatin effectively blocks tumor angiogenesis through still poorly understood mechanisms. Given the close association between immune and vascular regulation, we investigated the effects of angiostatin on angiogenesis-associated leukocytes. Angiostatin inhibited the migration of monocytes and, even more markedly, neutrophils. Angiostatin blocked chemotaxis of neutrophils to CXCR2 chemokine receptor agonists (IL-8, MIP-2, and GROalpha), formyl-Met-Leu-Phe (fMLP), and 12-O-tetradecanoylphorbol 13-acetate, and repressed fMLP-induced mitochondrial activity. Two different angiostatin forms (kringles 1-4 and 1-3) were effective, whereas whole plasminogen had no effect. IL-8, MIP-2, and GROalpha induced intense angiogenic reactions in vivo, but no angiogenic response to these factors was observed in neutropenic mice, demonstrating an essential role for neutrophils. Angiostatin potently inhibited chemokine-induced angiogenesis in vivo, and consistent with in vitro observations, both angiostatin forms were active and whole plasminogen had little effect. Angiostatin inhibition of angiogenesis in vivo was accompanied by a striking reduction in the number of recruited leukocytes. In vivo, the inflammatory agent lipopolysaccharide also induced extensive leukocyte infiltration and angiogenesis that were blocked by angiostatin. Neutrophils expressed mRNAs for ATP synthase and angiomotin, two known angiostatin receptors. These data show that angiostatin directly inhibits neutrophil migration and neutrophil-mediated angiogenesis and indicate that angiostatin might inhibit inflammation.
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PMID:Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation. 1177 50

Tumor-associated macrophages (TAM) have been shown to play an important role in tumor angiogenesis. The purpose of this study was to determine whether monocyte recruitment, activation and differentiation mediated by monocyte chemotactic protein-1 (MCP-1) and macrophage colony stimulating factor (M-CSF) modulate the expression of the angiogenic factor, Interleukin (IL)-8. Isolated human peripheral blood monocytes secreted low basal levels of IL-8. Incubation of monocytes with M-CSF or MCP-1 resulted in an up-regulation of IL-8 mRNA and protein expression. The differential expression of IL-8 by monocytes following MCP-1 and M-CSF treatments involved activation of the NFkB transcription factor. Further activation with lipopolysaccharide (LPS) caused an increase in IL-8 secretion in monocytes but not in monocyte-derived macrophages (MDM). MDM-conditioned media significantly up-regulated IL-8 expression in human malignant melanoma cells in vitro. In summary, we demonstrated that MCP-1 and M-CSF, critical for monocyte recruitment, activation and differentiation, differentially regulate IL-8 expression and may play an important role in monocyte/macrophage-mediated tumor angiogenesis.
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PMID:Monocyte/macrophage recruitment, activation and differentiation modulate interleukin-8 production: a paracrine role of tumor-associated macrophages in tumor angiogenesis. 1249 91

The mechanisms involved in the anti-angiogenic actions of the proteasome inhibitors are poorly understood. Here, we report that the gene expression of the VEGF receptor Flt-1 (vascular endothelial growth factor receptor 1) was down-regulated by the reversible proteasome inhibitor MG262 in explant cultures of the developing chicken pecten oculi, a vascular organ consisting of endothelial cells, pericytes, and macrophages. In addition, the inhibitor prevented the induction of Flt-1 by lipopolysaccharide (LPS) in macrophages and down-regulated the expression of Flt-1 after LPS induction. Flt-1 gene expression was also down regulated by MG262 in cultures of human microvascular endothelial cells. Interestingly, a transcript of Flt-1, coding for a soluble form of the receptor (sFlt-1) with anti-angiogenic properties, was not down-regulated in the same extent. Only a small decrease in the expression of VEGF and Ang-2 was detected in the pecten oculi upon inhibition of the proteasome, while no major changes were observed in the expression of other angiogenic molecules, such as KDR or Ang-1. Since recent experiments have demonstrated the importance of anti-Flt-1 therapy in the inhibition of tumor angiogenesis, retinal angiogenesis, arthritis, and atherosclerosis (Luttun et al. [2002]: Nat Med 8:831-840), our observation on down-regulation of Flt-1 in microvascular endothelial cells and macrophages by MG262 supports the postulated role of the proteasome inhibitors as potential candidates for therapeutic modulation of angiogenesis and inflammation.
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PMID:Down-regulation of Flt-1 gene expression by the proteasome inhibitor MG262. 1289 12

Our understanding of angiogenesis has increased significantly in the past few years with the discovery of angiopoietins (Ang). Specifically, Ang2 has been associated with pathologic as well as normal vascularization. While previous studies have shown that a major source of Ang2 has been endothelial cells and tumor cells, we reasoned that macrophages would also have the ability to express angiopoietins, specifically Ang2, due to that cell's role in wound healing, tumor angiogenesis, and a number of non-oncological diseases, such as rheumatoid arthritis and psoriasis. In this study, murine macrophages constitutively expressed both transcripts and protein for Ang2 but not Ang1 or Ang3. The secretion of Ang2 was enhanced by treatment with lipopolysaccharide, interferon-gamma, prostaglandin E2 and other cyclic AMP-elevating agents, as well as vascular endothelial growth factor (VEGF). Cyclic AMP-dependent protein kinase (PKA) played a major role in this enhancement since the PKA inhibitor, H89, blocked secretion of Ang2. Since stimulation of the PKA pathway can lead to macrophage production of VEGF, it is possible that enhancement of Ang2 production by macrophages may be due to autocrine responsiveness to VEGF. Adding anti-VEGF antibodies to the supernatants of stimulated macrophages blocked secretion of Ang2. This study is the first to show murine macrophage production of Ang2 and to provide evidence that it can be regulated. Understanding the regulation of macrophage Ang2 production is especially important in an effort to target the pathologic role of macrophages while preserving their role in immunity and homeostasis.
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PMID:Expression and regulation of murine macrophage angiopoietin-2. 1604 2

Tumor-associated macrophages are major infiltrates of human solid malignancies and play an important role in tumor angiogenesis by production of angiogenic factors. In the present study, we examined whether macrophage- melanoma cell interaction regulates vascular endothelial cell growth factor-A (VEGF-A) expression in macrophages. We analyzed the expression of mediators of monocyte recruitment and differentiation, such as monocyte chemotactic protein-1 (MCP-1) and macrophage colony-stimulating factor (M-CSF) in malignant melanoma specimens and tumor cells with different metastatic potential. Our data demonstrate that MCP-1 and M-CSF are differentially expressed in human malignant melanomas from different thickness and depth of invasion and cell lines. Next, we examined the effect of MCP-1 and M-CSF on modulation of VEGFA expression in monocytes/macrophages. Treatment of human monocytes with M-CSF and MCP-1 enhanced VEGF-A expression by increased hypoxia-inducible factor-1alpha (HIF-1alpha) expression and enhanced activation of the hypoxia response element (HRE). Further activation of monocytes and monocyte-derived macrophages (MDM) by lipopolysaccharide (LPS) caused an increase in VEGF-A expression. We demonstrate that coculture of melanoma cells with monocytes enhanced VEGF-A secretion, and conditioned medium from MDMs enhanced melanoma cell expression of VEGF-A. Furthermore, conditioned medium from melanoma cells enhanced VEGF-A expression in human monocytes, which was abrogated by anti-M-CSF neutralizing antibody. In summary, we demonstrate that MCP-1 and M-CSF, critical for monocyte recruitment, activation, and differentiation, differentially regulate VEGF-A expression and may play an important role in monocyte/macrophage- mediated tumor angiogenesis.
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PMID:Paracrine regulation of vascular endothelial growth factor--a expression during macrophage-melanoma cell interaction: role of monocyte chemotactic protein-1 and macrophage colony-stimulating factor. 1631 81

The preservation of vascular endothelial cell (EC) barrier integrity is critical to normal vessel homeostasis, with barrier dysfunction being a feature of inflammation, tumor angiogenesis, atherosclerosis, and acute lung injury. Therefore, agents that preserve or restore vascular integrity have important therapeutic implications. In this study, we explored the regulation of hepatocyte growth factor (HGF)-mediated enhancement of EC barrier function via CD44 isoforms. We observed that HGF promoted c-Met association with CD44v10 and recruitment of c-Met into caveolin-enriched microdomains (CEM) containing CD44s (standard form). Treatment of EC with CD44v10-blocking antibodies inhibited HGF-mediated c-Met phosphorylation and c-Met recruitment to CEM. Silencing CD44 expression (small interfering RNA) attenuated HGF-induced recruitment of c-Met, Tiam1 (a Rac1 exchange factor), cortactin (an actin cytoskeletal regulator), and dynamin 2 (a vesicular regulator) to CEM as well as HGF-induced trans-EC electrical resistance. In addition, silencing Tiam1 or dynamin 2 reduced HGF-induced Rac1 activation, cortactin recruitment to CEM, and EC barrier regulation. We observed that both HGF- and high molecular weight hyaluronan (CD44 ligand)-mediated protection from lipopolysaccharide-induced pulmonary vascular hyperpermeability was significantly reduced in CD44 knock-out mice, thus validating these in vitro findings in an in vivo murine model of inflammatory lung injury. Taken together, these results suggest that CD44 is an important regulator of HGF/c-Met-mediated in vitro and in vivo barrier enhancement, a process with essential involvement of Tiam1, Rac1, dynamin 2, and cortactin.
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PMID:CD44 regulates hepatocyte growth factor-mediated vascular integrity. Role of c-Met, Tiam1/Rac1, dynamin 2, and cortactin. 1770 46


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