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ABSTRACT: Prostaglandin (PG)E(2) is relevant in tumor biology, and interactions between tumor and stroma cells dramatically influence tumor progression. We tested the hypothesis that cross-talk between head and neck squamous cell carcinoma (HNSCC) cells and fibroblasts could substantially enhance PGE(2) biosynthesis. We observed an enhanced production of PGE(2) in cocultures of HNSCC cell lines and fibroblasts, which was consistent with an upregulation of COX-2 and microsomal PGE-synthase-1 (mPGES-1) in fibroblasts. In cultured endothelial cells, medium from fibroblasts treated with tumor cell-conditioned medium induced in vitro angiogenesis, and in tumor cell induced migration and proliferation, these effects were sensitive to PGs inhibition. Proteomic analysis shows that tumor cells released IL-1, and tumor cell-induced COX-2 and mPGES-1 were suppressed by the IL-1-receptor antagonist. IL-1α levels were higher than those of IL-1β in the tumor cell-conditioning medium and in the secretion from samples obtained from 20 patients with HNSCC. Fractionation of tumor cell-conditioning media indicated that tumor cells secreted mature and unprocessed forms of IL-1. Our results support the concept that tumor-associated fibroblasts are a relevant source of PGE(2) in the tumor mass. Because mPGES-1 seems to be essential for a substantial biosynthesis of PGE(2), these findings also strengthen the concept that mPGES-1 may be \a target for therapeutic intervention in patients with HNSCC.
The Journal of Lipid Research 02/2012; 53(4):630-42. · 5.56 Impact Factor
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Luis Vila,
Angel Martinez-Perez,
Mercedes Camacho,
Alfonso Buil,
Sonia Alcolea,
Nuria Pujol-Moix, Marta Soler,
Rosa Antón,
Juan-Carlos Souto,
Jordi Fontcuberta,
José-Manuel Soria
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ABSTRACT: Prostanoids play a critical role in clinical areas such as inflammation, thrombosis, immune response, and cancer. Although some studies suggest that there are genes that determine variability of some prostanoid-related phenotypes, the genetic influence on these traits has not been evaluated.
The relative contributions of genetic and environmental influences to the prostanoid biosynthetic pathway-related phenotypes, cyclooxygenase isoenzymes, microsomal-PGE-synthase-1 and TxA-synthase expression, and thromboxane-A(2) and prostaglandin-E(2) production by stimulated whole blood, were assessed in a sample of 308 individuals in 15 extended families. The effects of measured covariates (such as sex, age, and smoking), genes, and environmental variables shared by members of a household were quantified. Heritabilities ranging from 0.406 to 0.634 for enzyme expression and from 0.283 to 0. 751 for prostanoid production were found.
These results demonstrate clearly the importance of genetic factors in determining variation in phenotypes that are components of the prostanoid biosynthetic pathways. The presence of such strong genetic effects suggest that it will be possible to localize previously unknown genes that influence quantitative variation in these phenotypes, some of which affect multiple aspects of cell biology, with important clinical implications.
Arteriosclerosis Thrombosis and Vascular Biology 10/2009; 30(1):128-34. · 6.37 Impact Factor
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ABSTRACT: There is evidence that polymorphonuclear neutrophils (PMNs) can exert severe antineoplastic effects. Cross-talk between tumour cells and endothelial cells (ECs) is necessary for the accumulation of PMN around a tumour. This work reports the ability of two PMN-sensitive, human, permanent cell lines-colorectal adenocarcinoma (HT-29) and pharyngeal squamous-cell carcinoma (FaDu) cells-to act as inflammatory foci. PMNs were cytotoxic to both lines, the adhesion of the PMNs to the tumour cells being important in this effect. The tumour cells released appreciable amounts of IL-8 and GROalpha, and induced the transmigration of PMN through human microvascular-EC monolayers. Conditioning media associated with both lines induced the adhesion of PMN and the surface expression of ICAM-1 in microvascular-EC. In addition, FaDu-conditioning-medium strongly induced the production of proinflammatory cytokines by microvascular-EC. These results support the idea that tumour cells might normally induce a potent acute inflammatory response, leading to their own destruction.
Mediators of Inflammation 01/2009; 2009:817498. · 3.26 Impact Factor
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ABSTRACT: Human umbilical vein endothelial cells were exposed to free-form and lipid-complexed versions of amphotericin B (alone or in combination with human recombinant interleukin [IL]-1 beta) and to culture medium from the human macrophage cell line THP-1 that had been exposed to amphotericin B. Endothelial cells were then incubated with exogenous-labeled arachidonic acid or were stimulated with histamine. Measurement of the resulting prostanoids indicated that amphotericin B and IL-1 beta acted synergistically to increase the ability of endothelial cells to synthesize prostanoids from endogenous and exogenous substrate and to increase expression of cyclooxygenase-2. This resulted in an increase of the ratio of untransformed prostaglandin (PG) H2 to PGI2 released by endothelial cells. Culture medium from amphotericin B-activated macrophages caused similar effects in endothelial cells. The synergistic effect with IL-1 beta was observed with free-form amphotericin B and, to a lesser extent, with lipid-complexed amphotericin B (Abelcet). Differences between Abelcet and the lipisome carrier (AmBisome) were not significantly different with respect to any of the parameters analyzed.
The Journal of Infectious Diseases 10/2004; 190(5):1026-32. · 6.41 Impact Factor
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ABSTRACT: Overnight exposure to interleukin (IL)-1beta caused a dramatic hyporesponsiveness to phenylephrine, increased nitric oxide (NO) and prostacyclin production, and induced cycloxygenase-2 expression in rat aortic rings. Using different inhibitors, we found that this hyporeactivity was mediated by NO, prostacyclin, and activation of charybdotoxin-sensitive K(+) channels. The latter was independent of the presence of endothelium and NO and prostanoid synthesis during the challenge with phenylephrine. Activation of charybdotoxin-sensitive K(+) channels was probably due to NO stores formed during the exposition to IL-1beta; 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO), either when added with IL-1beta or in the organ bath, partially restored the contractility of IL-1beta-treated vessels. The cPTIO effect was mimicked by combinations of cyclooxygenase and NO-synthase inhibitors and by charybdotoxin. cPTIO significantly inhibited prostacyclin formation and prostacyclin-synthase activity during incubation with the cytokine. cPTIO antagonized the effect of IL-1beta by scavenging NO, reducing prostacyclin-synthase activity, and avoiding the contribution activation of K(+) channels.
The Journal of Infectious Diseases 10/2003; 188(6):927-37. · 6.41 Impact Factor
