Increased PGE&lt;sub&gt;2&lt;/sub&gt; Levels in Nonmalignant Mucosa Adjacent to Squamous Cell Carcinoma of the Head and Neck

Schuon, Robert; Brieger, Juergen; Franke, R. L.; Jakob, R.P.; Mann, W

doi:10.1159/000084996

Cited by 9 publications

(6 citation statements)

References 49 publications

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“…This concept was supported by data showing that samples from surrounding nontumoral mucosa produced more PGE 2 than samples from tumor. This is in agreement with data reported by Schuon et al ( 39 ), who found high levels of PGE 2 in the tumor-surrounding nonmalignant mucosa in patients with HNSCC. PGE 2 -dependent tumor angiogenesis has been attributed to COX-2 and mPGES-1 expression in tumors such as HNSCC (5,(40)(41)(42).…”

Section: Discussionsupporting

confidence: 94%

Interaction between head and neck squamous cell carcinoma cells and fibroblasts in the biosynthesis of PGE2

Alcolea

Antón

Camacho

et al. 2012

Journal of Lipid Research

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Eicosanoids derived from polyunsaturated fatty acids are soluble mediators that exert a key role in the physiopathology of many disorders, including infl ammation, thrombosis, and cancer. Prostanoids derived from arachidonic acid (AAc) through the cyclooxygenase (COX) pathway are particularly relevant. The increasing interest in the role of prostanoids in the context of cancer originates in the large epidemiological trials that showed that COX-inhibiting nonsteroidal anti-infl ammatory drugs could be benefi cial against the development and growth of malignancies ( 1 ).Prostaglandin (PG)H 2 is the common cyclic-peroxide intermediate in the biosynthesis of prostanoids derived from AAc. The other prostanoids are formed in reactions catalyzed by specifi c synthases acting on PGH 2 ( 2 ). In contrast with the ubiquitous expression of COXs, expression of downstream synthases confers a cell-specifi c prostanoid profi le. COX-2 receives the most attention because, unlike COX-1, which is widely expressed, its expression is restricted in nonpathologic settings to a few cell types and tissues, but it is over-expressed in a wide range of cell types in tumors and infl amed tissues. COX-2 is transiently and Abstract Prostaglandin (PG)E 2 is relevant in tumor biology, and interactions between tumor and stroma cells dramatically infl uence tumor progression. We tested the hypothesis that cross-talk between head and neck squamous cell carcinoma (HNSCC) cells and fi broblasts could substantially enhance PGE 2 biosynthesis. We observed an enhanced production of PGE 2 in cocultures of HNSCC cell lines and fi broblasts, which was consistent with an upregulation of COX-2 and microsomal PGE-synthase-1 ( mPGES-1) in fi broblasts. In cultured endothelial cells, medium from fi broblasts 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-1 ␣ levels were higher than those of IL-1 ␤ in the tumor cell-conditioning medium and in the secretion from samples obtained from 20 patients with HNSCC. Fractionation of tumor cellconditioning media indicated that tumor cells secreted mature and unprocessed forms of IL-1. Our results support the concept that tumor-associated fi broblasts 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 fi ndings also strengthen the concept that mPGES-1 may be \a target for therapeutic intervention in patients with HNSCC. Abbreviations: AAc, arachidonic acid; COX, cyclooxygenase; cPGES, cytosolic isoform of prostaglandin E synthase; FaDu-CM, FaDu-conditioned medium; HNSCC, head and neck squamous cell carcinoma; HUVEC, human umbilical vein endothelial cells; IL-1ra, interleukin-1 receptor antagonist; mPGES-1, microsomal prostaglandin E-synthase-1; MW, molecular weig...

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Section: Discussionsupporting

confidence: 94%

Interaction between head and neck squamous cell carcinoma cells and fibroblasts in the biosynthesis of PGE2

Alcolea

Antón

Camacho

et al. 2012

Journal of Lipid Research

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“…Consequently, HNSCC are able to secrete PGE2 16,18-19, but the contribution of PGE2 receptors to HNSCC progression is not fully established. In colon cancer, COX-2 overexpression and PGE2 production is often linked with EP2 activation, which triggers growth promoting signaling pathways such as β-catenin20 as well as leukocyte recruitment and angiogenesis21 by multiple G-protein regulated intracellular signaling pathways4, 21, 22.…”

Section: Discussionmentioning

confidence: 99%

A role for COX2-derived PGE2 and PGE2-receptor subtypes in head and neck squamous carcinoma cell proliferation

et al. 2010

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The overexpression of cyclooxygenase (COX)-2 is a frequent event in squamous cell carcinomas of the head and neck (HNSCC), and non-steroidal anti-inflammatory drugs, which are potent inhibitors of COX-1 and COX-2, exert chemopreventive effects on HNSCC cancer development. COX-2 promotes the release of the pro-inflammatory mediator prostaglandin E2 (PGE2), which acts on its cell surface G protein-coupled receptors EP1, EP2, EP3, and EP4. Here, we investigated the role of PGE2 and its receptors in cellular proliferation in HNSCC. The expression of COX-2 and EP1-4 was examined in immortalized oral epithelial cells and in a representative panel of HNSCC cell lines, and based on these data EP1-EP3 and COX-2 expression were evaluated by immunohistochemistry in a large clinical sample collection using HNSCC tissue microarrays. The ability of selective COX-2 inhibition to block PGE2 secretion was measured by ELISA specific assays. The effects of PGE2 on cell proliferation were evaluated using PGE2, its stable analog, and EP2 and EP3-specific synthetic agonists. The results presented here show that HNSCC tumoral lesions and their derived cell lines constitutively express COX-2 and the EP1, EP2 and EP3 receptors for PGE2. HNSCC cells secrete PGE2, which can be suppressed by low concentrations of COX-2 selective inhibitors, without inhibiting cell proliferation. Exogenously added stable PGE2 and EP3-specific agonists induce DNA synthesis in all HNSCC cell lines tested. Overall, our study supports the emerging notion that PGE2 produced in the tumor microenvironment by the overexpression of COX-2 in tumoral and inflammatory cells may promote the growth of HNSCC cells in an autocrine and paracrine fashion by acting on PGE2 receptors that are widely expressed in most HNSCC cancer cells. In particular, our findings suggest that EP3 receptor may play a more prominent role in HNSCC cell growth promotion, thus providing a rationale for the future evaluation of this PGE2 receptor as a target for HNSCC prevention strategies.

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“…Overexpression of cycloxygenase‐2 (COX‐2) in the oral mucosa has been associated with increased risk of head and neck cancer 6, 9–13. Several processes linked to carcinogenesis can be influenced by the enhanced synthesis of prostaglandin E 2 (PGE 2 ) 14–17. Therefore, COX‐2 has been intensively studied for development of chemopreventive agents.…”

mentioning

confidence: 99%

Salvianolic acid B inhibits growth of head and neck squamous cell carcinoma in vitro and in vivovia cyclooxygenase‐2 and apoptotic pathways

Hao

Xie²,

Korotcov

et al. 2009

Intl Journal of Cancer

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Overexpression of cyclooxygenase‐2 (COX‐2) in oral mucosa has been associated with increased risk of head and neck squamous cell carcinoma (HNSCC). Celecoxib is a nonsteroidal anti‐inflammatory drug, which inhibits COX‐2 but not COX‐1. This selective COX‐2 inhibitor holds promise as a cancer preventive agent. Concerns about cardiotoxicity of celecoxib, limits its use in long‐term chemoprevention and therapy. Salvianolic acid B (Sal‐B) is a leading bioactive component of Salvia miltiorrhiza Bge, which is used for treating neoplastic and chronic inflammatory diseases in China. The purpose of this study was to investigate the mechanisms by which Sal‐B inhibits HNSCC growth. Sal‐B was isolated from S. miltiorrhiza Bge by solvent extraction followed by 2 chromatographic steps. Pharmacological activity of Sal‐B was assessed in HNSCC and other cell lines by estimating COX‐2 expression, cell viability and caspase‐dependent apoptosis. Sal‐B inhibited growth of HNSCC JHU‐022 and JHU‐013 cells with IC50 of 18 and 50 μM, respectively. Nude mice with HNSCC solid tumor xenografts were treated with Sal‐B (80 mg/kg/day) or celecoxib (5 mg/kg/day) for 25 days to investigate in vivo effects of the COX‐2 inhibitors. Tumor volumes in Sal‐B treated group were significantly lower than those in celecoxib treated or untreated control groups (p < 0.05). Sal‐B inhibited COX‐2 expression in cultured HNSCC cells and in HNSCC cells isolated from tumor xenografts. Sal‐B also caused dose‐dependent inhibition of prostaglandin E2 synthesis, either with or without lipopolysaccharide stimulation. Taken together, Sal‐B shows promise as a COX‐2 targeted anticancer agent for HNSCC prevention and treatment. © 2008 Wiley‐Liss, Inc.

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Increased PGE<sub>2</sub> Levels in Nonmalignant Mucosa Adjacent to Squamous Cell Carcinoma of the Head and Neck

Cited by 9 publications

References 49 publications

Interaction between head and neck squamous cell carcinoma cells and fibroblasts in the biosynthesis of PGE2

Interaction between head and neck squamous cell carcinoma cells and fibroblasts in the biosynthesis of PGE2

A role for COX2-derived PGE2 and PGE2-receptor subtypes in head and neck squamous carcinoma cell proliferation

Salvianolic acid B inhibits growth of head and neck squamous cell carcinoma in vitro and in vivovia cyclooxygenase‐2 and apoptotic pathways

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