Cyclooxygenase 2 expression is increased in the stroma of colon carcinomas from IL–10−/− mice

Shattuck-Brandt, Rebecca L.; Varilek, Gary W.; Aramandla, Radhika; Yang, Fajun; Washington, M. Kay; DuBois, Raymond N.

doi:10.1016/s0016-5085(00)70216-2

Cited by 160 publications

(111 citation statements)

References 24 publications

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“…12,14,36 Some authors found that COX-2-positive interstitial cells correspond mainly to macrophages [10][11][12] but others demonstrate COX-2 expression mainly in fibroblasts. 13,14 Our results indicate that superficial fibroblasts and myofibroblasts may express cytoplasmic PLA2 as well as COX-2 and are thus in accordance with these latter studies. In these superficial stromal cells, COX-2 was situated in the cytoplasm and the perinuclear region in accordance with the endoplasmic reticulum and perinuclear membrane localization of COX-2.…”

Section: Discussionsupporting

confidence: 91%

“…[7][8][9] In colon adenomas and carcinomas, COX-2 is overexpressed in tumor cells but also in interstitial stromal cells. [10][11][12][13][14] COX-2 overexpression in interstitial stromal cells also induces tumor angiogenesis in several models of tumor development. 15,16 In intestinal tumors, angiogenesis induced by COX-2 expressing interstitial stromal cells is mediated by prostaglandin E2 through EP2 prostaglandin E2 receptor signaling.…”

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confidence: 99%

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Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer

et al. 2005

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In colorectal cancer, cyclooxygenase-2 (COX-2) overexpression in stromal cells induces angiogenesis through EP2 prostaglandin E2 receptor signaling. Cytoplasmic phospholipase A2 (PLA2) alpha preferentially hydrolyses arachidonic acid, which is the limiting substrate for prostaglandin production, from membrane phospholipids. We therefore investigated a possible relationship between cytoplasmic PLA2 and COX-2 overexpression in stromal cells, angiogenesis and microsatellite instability in 48 human colorectal adenocarcinomas. Cytoplasmic PLA2 and COX-2 expression in stromal cells and vascular endothelial growth factor (VEGF) expression in tumor cells were evaluated by immunohistochemistry. Microvessel density was assessed in 10 Â 400 fields after CD31 staining. Microsatellite instability was evaluated by PCR and immunohistochemistry. A total of 16 tumors had microsatellite instability. We found an overexpression of cytoplasmic PLA2 in superficial stromal cells. These cells corresponded to fibroblasts and myofibroblasts. There was an association between the number of cytoplasmic PLA2 and COX-2-expressing cells (P ¼ 0.006). Cytoplasmic PLA2-positive stromal cells usually also expressed COX-2. A high number of cytoplasmic PLA2-positive stromal cells was correlated with a high microvessel density (P ¼ 0.002), a strong VEGF (P ¼ 0.01) and the absence of microsatellite instability (P ¼ 0.001). The coordinate overexpression of cytoplasmic PLA2 and COX-2 in stromal cells could lead to an important prostaglandin production. These results suggest that cytoplasmic PLA2 overexpression in these cells regulates COX-induced angiogenesis probably by providing arachidonic acid, which is the limiting factor for prostaglandin production. The lower number of cytoplasmic PLA2-positive stromal cells in carcinomas with microsatellite instability could be related to their lower microvessel density and VEGF expression.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer

et al. 2005

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“…COX-1 is constitutively expressed in the mouse gastrointestinal tract; it can, however, be induced by radiation injury (10). COX-2 is barely detectable in the gastrointestinal tract under normal conditions, but it is induced in response to a wide variety of proinflammatory cytokines and mitogenic stimuli, including IL-1␤ and TNF-␣ (46,48,50), and is upregulated in some epithelial neoplasms (14,15,54). PGE 2 , the most abundant gastrointestinal PG, regulates many of the normal homeostatic functions of the gut, including motility and secretion (18,31,53).…”

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confidence: 99%

Prosurvival and antiapoptotic effects of PGE₂in radiation injury are mediated by EP₂receptor in intestine

Houchen

Sturmoski

Anant

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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The biological activities of PGE2 are mediated through EP receptors (EP1–EP4), plasma membrane G protein-coupled receptors that differ in ligand binding and signal-transduction pathways. We investigated gastrointestinal EP2 receptor expression in adult mice before and after radiation injury and evaluated intestinal stem cell survival and crypt epithelial apoptosis after radiation injury in EP2 null mice. EP2 was expressed throughout the gut. Intestinal EP2 mRNA increased fivefold after γ-irradiation. Crypt survival was diminished in EP2 −/− mice (4.06 crypts/cross section) compared with wild-type littermates (8.15 crypts/cross section). Radiation-induced apoptosis was significantly increased in EP2 −/− mice compared with wild-type littermates. Apoptosis was 1.6-fold higher in EP2 −/− mice (5.9 apoptotic cells/crypt) than in wild-type mice (3.5 apoptotic cells/crypt). The EP2receptor is expressed in mouse gastrointestinal epithelial cells and is upregulated following radiation injury. The effects of PGE2on both crypt epithelial apoptosis and intestinal crypt stem cell survival are mediated through the EP2 receptor.

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“…Increased COX-2-derived prostaglandin (PG) synthesis has been repeatedly documented during acute and chronic intestinal inflammation (16,49). Although epithelial COX-2 expression has been demonstrated following invasion by Salmonella (13) and in individuals suffering from Crohn's disease and ulcerative colitis (51), significant expression of COX-2 in the lamina propria also occurs.…”

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confidence: 99%

“…For example, in a rat model of colitis, increased COX-2 mRNA levels are found in cells of the lamina propria and muscularis of the colon, in regions occupied by mast cells, neutrophils, smooth muscle cells, and subepithelial myofibroblasts (41). Likewise, recent studies using a rat model of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulceration (45), murine colitis (49), or ulcerated human specimens (24) have localized COX-2 expression to cells in the lamina propria that are consistent with myofibroblasts.…”

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confidence: 99%

Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction

Mifflin¹,

Saada²,

Mari³

et al. 2002

American Journal of Physiology-Cell Physiology

130

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Elevated mucosal interleukin-1 (IL-1) levels are frequently seen during acute and chronic intestinal inflammation, and IL-1 neutralization lessens the severity of inflammation. One major effect of IL-1 is the increased release of eicosanoid mediators via induction of cyclooxygenase-2 (COX-2). One site of COX-2-derived prostaglandin synthesis during acute and chronic intestinal inflammation is the intestinal myofibroblast. COX-2 expression has also been documented in these cells in colonic neoplasms. Thus an understanding of the regulation of COX-2 expression in human intestinal myofibroblasts is important. As an initial step toward this goal we have characterized IL-1α signaling pathways that induce COX-2 expression in cultured human intestinal myofibroblasts. IL-1 treatment resulted in a dramatic transcriptional induction of COX-2 gene expression. Activation of nuclear factor-κB (NF-κB), extracellular signal-regulated protein kinase (ERK), p38, and protein kinase C (PKC) signaling pathways was each necessary for optimal COX-2 induction. In contrast to what occurs in other cell types, including other myofibroblasts such as renal mesangial cells, PKC inhibition did not prevent IL-1-induced NF-κB or mitogen activated protein kinase/ stress-activated protein kinase activation, suggesting a novel role for PKC isoforms during this process. The stimulatory effects of PKC, NF-κB, ERK-1/2, and presumably c-Jun NH2-terminal kinase activation were exerted at the transcriptional level, whereas p38 activation resulted in increased stability of the COX-2 message. We conclude that, in intestinal myofibroblasts, IL-1-mediated induction of COX-2 expression is a complex process that requires input from multiple signaling pathways. Each parallel pathway acts in relative autonomy, the sum of their actions culminating in a dramatic increase in COX-2 transcription and message stability.

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Cyclooxygenase 2 expression is increased in the stroma of colon carcinomas from IL–10−/− mice

Cited by 160 publications

References 24 publications

Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer

Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer

Prosurvival and antiapoptotic effects of PGE₂in radiation injury are mediated by EP₂receptor in intestine

Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction

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Cyclooxygenase 2 expression is increased in the stroma of colon carcinomas from IL–10−/− mice

Cited by 160 publications

References 24 publications

Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer

Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer

Prosurvival and antiapoptotic effects of PGE2in radiation injury are mediated by EP2receptor in intestine

Regulation of COX-2 expression in human intestinal myofibroblasts: mechanisms of IL-1-mediated induction

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Prosurvival and antiapoptotic effects of PGE₂in radiation injury are mediated by EP₂receptor in intestine