Suppression of Intestinal Polyposis in ApcΔ716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2)

Oshima, Masanobu; Dinchuk, Joseph; Kargman, Stacia; Oshima, Hiroko; Hancock, Bruno C.; Kwong, Elizabeth; Trzaskos, James M.; Evans, Jilly F.; Taketo, Makoto Mark

doi:10.1016/s0092-8674(00)81988-1

Cited by 2,131 publications

(1,421 citation statements)

References 33 publications

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“…The median number of COX-2-positive superficial stromal cells in colon carcinomas was 212.8/mm 2 (Table 1). There was neither association between the number of COX-2-positive superficial stromal cells and VEGF expression and microvessel density (P ¼ 0.29 and 0.81, respectively).…”

Section: Cox-2 Expressing Stromal Cellsmentioning

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: Cox-2 Expressing Stromal Cellsmentioning

confidence: 99%

“…In animal models, COX-2 knockout or treatment with specific COX-2 inhibitors reduces intestinal tumor development. [2][3][4][5] COX-2 tumor promotion probably involves different biological mechanisms, among them being the induction of tumor angiogenesis. 6 Indeed, COX-2 overexpression in colon cancer cells regulates angiogenesis in vitro and in vivo.…”

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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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“…Expression of both COX-2 and mPGES-1 is also induced in a variety of cancer tissues 8 . It is established that COX-2 plays a key role in gastrointestinal cancer development 9 , and inhibition of COX-2 in mouse models by selective inhibitors suppresses gastric and intestinal tumorigenesis 10,11 . Furthermore, PGE 2 is also implicated in gastrointestinal tumor development 12,13 .…”

Section: Introductionmentioning

confidence: 99%

Carcinogenesis in Mouse Stomach by Simultaneous Activation of the Wnt Signaling and Prostaglandin E2 Pathway

et al. 2006

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“…Numerous studies indicate that Cox-2 is overexpressed in 85-90% of cancerous tissues from human colon and inhibition of Cox-2 by nonsteroidal anti-inflammatory drugs decreases the risk of colorectal cancer (revised by Gupta and Dubois, 2001;Chan, 2002). Experiments with Apc gene-deficient mice (Min mice) and Apc D716 /Cox-2 double-knockout mice revealed that either pharmacologic inhibition or genetic ablation of Cox-2 resulted in reduced intestinal tumorigenesis (Oshima et al, 1996;Williams et al, 1996). Enhanced synthesis of Cox-2-derived PGs may favor tumor growth by stimulating cell proliferation, promoting angiogenesis, inducing local immunosuppression, increasing invasiveness and inhibiting apoptosis (Kawai et al, 2002;Iniguez et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells

et al. 2006

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Cyclooxygenase-2 (Cox-2), the gastrin-release peptide (GRP) and its cognate receptor (GRP-R) are overexpressed in a significant percentage of colorectal carcinomas and are associated with cell growth, invasiveness and tumor progression. However, a molecular link between all of them in adenocarcinomas has not been established. Here, we show that bombesin (BBS), a GRP homolog, stimulates the expression of Cox-2 mRNA and protein in human colon adenocarcinoma Caco-2 cells, resulting in enhanced release of prostaglandin E 2 . These effects were markedly inhibited by the specific BBS antagonist RC-3940-II. BBS promotes the activation of the nuclear factor of activated T cells (NFAT) through a Ca 2 þ /calcineurin (Cn)-linked pathway. Upon BBS stimulation, the NFATc1 isoform translocates into the nucleus with a concomitant increase in NFATc1 binding to two specific recognition sites in the promoter region of the Cox-2 gene. Furthermore, inhibition of Cn activity by the immunosuppressive drug cyclosporin A impaired NFAT activation and diminished Cox-2 expression in BBSstimulated cells. Interestingly, BBS pretreatment strongly enhances the invasive capacity of carcinoma cells, effect which was inhibited by a Cox-2-specific inhibitor. These findings provide the first evidence for the involvement of the Ca 2 þ /Cn/NFAT pathway in BBS-mediated induction of genes involved in colon carcinoma invasiveness such as Cox-2. Oncogene (2007) 26, 958-969.

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Suppression of Intestinal Polyposis in ApcΔ716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2)

Cited by 2,131 publications

References 33 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

Carcinogenesis in Mouse Stomach by Simultaneous Activation of the Wnt Signaling and Prostaglandin E2 Pathway

Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells

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