Patients with adenomatous polyps and carcinomas have increased colonic mucosal prostaglandin E2.

Pugh, Stirling; Thomas, G. A. O.

doi:10.1136/gut.35.5.675

Cited by 243 publications

(149 citation statements)

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“…6,31 PGE 2 levels have been reported to be elevated in colorectal cancer compared with normal colorectal tissue. 32 Thus, PGE 2 may promote tumor progression via its action on cell surface EP 1-4 receptors in both tumor and tumor-surrounding normal cells. 6 However, there are contradictory reports on which EP receptor(s) that mediate effects by PGE 2 , where some reports claim that main effects are mediated mainly through nuclear receptors, (PPARs), although some evidence suggests that PPAR activation does not explain antiproliferative effects by NSAIDs.…”

Section: Discussionmentioning

confidence: 99%

EP_1–4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease‐specific mortality

Gustafsson

Hanssoń

Kressner

et al. 2007

Intl Journal of Cancer

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The importance of prostaglandins in tumor growth and progression is well recognized, including antineoplastic activities by cyclooxygenase (COX) inhibitors. Variation in treatment response to COX inhibition has questioned differences in expression of cell surface and nuclear membrane receptors among tumors with different disease progression. The purpose of this study was to evaluate whether EP 1-4 subtype, PPARc receptor and COX-1/COX-2 expression in colorectal cancer are related to tumor-specific mortality. Reverse transcription-polymerase chain reaction and immunohistochemistry were used to demonstrate expression and protein appearance in tumor tissue compared with normal colon tissue. EP 1 and EP 2 subtype receptor protein was highly present in tumor cells, EP 3 occurred occasionally and EP 4 was not visible. PPARc, EP 2 and EP 4 mRNA were significantly higher in normal colon tissue compared with tumor tissue, without any distinct relationship to Dukes A-D tumor stage. Multivariate analyses indicated that increased tumor tissue EP 2 and COX-2 expression predicted poor survival (p < 0.001). COX-1 expression was significantly higher than COX-2 expression in normal colon tissue. Average COX-2 mRNA was not increased in tumor tissue compared with normal colon. However, most tumor cells stained positive for COX-2 protein, which was low or undetectable in normal mucosa cells. COX-1 protein was preferentially visible in stroma. EP 1-4 subtype receptor mRNAs were generally positively correlated to both COX-1 and COX-2 in tumor tissue, but not in normal colon. Our results imply that both prostaglandin production (COX-2) and signaling via EP 1-4 subtype receptors, particularly EP 2 , predict disease-specific mortality in colorectal cancer ' 2007 Wiley-Liss, Inc.Key words: PGE 2 ; colon cancer; COX-1; COX-2; PPARc; EPreceptors It is well recognized that eicosanoids are related to growth and progression of experimental and clinical cancer. 1,2 Previous studies have also indicated that certain tumors may be more or less sensitive to alterations in prostaglandins (PGs) from both host and tumor cells, where prostanoids may act as either autocrine or paracrine mediators. Accordingly, our own research has demonstrated that both murine and human tumor progression can be attenuated by provision of cyclooxygenase (COX) inhibitors such as indomethacin, 1,3,4 although it is also clear that not all tumors are responsive to COX-treatment. 3 On the contrary, our recent experimental work has indicated that different nonsteroidal anti-inflammatory drugs (NSAIDs) are differently potent to attenuate tumor growth. 2 Preliminary studies in EP receptor knockout and wildtype tumor-bearing mice have also confirmed that EP 1-4 subtype receptor expression in cell surface membranes explains some variability among responders and nonresponders. 2 Our clinical studies demonstrate that human tumor disease may respond favorable to indomethacin treatment when provided adjunct in palliative care, although it is clear that even tumor-hosts reactions can ...

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Section: Discussionmentioning

confidence: 99%

EP_1–4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease‐specific mortality

Gustafsson

Hanssoń

Kressner

et al. 2007

Intl Journal of Cancer

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“…Aspirin covalently and irreversibly modifies the cyclo-oxygenase active site of both PGHS-1 and PGHS-2 by acetylation, whereas other NSAIDs reversibly block PGHS function and thus prostaglandin production via steric hindrance of the cyclo-oxygenase active site (Smith and DeWitt, 1996 (Marnett, 1992). These include: evidence that PGs stimulate proliferation of human colon cancer cell lines in vitro and normal rodent colon epithelial tissue in vivo (Qiao et al, 1995); evidence that progressively increased tissue prostaglandin EB (PGE2) levels are associated with progression of colon carcinogenesis (Pugh and Thomas, 1994); and a possible immunosuppressive effect of PGE2 (Goodwin, 1981). Thus, NSAID inhibition of intestinal prostaglandin production may have a number of direct chemopreventive activities against the progression of colorectal cancer.…”

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confidence: 99%

Non-steroidol anti-inflammatory drug effect on crypt cell proliferation and apoptosis during initiation of rat colon carcinogenesis

Barnes

Cameron²,

Hardman³

et al. 1998

Br J Cancer

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Summary Sustained use of non-steroidal anti-inflammatory drugs (NSAIDs) may prevent colorectal cancer. However, the optimal drug, period of efficacy and mechanism(s) of action are unknown. Experiments were undertaken to determine which of several NSAIDs would modulate colon crypt cell proliferation or apoptosis when given during the initiation phase of 1,2-dimethylhydrazine (DMH)-induced rat colon cancer. Colon crypts located both away from and over an aggregate of lymphoid nodules (ALN) were examined. Rats were injected with aspirin, indomethacin, nabumetone, sodium salicylate, 16,16-dimethyl prostaglandin E2 or saline for 3 days and DMH or DMH vehicle on day 4 of each week for 8 weeks, then killed 3 days after the last DMH injection. At the time of killing, DMH had significantly increased crypt cell proliferation but not apoptosis. There was significantly more cell proliferation and apoptosis in crypts over the ALN than away from the ALN. Aspirin and salicylate increased proliferation and apoptosis in crypts over the ALN. Finally, the distributional peaks of cell proliferation and apoptosis were shifted significantly closer together after DMH. Thus, DMH increases proliferation and alters the distribution of proliferating and apoptotic cells in colon crypts early in carcinogenesis. Aspirin may suppress tumour incidence via salicylate by enhancing apoptosis in carcinogen-initiated cells.Keywords: colon cancer; proliferation; apoptosis; non-steroidal anti-inflammatory drugs; lymphoid nodules; 1,2-dimethylhydrazine Data from human epidemiological research (Thun, 1994;Giovannucci et al, 1995) and from rodent experimental research (Craven and DeRubertis, 1992;Reddy et al, 1993) have demonstrated both correlative and direct evidence of a role for aspirin and possibly other non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of colon and rectal cancer morbidity and mortality. However, the optimal NSAID, the dose, the period of efficacy and the mechanism of this putative chemopreventive activity remain to be established (Earnest et al, 1992;Giardiello et al, 1995).One potential mechanism for this chemopreventive effect lies in the ability of aspirin and other NSAIDs to inhibit prostaglandin production by blocking the activity of one or both of the prostaglandin endoperoxide G/H synthase (PGHS) isozymes, PGHS-1 and PGHS-2 (Meade et al, 1993). PGHS-l is the constitutive form of the enzyme and is expressed in most tissues, whereas PGHS-2 is induced by mitogenic stimuli in inflammatory situations (Smith and DeWitt, 1996) and is expressed at high levels in colon tumour tissue (Eberhart et al, 1994;Kargman et al, 1995;Dubois et al, 1996). Aspirin covalently and irreversibly modifies the cyclo-oxygenase active site of both PGHS-1 and PGHS-2 by acetylation, whereas other NSAIDs reversibly block PGHS function and thus prostaglandin production via steric hindrance of the cyclo-oxygenase active site (Smith and DeWitt, 1996 (Marnett, 1992). These include: evidence that PGs stimulate proliferation of human colon can...

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“…PGE 2 , the most abundant gastrointestinal PG, regulates many of the normal homeostatic functions of the gut, including motility and secretion (18,31,53). Furthermore, PGE 2 influences mitogenesis (28), promotes growth of tumors (42), and stimulates gene transcription (47). PGE 2 upregulates VEGF in activated macrophages through a receptor-mediated mechanism (3).…”

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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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Patients with adenomatous polyps and carcinomas have increased colonic mucosal prostaglandin E2.

Cited by 243 publications

References 15 publications

EP_1–4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease‐specific mortality

EP_1–4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease‐specific mortality

Non-steroidol anti-inflammatory drug effect on crypt cell proliferation and apoptosis during initiation of rat colon carcinogenesis

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

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Patients with adenomatous polyps and carcinomas have increased colonic mucosal prostaglandin E2.

Cited by 243 publications

References 15 publications

EP1–4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease‐specific mortality

EP1–4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease‐specific mortality

Non-steroidol anti-inflammatory drug effect on crypt cell proliferation and apoptosis during initiation of rat colon carcinogenesis

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

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EP_1–4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease‐specific mortality

EP_1–4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease‐specific mortality

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