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

Abstract

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 ...

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

“…Along similar lines, evidence supports the involvement of the prostanoid receptors of the COX pathway. In particular, the four PGE receptors EP1-4 have been found to be positively correlated with COX-1 and -2 expression and tumour development, by affecting major signalling pathways such as the MAP kinase pathway as well as PPARγ-mediated transcription factor activation [163,164]. Therefore, it is questionable whether pursuing further upstream inhibitors of the AA cascade is the right way forward.…”

Receptor and enzyme expression for prostanoid metabolism in colorectal cancer related to tumor tissue PGE2

“…Therefore, it should be possible to specifically attenuate local and systemic progressive disease by understanding ligand receptor activities in prostanoid related metabolism and subsequently confirm main signaling pathways (12,23,27). In this context it is important to emphasize that up-regulation of COX-2 expression in tumor tissue is usually not a general phenomenon among tumor cells (3,28). Indeed, it is a scattered cellular phenomenon within colon cancer tumors showing 'hot spots' of COX-2 expression (28), reflected by overall lower content of transcripts for prostanoid related proteins in tumor tissue compared to normal colon tissue (3); contrary to findings in cell cultures of colon cancer (29).…”

“…We also investigated receptor and enzyme expression (subtype EP [1][2][3][4] , COX-1, COX-2, HPGD) in cultured colon cancer cells (HCA-7) in the presence of indomethacin, since PGE 2 is regarded a major prostaglandin produced by tumor cells (2). Specific effects by indomethacin on EP receptor expression were not apparent except for EP 1 .…”

“…Our previous investigations have indicated that expression of COX-2 and subtype EP 2 receptors in colorectal cancer tissue predict patient survival following intended curative operation (3). Thus, prostaglandins are involved in different metabolic pathways assumed to support tumor progression by alterations in cell proliferation, adhesion, migration, differentiation, apoptosis and angiogenesis (1,2,(4)(5)(6)(7)(8)(9)(10)(11).…”

“…Thus, cyclooxygenases are key enzymes in prostaglandin biosynthesis for conversion of arachidonic acid to the prostaglandin (PG) precursor PGH 2 , which is immediately converted to different prostaglandins (PGH 2 , PGE 2 , PGH 2· , PGI 2 /prostacyclin or TXA 2 ) depending on various cellular enzyme synthases (15). Net effects of COX enzymes in tumor tissue and cells depend on the balance between produced prostaglandins and interactions with corresponding receptors (3,11,(16)(17)(18). Enzymes catalyzing degradation of prostaglandins as 15-hydroxyprostaglandin dehydrogenase (HPGD) should also be of importance for overall tissue levels of PGE 2 (19), although less evaluated in relationship to tumor progression (12).…”