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 ...