In an effort to better understand the relationship, immunohistochemis try on paired tumour and normal mucosa from an addi tional 20 patients was performed to evaluate expression of AR and COX 2. COX 2 immunoreactivity was virtually absent in normal colonic mucosa. AR expression was detectable EPZ-5676 Histone Methyltransferase in all of the normal samples, Inhibitors,Modulators,Libraries with Inhibitors,Modulators,Libraries a character istic pattern of expression, being observed in the cyto plasm of the surface columnar epithelial cells while absent or reduced in crypt epithelial cells. Dif ferential expression of AR along the colonic crypt has been described previously. COX 2 and AR expression in tumour tissue showed greater variability. Six of twenty cases showed absent or low level for both COX 2 and AR.

In the remainder of patients, significant immunoreactivity Inhibitors,Modulators,Libraries for both molecules was observed and a concordance was observed in the localisation of positive staining within tumour specimens. COX 2 expression was observed exclusively in the cytoplasm of tumour epithelial cells. AR expression was mostly cyto plasmic, but focal areas of positive nuclear staining were also observed. Discussion COX 2 expression in colorectal tumours is biologically and clinically important and PGE2 is the major product of COX 2 activity in cancer cells. Four subtypes of membrane PGE2 receptor have been character ised, although the relative contribution of each of these to key signalling events in cancer has not been fully elucidated. We show that all of the EP receptor sub types are expressed in human colorectal cancers and that EP4 receptor is predominant.

We also demonstrate Inhibitors,Modulators,Libraries that the HT 29 cells share this relative distribution of recep tors, validating its use as an in vitro model. Animal studies demonstrate that all four EP receptors are expressed in azoxymethane induced tumours in rats. Forced expression of COX 2 in murine mam mary epithelial cells is associated with induction of EP 1, 2 and 4 receptors and down regulation of EP3. Knockout mice deficient in all four subtypes of EP receptor and with deletions of the DP, FP, IP or TP receptors have been gen erated. Inhibitors,Modulators,Libraries The formation of aberrant crypt foci follow ing AOM treatment was only different in animals with deletions of the EP1 and the EP4 receptor. While no difference in ACF formation with deletion of the EP2 receptor was detected. decreased polyp formation has been observed with deletion of the EP2 receptor in Apc?716 mice.

There are limited data on the relative expression of these receptors in CRC in humans. A down regulation of the EP3 receptor has recently been reported in human color ectal tumours. Paradoxically, a study combining immunocytochemistry and in situ hybridisation showed that EP3 selleck chem and EP4 were the major receptors expressed in adenomatous pol yps in patients with FAP. A further study failed to demonstrate EP4 receptor or COX 2 mRNA induction in tumour specimens. However, these observations are at variance with our findings and those of others.