007. INFLAMMATORY PATHWAYS IN ENDOMETRIAL CANCER 

Abstract

Endometrial cancer is the most common gynaecological malignancy and accounts for 5% of cancers in women (http://info.cancerresearchuk.org/cancerstats/). The majority of endometrial cancers occur in post-menopausal women and 80% of patients are diagnosed when the tumour is confined to the uterus (stage 1 disease). Many of the risk factors for developing endometrial cancer are associated with excess exposure to oestrogen unopposed by progesterone. It is well established that local inflammatory pathways contribute to the initiation and progression of endometrial cancers via the release of local mediators to facilitate immune cell recruitment, angiogenesis and neoplastic cell proliferation and metastasis. Prostaglandins are one class of molecules that are important mediators of these processes. Prostaglandins are bioactive lipids produced from arachidonic acid by cyclooxygenase (COX) enzymes and specific terminal prostanoid synthase enzymes. Following biosynthesis, prostaglandins are rapidly transported outside the cell and exert an autocrine/paracrine function by coupling to specific prostanoid G protein-coupled receptors (GPCR). Expression of COX enzyme, synthesis of prostaglandins and expression of various prostaglandin receptors are elevated in pathologies of the endometrium including cancer. Using genome wide array analysis, we have identified target genes that are regulated by prostaglandins such as PGF2α via interaction with its GPCR - FP receptor. Gene ontology analysis have highlighted significant elevation in expression of genes involved in inflammatory and vascular processes which are central to endometrial function. Moreover, using an array of cellular and molecular techniques and in vivo models we have established an important role for PGF2α-FP interaction in regulating inflammatory and vascular functions. To-date, suppression of the activity of prostaglandins in pathology has focussed on using inhibitors of cyclooxygenase enzymes, which are key enzymes in the pathway to prostaglandin synthesis. However, this has been associated with serious cardiovascular side effects. Development of novel drugs that target specific receptors may provide better therapeutic alternatives.