Prostaglandin E2 and the EP receptors in malignancy: Possible therapeutic targets?

Elevated expression of COX-2 and increased levels of PGE₂ are found in numerous cancers and are associated with tumour development and progression. Although epidemiological, clinical and preclinical studies have shown that the inhibition of PGE₂ synthesis through the use of either non-steroidal anti-inflammatory drugs (NSAIDs) or specific COX-2 inhibitors (COXibs) has the potential to prevent and treat malignant disease, toxicities due to inhibition of COX-2 have limited their use. Thus, there is an urgent need for the development of strategies whereby COX-2 activity may be reduced without inducing any side effects. The biological effects of PGE₂ are mediated by signalling through four distinct E-type prostanoid (EP) receptors - EP₁, EP₂, EP₃ and EP₄. In recent years, extensive effort has gone into elucidating the function of PGE₂ and the EP receptors in health and disease, with the goal of creating selective inhibitors as a means of therapy. In this review, we focus on PGE₂, and in particular on the role of the individual EP receptors and their signalling pathways in neoplastic disease. As knowledge concerning the role of the EP receptors in cancer grows, so does the potential for exploiting the EP receptors as therapeutic targets for the treatment of cancer and metastatic disease.