Prostaglandin E2 Receptor Function and Tumor Cell Metastasis

Prostaglandin receptors in many tissues have been described and the receptor for prostaglandin E₂ (PGE-R) has been studied extensively. In most tissues this receptor has a high affinity (K_d = nM); however, the capacity varies widely in different tissues. Recent successful cloning of one PGE-R should soon elucidate the structure of the receptor. In many tissues, PGE-R are coupled to adenyl cyclase to stimulate cAMP formation; however, PGE-R that inhibit cAMP, as well as PGE-R that are coupled to phosphoinositide metabolism, have been described. Despite this complexity, several schemes of classifying PGE-R have been proposed. Our studies in a murine mammary tumor system provide evidence for a functional role of the PGE-R in tumor metastasis. Using several PGE-R antagonists, we have shown that pharmacologic inhibition of [³H]PGE₂ binding and PGE₂-mediated cAMP elevation are associated with enhanced mammary tumor cell metastasis. These receptor antagonists also inhibit natural killer cell-mediated conjugation with and lysis of susceptible target cells. In addition, tumor cell adhesion to laminin is inhibited. Thus, we have proposed that the PGE-R may interact directly or indirectly with adhesive cell functions critical to the metastatic process.