including EP2, EP1, LTB4, bradykinin, nerve growth factor, and other receptors, these studies indicate that EP3 receptors contribute to the perception of at least certain types of pain in mice and may also do so in humans. Cancer Studies of the direct effects of EP3 receptor activation on cancer in animal and tissue models give contradictory results suggesting that this receptor does not play an important role in Carcinogenesis. However, some studies suggest an indirect pro-carcinogenic function for the EP3 receptor: The growth and metastasis of implanted Lewis lung carcinoma cells, a mouse lung cancer cell line, is suppressed in EP3 receptor deficient mice. This effect was associated with a reduction in the levels of Vascular endothelial growth factor and matrix metalloproteinase-9 expression in the tumor's stroma; expression of the pro-lymphangiogenic growth factor VEGF-C and its receptor, VEGFR3; and a tumor-associated angiogenesis and lymphangiogenesis. Clinical significance Therapeutics Many drugs that act on EP3 and, often, other prostaglandin receptors, are in clinical use. A partial list of these includes: Misoprostol, an EP3 and EP4 receptor agonist, is in clinical use to prevent ulcers, to induce labor in pregnancy, medical abortion, and late miscarriage, and to prevent and treat postpartum bleeding (see Misoprostol). Sulprostone, relatively selective EP3 receptor agonist with a weak ability to stimulate the EP1 receptor is in clinical use for inducing medical abortion and ending pregnancy after fetal death (see Sulprostone). Iloprost activates EP2, EP3, and EP4 receptors; it is in clinical use to treat diseases involving pathological constriction of blood vessels such as pulmonary hypertension, Raynauds disease, and scleroderma. Presumably, Iloprost works by stimulating EP2, and EP4 receptors which have vasodilation actions. Other drugs are in various stages of clinical development or have been proposed to be tested for clinical development. A sampling of these includes: Enprostil, which binds to and activates primarily the EP3 receptor, was found in a prospective multicenter randomized controlled trial conducted in Japan to significantly improve the effects of cimetidine in treating gastric ulcer. It is considered to be an efficient and safe treatment for gastric and duodenal ulcers. ONO-9054 (Sepetoprost), a dual an EP3/Prostaglandin F receptor agonist, is in phase 1 clinical trial studies for the treatment of ocular hypertension and open-angle glaucoma. DG-041, a highly selective EP3 antagonist, has been proposed to warrant further study as anti-thrombosis agent. GR 63799X, MB-28767, ONO-AE-248, and TEI-3356 are putative EP3 receptor-selective agonists that have