The cyclooxygenase-2-mediated prostaglandin signaling is causally related to epithelial carcinogenesis

Epidemiologic, pharmacologic, clinical, and experimental studies document the importance of prostaglandin (PG) signaling in cancer development, including non-melanoma skin cancer lesions in humans and mice. First of all, enzymes involved in PG biosynthesis, such as cyclooxygenase (COX)-2 and/or membrane prostaglandin E synthase (mPGES)-1, were found to be overexpressed in a wide range of premalignant and malignant epithelial tumors, including those of the skin, breast, esophagus, stomach, colorectum, pancreas, and bladder. On the other hand, 15-hydroxy-prostaglandin dehydrogenase (15-PGDH), which is involved in the degradation pathway of PG including PGE(2,) thus counteracting the activities of COX-2 and PGES, was found to be downregulated in human epithelial tumors, indicating a tumor suppressor activity of this enzyme. Most remarkably, genetic studies showed that mice, which are deficient in COX-2 and/or PGES are resistant to the development of cancer of skin, colon, and stomach. In contrast, the forced overexpression of COX-2 in proliferative compartments of simple or stratified epithelia such as skin epidermis, urinary bladder, mammary gland, and pancreas results in spontaneous hyperplasia and dysplasia in transgenic mice. In skin, the pathological changes are found to be due to an abnormal process of terminal differentiation, while in other tissues, hyperproliferation seems to be the main contributor to the pre-invasive neoplasms. Moreover, the COX-2 transgenic mouse lines are sensitized for cancer development.