Expression of COX-2 in Gastrointestinal Cancer : As a Target for Cancer Prevention and Therapy (1)

Prostaglandin (PG) E_2 plays a key role in colon carcinogenesis. Evidence continues to accumulate that cyclooxygenase (COX)-2, an inducible COX isoform, represents a potential pharmacological target for the prevention and treatment of cancer, including tumors affecting the large bowel. Several mechanisms of COX-2-related tumor promotion have been identified. Some (such as induction of cell proliferation, angiogenesis or local immunosuppression, inhibition of apoptosis, increase in cell motility) are dependent on PGE_2 production. COX-2 expression has been demonstrated in the epithelial cells of colorectal cancers and adenomas. Studies in experimental models of colon carcinogenesis show that selective COX-1 or COX-2 inhibitors reduce tumor formation and growth. Clinical studies have been initiated to determine the chemo-preventive effects of selective COX-2 inhibitors in patients with familial adenomatous polyposis. However, meta-analysis has revealed that COX-2 inhibitors can actuate cardiovascular events. Therefore, the possibility of cardiovascular effects will need to be taken into account in assessing the potential ability of any of these drugs to prevent neoplasia in the large bowel. Since PGE_2 was involved in most events related to carcinogenesis, further examinations focusing on microsomal prostaglandin E synthase-1 (mPGES-1), which is a catalyst in PGE_2 production, EP receptors, the receptors for PGE_2 that contribute to proliferation signaling, and 15-prostaglandin dehydrogenase (15-PGDH), which degrades PGE_2 as a tumor suppressor, should all be targeted in the quest for colon cancer prevention and therapy. The need is therefore not for simple COX-2-related preventive and therapeutic models to be prepared, but detailed analyses that assist in the clarification of PGE_2-related carcinogenesis