There has been considerable interest in the role of prostaglandins, and in particular the COX-2 pathway, in the development of malignancies. Pharmacologic inhibition or genetic deletion of COX-2 restrains tumor formation in models of colon, breast, lung, and other cancers. Large human epidemiologic studies have found that the incidental use of NSAIDs is associated with significant reductions in relative risk for developing these and other cancers. Chronic low-dose aspirin does not appear to have a substantial impact on cancer incidence; however, it is associated with reduced cancer death in a number of studies. The anticancer efficacy of aspirin in humans may be related to hyperactivity of the PI3 kinase/Akt pathway in tumor cells. In patients with familial polyposis coli, COX inhibitors significantly decrease polyp formation. Polymorphisms in COX-2 have been associated with increased risk of some cancers. Several studies have suggested that COX-2 expression is associated with markers of tumor progression in breast cancer. In mouse mammary tissue, COX-2 is oncogenic whereas NSAID use is associated with a reduced risk of breast cancer in women, especially for hormone receptor-positive tumors. Despite the support for COX-2 as the predominant source of oncogenic prostaglandins, randomized clinical trials have not been performed to determine whether superior anti-oncogenic effects occur with selective inhibition of COX-2, compared with nonselective NSAIDs. Indeed data from animal models and epidemiologic studies in humans are consistent with a role for COX-1 as well as COX-2 in the production of oncogenic prostanoids.
PGE2, which is considered the principal oncogenic prostanoid, facilitates tumor initiation, progression, and metastasis through multiple biologic effects, increasing proliferation and angiogenesis, inhibiting apoptosis, augmenting cellular invasiveness, and modulating immunosuppression. Augmented expression of mPGES-1 is evident in tumors, and preclinical studies support the potential use of mPGES-1 inhibitors in chemoprevention or treatment. In tumors, reduced levels of OATP2A1 and 15-PGDH, which mediate cellular uptake and metabolic inactivation of PGE2, respectively, likely contribute to sustained PGE2 activity. The proand anti-oncogenic roles of other prostanoids remain under investigation, with TXA2 emerging as another likely procarcinogenic mediator, deriving either from macrophage COX-2 or platelet COX-1. Studies in mice lacking EP1, EP2, or EP4 receptors confirm reduced disease in multiple carcinogenesis models. EP3, in contrast, plays no role or may even play a protective role in some cancers. Transactivation of epidermal growth factor receptor (EGFR) has been linked with the oncogenic activity of PGE2. PGD2, acting on the DP1 receptor, may reduce angiogenesis, thereby reducing tumor progression.
Effects of Lipoxygenase & Cytochrome P450-Derived Metabolites
Lipoxygenases generate compounds that can regulate specific cellular responses that are important in inflammation and immunity. Cytochrome P450-derived metabolites affect nephron transport functions either directly or via metabolism to active compounds (see below). The biologic functions of the various forms of hydroxyand hydroperoxyeicosaenoic acids are largely unknown, but their pharmacologic potency is impressive.
A. Blood Cells and Inflammation