Increased eicosanoid production occurs in a number of different types of cancer, including colon, lung, breast and pancreatic. Inhibitors of eicosanoid production (NSAIDs) block tumor growth in animal models, and are currently in clinical trials. Constitutive increases in eicosanoid production are mediated through elevated expression of key enzymes in this pathway- cytosolic phospholipase A2(cPLA2) and cyclooxygenase-2 (COX-2), and mice deficient in expression for either of these enzymes are protected from developing intestinal tumors. Downstream effectors of COX, which control production of specific prostaglandins also play a critical role in tumorigenesis. Specifically, mice overexpressing prostacyclin synthase are protected against developing lung tumors and increased expression of prostaglandin E synthase (mPGES) is observed in lung tumors. We have demonstrated that increased expression of cPLA2 and COX-2 in non-small cell lung cancer cell lines (NSCLC) are associated with expression of gain-of-function mutations in the ras gene, and that growth of these cells is blocked by NSAIDs. However, a definitive role for eicosanoid production in the progression of lung cancer has not been established, and molecular pathways whereby activated Ras leads to increased expression of cPLA2 are only partially understood. This competing continuation has two major specific aims 1) to establish the role of cPLA2, COX-2 and downstream effectors in lung tumorigenesis using genetic models in mice as well as samples from human lung cancers, and 2) to define the molecular events leading to increased expression of cPLA2. To address Specific Aim 1, we have obtained from other investigators and developed in our own laboratory mice which are either deficient in cPLA2 or COX-2, or overexpress these enzymes specifically in the lung. We have also made mice overexpressing mPGES, and mice deficient in the PGE2 receptor EP2. Development of lung tumors will be assessed in these animals using a well-characterized carcinogenesis protocol. Expression of these enzymes will also be evaluated in human tumors, and correlated with pathological diagnosis and clinical outcome. In the second specific aim, the signaling pathways mediating Ras induction of cPLA2 will be defined. Employing a variety of strategies transcription factors mediating this effect will be identified. Understanding the mechanisms and physiologic role of increased cPLA2 expression and eicosanoid production in non-small cell lung cancer is likely to be applicable to a broad variety of carcinomas, The ready availability of a large array of pharmacologic agents which act on these enzymes may result in new strategies for treatment and prevention of these types of cancer. ? ? ?
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