Decreased lung tumorigenesis in mice genetically deficient in cytosolic phospholipase A2

Epidemiological investigations suggest that chronic lung inflammation increases lung cancer risk. Pharmacologic and genetic evidence in mouse models indicates that lipid mediators released during pulmonary inflammation enhance lung tumor formation. Cytosolic phospholipase A(2) (cPLA(2)) catalyzes arachidonic acid (AA) release from membrane phospholipids. AA can then lead to the synthesis of several classes of lipid mediators, including prostaglandin (PG) biosynthesis through the cyclooxygenase (COX) pathway. We investigated a role for cPLA(2) in mouse lung tumorigenesis by using mice genetically deficient in cPLA(2). After multiple urethane injections into cPLA(2) null mice and wild-type littermates, the number of lung tumors was determined. cPLA(2) null mice developed 43% fewer tumors (from 16 +/- 2 to 9 +/- 2 tumors/mouse; P < 0.05) than wild-type littermates. cPLA(2), COX-1, COX-2 and microsomal prostaglandin E-2 synthase (mPGES), examined by immunohistochemistry, are present in alveolar and bronchiolar epithelia and in alveolar macrophages in lungs from naive mice and tumor-bearing mice. Tumors express higher levels of each of these four enzymes than control lungs, as determined by immunoblotting. No differences were detected in the contents of COX-1, COX-2 and mPGES between wild-type and cPLA(2) null mice. Although the steady-state levels of prostaglandin E-2 and prostaglandin I-2 in lung tissue extracts prepared from wild-type or cPLA(2) (-/-) mice were not significantly different, both prostaglandins markedly increased in tumors from wild-type mice, an increase that was significantly blunted in tumors from cPLA(2) (-/-) mice. These results demonstrate a role for cPLA(2) in mouse lung tumorigenesis that may be mediated by decreased prostaglandin synthesis.