Carcinogenesis Advance Access published online on March 19, 2004
Carcinogenesis, doi:10.1093/carcin/bgh150
© 2004 by Oxford University Press
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CARCINOGENESIS
1 Department of Medicine, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262
* Corresponding author. E-mail: al.malkinson{at}uchsc.edu.
Received 14 November 2003
; revised 8 March 2004
; accepted 9 March 2004
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 A2 (cPLA2) 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 cPLA2 in mouse lung tumorigenesis by using mice genetically deficient in cPLA2. After multiple urethane injections into cPLA2 null mice and wild-type littermates, the number of lung tumors was determined. cPLA2 null mice developed 43% fewer tumors (from 16 ± 2 to 9 ± 2 tumors/mouse; p<0.05) than wild-type littermates. cPLA2, COX-1, COX-2, and microsomal prostaglandin E2 synthase (mPGES), examined by immunohistochemistry (IH), are present in alveolar and bronchiolar epithelia and in alveolar macrophages in lungs from naive mice and tumorbearing 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 cPLA2 null mice. Although the steady-state levels of PGE2 and PGI2 in lung tissue extracts prepared from wild-type or cPLA2 (-/-) mice were not significantly different, both prostaglandins markedly increased in tumors from wild-type mice, an increase that was significantly blunted in tumors from cPLA2 (-/-) mice. These results demonstrate a role for cPLA2 in mouse lung tumorigenesis that may be mediated by decreased prostaglandin synthesis.
cytosolic phospholipase A2, prostaglandin, mouse lung tumorigenesis, carcinogenesis
Decreased lung tumorigenesis in mice genetically deficient in cytosolic phospholipase A2
2 Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262
3 Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine; Denver VA Medical Center, Denver, CO 80220
4 Department of Medicine, Harvard Medical School, and Harvard-MIT Division of Health Sciences and Technology, 149 13th St., Charlestown, MA 02129
5 Department of Surgery, Washington University, 660 S. Euclid Ave., St. Louis, MO 63110
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