Decreased lung tumorigenesis in mice genetically deficient in cytosolic phospholipase A2

Abstract

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, 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 cPLA2 null mice. Although the steady-state levels of prostaglandin E2 and prostaglandin I2 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.

Antitumorigenic Effects of Peroxisome Proliferator-Activated Receptor-γ in Non-Small-Cell Lung Cancer Cells Are Mediated by Suppression of Cyclooxygenase-2 via Inhibition of Nuclear Factor-κB

“…These data suggest that PGE 2 production is critical for the initiation of lung tumorigenesis in mice. Further support for that hypothesis comes from studies showing that cPLA 2 -deficient mice also develop significantly fewer lung tumors in response to the same chemical carcinogenesis model (Meyer et al, 2004). However, data from our laboratory indicate that mice with targeted overexpression of mPGES fail to show alterations in lung tumor formation using the urethane model (Blaine et al, 2005).…”

Cytoplasmic Phospholipase A2 Deletion Enhances Colon Tumorigenesis

“…In a recent report (56), cPLA 2 deletion afforded partial protection against urethane-induced lung cancer. These findings contrast with our results in which cPLA 2 deletion may have accelerated spontaneous lung tumorigenesis.…”

“…BALB/c mice were used in our study, whereas the urethane study was conducted on a mixed genetic background consisting of lung tumor sensitive (129/Sv) and resistant (C57Bl/6) backgrounds (56). Furthermore, Meyer et al (56) argued that impaired PGE 2 production in the lung underlies the protection afforded by cPLA 2 deletion, an explanation that is consistent with the phenotype observed in the small intestine (38,52). Our data, however, indicate that reduced PGE 2 production in the colon does not protect against tumorigenesis.…”

Cytosolic phospholipase A2: physiological function and role in disease

“…Using the chemical carcinogen urethane to initiate lung cancer, cPLA 2 ␣ KO mice developed fewer lung tumors than WT mice, and much lower levels of tumor-associated PGs ( 219 ). Another study investigated whether the presence of cPLA 2 ␣ in the tumor microenvironment infl uenced lung cancer progression and metastasis ( 220 ).…”