Cytoplasmic Phospholipase A2 Metabolites Play a Critical Role in Pulmonary Tumor Metastasis in Mice

Cytoplasmic PLA(2) (cPLA2) has been shown to be the major enzyme responsible for arachidonic acid (AA) release. Because of this key role of cPLA(2) in AA production, cPLA(2) involvement in tumorigenesis has been suggested. However, contradictory data are found in the literature. Additionally, little is known regarding the role of cPLA(2) in pulmonary tumor metastasis. Tumor metastases were detected by lung colonization and angiogenesis was assayed as growth of blood vessels from subcutaneous tissue into an implanted matrigel of basement membrane. The matrix metalloproteinases (MMP)-2, and MMP-9 were detected by PCR with sequence-specific primers. In this study, the effects of inhibitors of cPLA2, 5-lipoxygenase (5-LO), and cyclooxygenase (COX)-2 on pulmonary metastasis formation by B16F10 melanoma cells were investigated. All of these inhibitors reduced B16F10 pulmonary metastasis formation in a dose-dependent manner. Importantly, cPLA2, and 5-LO, and COX-2 inhibitors reduced platelet-activating factor-induced angiogenesis in an in vivo mouse model employing Matrigel injected subcutaneously, and also reduced expression of MMP-2 and MMP-9 in the lungs. This study demonstrates that cPLA(2) metabolites play critical roles in tumor metastasis via the promotion, at least in part, of angiogenesis and MMP expression.