Group VIA phospholipase A₂ in both host and tumor cells is involved in ovarian cancer development

Host-tumor cell interactions are recognized to be critical in tumor development. We have shown that group VIA phospholipase A₂ [calcium-independent phospholipase A₂β (iPLA₂β)] is important in regulating extracellular lysophosphatidic acid (LPA) levels around human epithelial ovarian cancer (EOC) cells. To explore the role of iPLA₂β in host-tumor cell interactions, we have used immunocompetent iPLA₂β knockout (iPLA₂β ^-/-) mice and the mouse EOC cell line ID8. Tumorigenesis and ascites formation were reduced in iPLA₂β^-/- mice compared with wild-type (WT) mice by more >50% and were reduced further when ID8 cell iPLA₂β levels were lowered (by >95%) with shRNA. LPA and lysophosphatidylcholine (LPC) levels in the tumor microenvironment were reduced to ∼80% of WT levels in iPLA₂β^-/- mice. LPA, but not LPC, stimulated ID8 cell migration and invasion with cells in which iPLA₂β expression had been down-regulated in vitro. LPA, but not LPC, also enhanced in vivo ascites formation (by ∼5-fold) and tumorigenesis in iPLA₂β^-/- mice. This is the first demonstration of a role for host cell iPLA₂β in cancer, and these findings suggest that iPLA₂β is a potential target for developing novel antineoplastic therapeutic strategies.