Induction of protein growth factor systems in the ovaries of transgenic mice overexpressing human type 2 lysophosphatidic acid G protein-coupled receptor (LPA2)

The lipid growth factor lysophosphatidic acid (LPA) is produced by ovarian cancer cells in quantities sufficient to attain concentrations of up to 10 microM. An autocrine circuit was demonstrated when ovarian cancer cells, but not normal ovarian surface epithelial cells, were proven to express LPA(2) (Edg-4) and LPA(3) (Edg-7) G protein-coupled receptors for LPA. Human LPA(2) now has been expressed transgenically in C57BL/6 mouse ovaries under direction of the alpha-inhibin large promoter. Human LPA(2) mRNA and protein were detected in all transgenic (TG) mouse ovaries at levels far higher than in other tissues and at least fivefold higher than in cultured lines of human ovarian cancer cells, with the expected sex cord-stromal distribution. Most LPA(2) TG ovaries produced significantly higher levels than non-TG ovaries of type A, but not type B, vascular endothelial growth factor (VEGF), isomers of VEGF-A, and urokinase-type plasminogen activator (uPA). Many LPA(2) TG ovaries had elevated expression of VEGF receptors 1 and 2, and a depressed level of type 2 PA inhibitor. Thus, the LPA-LPA(2) circuit regulates ovarian cells both directly and through increases in protein growth factor systems.