prostaglandin-b2 and Neoplasm-Metastasis

Bone metastasis is the major reason for death caused by breast cancer. We used human breast cancer (MCF-7) cells that are poorly metastatic but show highly inducible migration to determine bone-derived factors that induce migration of initially non-disseminating breast cancer cells. We have found that a lipid fraction from human osteoblast-like MG63 cell-conditioned medium (MG63CM) contains a migration-inducing factor for MCF-7 cells. In this fraction, we have identified oxysterol (OS) as a lipid mediator for tumor cell migration. In MCF-7 cells, insulin-like growth factor 1 elevates the expression of OS-binding protein-related protein 7. Binding of OS to OS-binding protein or OS-binding protein-related protein is known to trigger elevation of sphingomyelin, a sphingolipid that organizes lipid microdomains in the cell membrane. In MCF-7 cells, OS increases the intracellular concentration of sphingomyelin and other phospholipids and induces the translocation of the small GTPase p21Ras to GM1- and cholesterol-rich membrane areas. The induction of migration by MG63CM is prevented by incubation of MG63 cells with mevinolin, a statin-type cholesterol biosynthesis inhibitor that depletes the conditioned medium of OS. Osteoblast-derived OS may, thus, be a yet unrecognized lipid mediator for bone metastasis of breast cancer and a new target for anti-metastasis chemotherapy with statins.

Topics: Arachidonic Acid; Aspirin; Breast Neoplasms; Cell Membrane; Cell Movement; Cholesterol; Chromatography, High Pressure Liquid; Coculture Techniques; Culture Media, Conditioned; Dinoprostone; Electrophoresis, Polyacrylamide Gel; HSP70 Heat-Shock Proteins; Humans; Insulin-Like Growth Factor I; Lipid Metabolism; Lovastatin; MAP Kinase Signaling System; Microscopy, Fluorescence; Neoplasm Metastasis; Osteoblasts; Phospholipids; Phosphorylation; Prostaglandins B; Protein Transport; Proto-Oncogene Proteins p21(ras); Reverse Transcriptase Polymerase Chain Reaction; Sepharose; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sphingolipids; Sterols; Trypsin; Tumor Cells, Cultured