Bioactive Lipids Lysophosphatidic Acid and Sphingosine 1-Phosphate Mediate Breast Cancer Cell Biological Functions Through Distinct Mechanisms

Abstract

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are structurally related bioactive lipids with growth factor-like activities. LPA and S1P are naturally produced in vivo by blood platelets upon platelet aggregation and at least in vitro by fibroblasts, adipocytes, and multiple types of tumor cells. Breast cancer cells respond to LPA and S1P. However, their specific actions on breast cancer cell biological functions remain unclear. We therefore conducted an in vitro side-by-side study of these two lipids on breast cancer cells. LPA mediates human breast cancer MDA-BO2 cell proliferation, migration, and invasion through activation of a G(alpha i)/ERK1/2-dependent signaling pathway, whereas activation of G(alpha i)/PI3K predominates upon S1P stimulation. In MDA-BO2 cells, LPA but not S1P activities were dependent on active type 1 insulin-like growth factor and epithelial growth factor receptors. LPA and S1P act directly on endothelial cells to induce angiogenesis. We demonstrate that LPA and S1P have indirect angiogenic properties as judged by induced secretion of angiogenic factors by breast cancer cells primed with these lysophospholipids. S1P, but not LPA, controlled the expression of VEGF-A by breast cancer cells, while LPA, but not S1P, controlled the expression of GM-CSF, Gro-alpha, MCP-1, and IL-6. According to the secretion of these paracrine osteoclastic factors, LPA, but not S1P, stimulates breast cancer cell-induced osteoclastogenesis. These findings suggest that, in vivo, LPA and S1P can coordinate their action on tumor and surrounding cells to induce breast cancer progression both at primary and bone metastatic sites.