Polychlorinated biphenyls induce adhesion of breast cancer cells to human brain endothelium through lipid raft‐dependent upregulation of cell adhesion molecules

Abstract

During blood‐borne metastasis, upregulation of endothelial cell adhesion molecules can accelerate metastatic processes through increased adhesion of tumor cells to the endothelium. Chronic exposure to polychlorinated biphenyls (PCBs) produces a variety of effects including tumor‐promoting effects. Because the cerebrovascular endothelium can play a regulatory role in tumor metastatic processes in the brain, we have explored whether PCB 153 can upregulate adhesion of breast cancer cells to the brain endothelium. Exposure to PCB 153 increased expression of ICAM‐1 and VCAM‐1, and increased adhesion of MDA‐MB‐231 cells to endothelial cells. PCB 153‐induced ICAM‐1 expression was blocked by pretreatment with lipid rafts disrupting agent, methyl‐beta‐cyclodextrin (MβCD) or chemical inhibitors against the Src family kinases or PI3K/Akt. MβCD also inhibited PCB 153‐induced phosphorylation of Src kinase and Akt. Knockdown of caveolin‐1 using siRNA interference did not affect PCB153‐mediated upregulation of ICAM‐1 and VCAM‐1. Results of the present study indicate that PCB 153 can increase adhesion of tumor cells to brain microvascular endothelium and transendothelial migration of tumor cells through increased expression of ICAM‐1 and VCAM‐1 via lipid rafts‐dependent activation of the Src family kinases and/or PI3K/Akt signaling pathways. Supported in part by P42 ES 07380, MH63022, MH072567, and NS39254.