Proinflammatory Adhesion Molecules Facilitate Polychlorinated Biphenyl-Mediated Enhancement of Brain Metastasis Formation

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Abstract
Polychlorinated biphenyls (PCBs) are environmental toxicants that cause vascular inflammation and facilitate the development of brain metastases. The crucial event in metastasis formation is adhesion of blood-borne tumor cells to the vascular endothelium, followed by their transcapillary migration. The aim of the present study was to examine the mechanisms of PCB118-induced brain metastasis formation at the blood-brain barrier level with the focus on tumor cell adhesion to the brain endothelium. PCB118 was administered orally to wild-type or intercellular cell adhesion molecule-1 (ICAM-1)–deficient mice, followed by an injection of Lewis lung carcinoma cells into the carotid artery. Treatment with PCB118 resulted in enhanced development of brain metastases. Injection of tumor cells induced overexpression of ICAM-1 and vascular endothelial cell adhesion molecule-1 (VCAM-1) in brain endothelium that was further potentiated in mice exposed to PCB118. PCB118 did not affect the number of adhered and extravasated tumor cells in ICAM-1–deficient mice. Additional in vitro studies indicated that VCAM-1–neutralizing antibody protected against PCB118-induced adhesion of tumor cells to cultured brain endothelial cells. These results indicate that exposure to selected PCB congeners, such as PCB118, induces adhesion and transcapillary migration of tumor cells. This process is facilitated by proinflammatory adhesion molecules and results in potentiation of brain metastasis formation.