Polychlorinated biphenyl (PCB) congeners, a group of worldwide, persistent environmental contaminants, are known to cause
carcinogenesis and
tumor promotion, and may also affect the development of
cancer metastasis. Because vascular endothelial cells create a selective barrier to the passage of
cancer cells, we hypothesize that specific PCB congeners can disrupt endothelial integrity and increase the transendothelial migration of
tumor cells. To examine this hypothesis, we elucidated the effects of
2,2',4,6,6'-pentachlorobiphenyl (
PCB 104), a representative of highly ortho-substituted non-coplanar PCB congeners, on the endothelial permeability and transendothelial migration of MDA-MB-231
breast cancer cells. Exposure of human microvascular endothelial cell 1 (HMEC-1) to
PCB 104 induced endothelial hyperpermeability and markedly increased transendothelial migration of MDA-MB-231 cells. These effects were associated with overexpression of
vascular endothelial growth factor (
VEGF). PCB 104-mediated elevation of
VEGF expression was induced by
phosphatidylinositol 3-kinase (PI3K) but not affected by co-treatments with
antioxidants or the
NF-kappaB inhibitor SN50. In addition, the PI3K-dependent pathway was involved in PCB 104-induced activation of
AP-1, a
transcription factor implicated in the regulation of
VEGF gene expression. The
VEGF receptor (KDR/Flk-1) antagonist
SU1498 and the PI3K inhibitor
LY294002 inhibited PCB 104-induced hyperpermeability. These results indicate that
PCB 104 may contribute to
tumor metastasis by inducing
VEGF overexpression that stimulates endothelial hyperpermeability and transendothelial migration of
cancer cells.