VEGF regulates PCB 104-mediated stimulation of permeability and transmigration of breast cancer cells in human microvascular endothelial cells.
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.
Eum
Sung Yong
SY
Department of Surgery, University of Kentucky, Lexington, KY 40536, USA.
Lee
Yong Woo
YW
Hennig
Bernhard
B
Toborek
Michal
M
D001943:Breast Neoplasms / Q000473:pathology*; D002199:Capillary Permeability; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000502:physiology*
D042461:Vascular Endothelial Growth Factor A; D011078:Polychlorinated Biphenyls; D019869:Phosphatidylinositol 3-Kinases; C417207:2,2',4,6,6'-pentachlorobiphenyl