Superfund Research Program
Vascular Mechanisms of PCB-Induced Brain Metastases
Project Leader: Michal Toborek (University of Miami)
Grant Number: P42ES007380
Funding Period: 2000-2014
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During the formation of blood-borne metastasis, tumor cells disseminate from the primary tumor to secondary sites in various organs. Because vascular endothelial cells form a continuous monolayer, which functions as a selective barrier to the passage of cancer cells from the blood stream to the underlying tissues, endothelial dysfunction has a significant influence on the fate of circulating cancer cells in the blood vessel. Specifically, an increase in endothelial permeability can accelerate the metastatic process through facilitated transmigration of cancer cells across the microvascular endothelial monolayer.
Endothelial hyperpermeability can be induced either by intracellular or extracellular stimuli, such as reactive oxygen species (ROS), cytokines, and growth factors. It appears that one of the most important factors involved in the regulation of endothelial permeability is vascular endothelial growth factor (VEGF). Evidence indicates that VEGF can disrupt endothelial integrity and increase permeability across the endothelial monolayers in vivo or in vitro and promote transendothelial migration of leukocytes and cancer cells, including breast cancer cells.
Due to the importance of VEGF in the development of cancer metastases, the team’s research has been concentrated on the effects ortho-substituted non-coplanar PCBs on the signaling mechanisms which regulate VEGF expression. The researchers provide evidence that VEGF can mediate PCB-induced endothelial hyperpermeability. In addition, PCB-mediated elevation of VEGF expression was induced by phosphatidylinositol 3-kinase (PI3K) activation, but not affected by co-treatments with antioxidants or inhibition of NF-kappaB. To support these findings, the project investigators demonstrated that VEGF receptor antagonists and the PI3K inhibitors inhibited PCB-induced hyperpermeability. These results indicate that ortho-substituted non-coplanar PCBs may contribute to tumor metastasis by inducing VEGF overexpression that stimulates endothelial hyperpermeability and transendothelial migration of cancer cells. Data from the present study support the hypothesis that specific PCBs can induce prometastatic conditions in human endothelial cells through induction of inflammatory and angiogenic mediators, including overproduction of VEGF. In addition, they illustrate the importance of the development of new anti-inflammatory and anti-angiogenic treatment regimes targeting VEGF activity for the anticancer strategy in populations exposed to PCBs.