Polychlorinated biphenyls (PCBs) are industrial chemicals mass produced and sold on a large scale in the U.S. for approximately 50 years. Evidence indicates that PCBs have both tumor promoting and vascular effects. However, very little is known about the influence of specific PCBs on cancer metastasis formation and, in particular, on the development of brain metastatic disease. Brain metastases belong to most common forms of metastases and their development dramatically worsens the prognosis and survival of cancer patients. We have evidence that selected coplanar and non-coplanar PCB congeners with multiple rtho-chlorine-substituents stimulate metastatic events such as disruption of endothelial cell integrity, tumor cell adhesion to the endothelium and transendothelial migration. Based on these data, we propose a novel hypothesis that specific PCBs can induce endothelial cell activation, disrupt the blood-brain barrier (BBB) and thus stimulate the development of brain metastases. In addition, we hypothesize that nutritional intervention can protect against PCB-mediated metastases formation. To study these hypotheses, this research proposal will focus on the effects of specific PCBs on critical events in the development of brain metastases, such as: a) alterations of cellular redox status and overexpression of prometastatic/proinflammatory genes; b) overexpression of matrix metalloproteinases (MMPs); and c) alterations of expression of junctional proteins and disturbances of endothelial barrier function. The proposed research combines elements of clinical approaches (brain metastases), environmental toxicology with molecular and vascular biology. In addition, it is based on a variety of model systems, such as cultures of endothelial cells, Transwell systems to study permeability across the model of brain endothelium, and animal studies. The long-term goals of this proposal are to determine the mechanisms which are responsible for PCB-induced injury to brain endothelial cells, disruption of the BBB and the development of brain metastases. Data arising from this proposal will be critical for a better understanding of the molecular mechanisms of brain metastasis formation. In a broader aspect, this proposal will contribute to better knowledge on how air pollution contributes to cancer biology and the development of metastases.
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