RGBs have both tumor promoting and vascular effects; however, little is known about their influenceon the development of metastatic disease. We indicated that selected non-coplanar PCB congenersaccumulate in the brain, stimulate dysfunction of brain microvascular endothelial cells (BMEC), andfacilitate the interaction of tumor cells with the vascular endothelium. Our new data provide evidence thatPCBs localize to caveolae in endothelial cells. This is an important finding because a variety of cellsurface receptors and signaling pathways are also localized in these membrane domains. Thus,caveolae may provide the crucial signaling platform for cerebral vascular toxicity of PCBs. Wehypothesize that PCB-induced stimulation of caveolar-associated pathways, such as the Ras andRho cascades, underlie the mechanisms of PCB-induced injury to BMEC, disruption of the bloodbrainbarrier (BBB) integrity, and the development of brain metastases. Mechanistically, we willfocus on the involvement of the Ras and Rho pathways in PCB-induced alterations of expression of tightjunction proteins, which are associated with caveolae and are detrimental for the normal functions of thebrain endothelium and regulate the barrier properties of the BBB. Diet is one of the most powerfulmodifiable behavioral factors which can influence cancer development and progression. Moreover, ourdata indicate that exposure to PCBs can upregulate expression of CD36, a receptor which is localized incaveolae and is involved in cellular uptake of fatty acids. Therefore, we will also study the influence ofdietary polyunsaturated fatty acids (namely fatty acids of the omega-6 and omega-3 family) on thevascular toxicity of PCBs and PCB-induced brain metastases. Specifically, we hypothesize that omega-6 fatty acids (e.g., linoleic acid) potentiate the pro-metastatic properties of selected PCBs and thatomega-3 fatty acids (e.g., alpha-linolenic acid) protect against these effects.The proposed research combines elements of clinical and translational approaches (brainmetastases) with environmental toxicology and molecular biology. In addition, it is based on a variety ofmodel systems, such as unique cultures of brain endothelial cells, Transwell systems, and in vivo studiesbased on genetically altered mice (caveolin-1 deficient mice). The long term goals of this application areto determine molecular mechanisms of metastatic events induced by PCBs. However, an even moreimportant goal of this proposal is to evaluate how dietary factors can influence the development of tumormetastases induced by Superfund chemicals. Therefore, our application has strong clinical implicationsand can significantly contribute to the improvement of public health.
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