It is postulated that exposure to specific polychlorinated biphenyls (PCBs) may enhance the risk fore the development of tumor metastasis. The potential mechanisms of this process may involved PCB-induced effects on adhesion molecule expression on the surface of vascular endothelial cells. This process may allow interaction between tumor cell and endothelial cells and thus facilitate migration of tumor cells across the endothelium and metastatic invasion on the surrounding tissues. One of the most important adhesion molecules involved in metastasis is intercellular adhesion molecule-1 (ICAM-1). The expression of this adhesion molecule on vascular endothelium is increased in almost all of the common human cancers. Our preliminary data indicate that selected PCBs are potent inducers of ICAM-1 in endothelial cells. It is our working hypothesis that exposure to selected PCBs can induce ICAM-1 and thus contribute to tumor metastasis. The main hypothesis will be tested at molecular, cellular and animal levels, and is reflected in four specific aims. At the molecular level, the proposed research will allow us to identify PCB-mediated transcriptional regulation of ICAM-1 expression. The proposed co-culture experiments of endothelial cells and tumor cells will provide substantial information about the significance of PCB-induced up-regulation of ICAM-1 in cancer metastatic formation. Finally, the proposed animal studies will provide the ultimate proof that PCB-induced over-expression of ICAM is a critical factor in increased cancer metastatic formation. The long-term goal of the proposed research is to determine fundamental signaling mechanisms underlying PCB- induced activation of ICAM-1 expression, tumor cell adherence and transmigration across the endothelium, and finally the progression of cancer metastasis. We also hypothesize that certain antioxidant nutrients (such as vitamins E and C) can down-regulate PCB-induced over- expression of ICAM-1 and tumor cell migration across the vascular endothelium. Thus, data arising from this study may lead to novel dietary and molecular interventions to protect against cancer metastasis induced by PCBs.
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