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 ortho-chlorine-substituents stimulate metastatic events such as disruption of endothelial cell integrity, tumor cell adhesion to the endothelium and transendothelial migration.
Our new data indicate that exposure of endothelial cells to PCBs results in localization of PCBs to caveolae, the subset of lipid rafts characterized by the presence of proteins termed caveolins. This is an important finding because a variety of cell surface receptors and signaling pathways are also localized in these membrane domains. In addition, tight junction proteins, which are crucial for the integrity of the blood-brain barrier (BBB), are also associated with caveolae. Thus, caveolae may provide the crucial signaling platform for cerebral vascular toxicity of PCBs and their interaction with dietary fatty acids. We hypothesize that PCB-induced alterations of caveolar-associated pathways, such as the Ras and Rho signaling cascades, underlie the mechanisms of PCB-induced injury to brain microvascular endothelial cells (BMEC), disruption of the BBB, and the development of brain metastases.
To study these hypotheses, this research proposal focuses on the effects of fatty acids and 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) disruption of junctional proteins and disturbances of endothelial barrier function.
The long-term goals of this project 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 project will contribute to better knowledge on how air pollution contributes to cancer biology and the development of metastases.