MECHANISMS OF TUMOR CELL INVASION AND EXTRAVASATION

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This research seeks to improve our understanding of the basic mechanisms of tumor cell extravasation. Using capillary endothelial cell monolayers and primary tumor cells in vitro, we will document, in detail, the nature of the cell surface components involved in tumor:endothelial attachment. Those monoclonal antibodies reacting with endothelial cell surface components, which we have found to block tumor:endothelial attachment in vitro will be studied for the ability to block lung colonization. The tumor specificity (or lack thereof) of the blocking effect will be determined as well as the nature of the cell surface components involved. The mechanisms whereby neutrophils or activated macrophages can induce increased tumor:endothelial attachment, tumor localization in the lung and lung colonization will be investigated. The biochemical nature of actual basement membrane matrix degradation by tumor cells will be examined using isolated lens capsule analyzed in various ways including electrophoresis and immunoblot techniques, and the relationship of matrix degradation to basement membrane invasion directly determined using the same matrix substrate. These studies will include the use of tumor variants selected for the ability to invade across the lens capsule basement membrane, broad spectrum antiproteases and mixtures of complementary protease inhibitors. Possible contributions of various classes of leukocytes to the invasive steps of tumor cell extravasation will be examined. In addition to the intrinsic value of these studies to the understanding of tumor pathogenesis, these studies will provide information relevant to the design of antimetastatic therapies which seek to block extravasation forcing tumor emboli to remain in the circulation . . . . a naturally adverse environment for them and one which is very amenable to therapeutic manipulation.