Cancer is characterized by its ability to invade surrounding tissue, gain access to the blood vascular system and spread to distant organ systems. The process of blood-borne metastasis is highly complex and requires the completion of a series of steps by which tumor cell emboli finally arrest in the microvasculature. Extravasation is completed when the tumor cell successfully invades both the endothelial layer and associated basement membrane -- a process that is poorly understood.
The specific aims i n this proposal are (1) to determine by morphological and ultrastructural techniques how tumor cells invade microvascular endothelial cell monolayers and induce their retraction, (2) to identify and characterize by biochemical and immunochemical methods the types of surface adhesion receptors on metastatic tumor cells that mediate their attachment to and migration through the subendothelial matrix, and (3) to determine the potential role of plasmin (generated by tumor cell-associated plasminogen activator) and a tumor cell gelatinase in degrading type IV collagen present in the subendothelial basement membrane matrix. These studies will be performed using an in vitro model consisting of human metastatic tumor cells and human dermal microvascular endothelial cells. The microvascular endothelial cells are well characterized and have been shown to produce a basement membrane-like matrix composed of type IV collagen, laminin, fibronectin, and heparan sulfate proteoglycan. Information gained from these experiments should increase our understanding of the mechanisms by which malignant tumor cells complete the final phase of the metastatic cascade.
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