Endothelial cells are a polarized cell type with a distinct apical side which faces the vascular lumen and a basal side which mediates attachment to the subendothelial basement membrane. In vitro studies were carried out on the effects of tumor cells and cytokines on polarized secretion of matrix metalloproteinases (MMPs) and plasminogen activators (PAs) by endothelial cells. Constitutive MMP and PA expression by a confluent monolayer of endothelial cells was directed basally. Exposure to interleukin-1alpha (IL-1alpha) or melanoma conditioned medium (MCM) resulted in stimulated expression of both MMP and PA activities basally. The rise in proteolytic activity was reflected by increased capability to degrade basement membrane in situ. These findings suggest that activated endothelial cells can contribute to proteolytic degradation of vascular basement membrane and may thus facilitate tumor cell extravasation. MMPs are secreted as latent proenzymes which become activated upon removal of an N-terminal fragment. The mechanism for the in vivo activation of MMPs has not been elucidated. We discovered that binding of the lectin Ulex europaeus agglutinin I (UEA-I) to fucose residues on the surface of endothelial cells resulted in activation of the gelatinase MMP-2. It has been proposed that surface lectins on tumor cells contribute to metastatic potential. Therefore, lectin-mediated MMP-2 activation may represent one of the mechanisms by which tumor cells stimulate vascular endothelial cells to degrade the subendothelial basement membrane. We are developing an in vivo model to study the interactions between tumor cells and the microvasculature. This model utilizes porous biocompatible polymers which, when transplanted, will provide scaffolding for tumor cell growth and vascularization. The biopolymers can also be used to evaluate the in vivo effects of angiogenesis inhibitors on tumor neovascularization.
