Recent research indicates that tumor cell invasion is dependent upon synergistic interactions between proteinases with different catalytic mechanisms. The stimulation of host cells to produce proteinases within the tumor microenvironment may be more important than the expression of tumor derived proteinases; and, indeed, in some cases tumor cells were found to stimulate host cells, such as fibroblasts and endothelial cells (EC), to express the proteinases involved in tumor cell invasion. Endothelial cells are polarized with distinct apical and basal secretion patterns. We have used monkey aortic EC (MAEC) grown in a 2 chamber culture system to investigate the polarized secretion of matrix metalloproteinases (MMP), plasminogen activators (PA), and their inhibitors (TIMP and PAI, respectively). MMP-2 was found to be constitutively secreted with a basal preference, TIMP-1 and TIMP-2 secretion was unpolarized. Urokinase PA (u-PA), tissue PA (t-PA) and PAI- 1 were secreted with a slight basal preference. The effects of 12-0- tetradecanoyl phorbol-13-acetate (TPA), interleukin-1 (IL-1) and melanoma conditioned medium (MCM), which has previously been shown to contain IL-1, were used to modulate MAEC proteinase and inhibitor levels. TPA induced apical MMP-9 secretion and increased basal u-PA secretion. IL-1 induced basal MMP-9 secretion and increased basal u-PA secretion. MCM induced basal MMP-9 secretion and increased basal t-PA activity, MMP-2, and TIMP-2 secretion. Thus, tumor cells have the ability to stimulate EC to produce a wide variety of proteinases which are directed towards the basement membrane. Induced EC proteinase levels are higher than tumor cell levels. These observations may have important implications for tumor invasion and metastasis.
