IMMUNOHISTOCHEMICAL LOCALIZATION OF UROKINASE-TYPE PLASMINOGEN-ACTIVATOR, TYPE-1 PLASMINOGEN-ACTIVATOR INHIBITOR, UROKINASE RECEPTOR AND ALPHA(2)-MACROGLOBULIN RECEPTOR IN HUMAN BREAST CARCINOMAS

We have investigated the localization of urokinase-type plasminogen ac tivator (u-PA), type-1 plasminogen-activator inhibitor (PAI-1), u-PA r eceptor (u-PAR) and 2)-macroglobulin-receptor/low-density-lipoprotein- receptor-related protein (alpha(2)MR/LRP) in human breast tumors by i mmunohistochemical methods. Frozen sections of 133 primary breast carc inomas, 6 ductal carcinomas in situ and 33 lymph-node metastases were stained with monoclonal antibodies. Formalin-fixed sections of 15 prim ary tumors and 2 lymph-node metastases were stained with polyclonal an tibodies. In primary tumors, u-PA and PAI-1 immunoreactivities were in tense in macrophages and mast cells, and moderate in benign and malign ant epithelial cells as well as in myofibroblasts and endothelial cell s. A sub-group of poorly differentiated tumors showed particularly str ong staining of stromal fibroblasts. u-PA immunoreactivity was also pr esent in lymphocytes. alpha(2)MR/LRP and u-PAR immunoreactivities were intense in macrophages, but apart from these cells, alpha(2)MR/LRP wa s found only in fibroblasts, and u-PAR only in tumor cells located per ipherally in tumor-cell clusters and glands and some myofibroblasts in the adjacent stroma. Lymphnode metastases showed staining for u-PA an d PAI-1 both of cancer cells and of stromal fibroblasts, also staining for u-PA of lymphocytes. Similarly to some of the poorly differentiat ed primary tumors, approximately half of the metastases showed very st rong staining of stromal fibroblasts, and extracts of these metastases had higher u-PA and PAI-1 levels, as determined by ELISA, than extrac ts of metastases without this staining pattern. alpha(2)MR/LRP was pre sent only in fibroblasts and u-PAR only in some tumor cells. The prese nce of u-PA, PAI-1, alpha(2)MR/LRP and u-PAR was controlled biochemica lly by immunoblotting analyses, ligand-blotting analyses, and direct a nd reverse zymography. The spatial distribution and the variation in c oncentration of the various components of the plasminogen-activation s ystem point to a complex, multifunctional role for the 4 proteins in a nd/or during the development and spread of breast cancer. (C) 1996 Wil ey-Liss, Inc.