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 activator (u-PA), type-1 plasminogen-activator inhibitor (PAI-1), u-PA receptor (u-PAR) and alpha(2)-macroglobulin- receptor/low-density-lipoprotein-receptor-related protein (alpha(2)MR/LRP) in human breast tumors by immunohistochemical methods. Frozen sections of 133 primary breast carcinomas, 6 ductal carcinomas in situ and 33 lymph-node metastases were stained with monoclonal antibodies. Formalin-fixed sections of 15 primary tumors and 2 lymph-node metastases were stained with polyclonal antibodies. In primary tumors, u-PA and PAI-1 immunoreactivities were intense in macrophages and mast cells, and moderate in benign and malignant epithelial cells as well as in myofibroblasts and endothelial cells. A sub-group of poorly differentiated tumors showed particularly strong staining of stromal fibroblasts. u-PA immunoreactivity was also present in lymphocytes. alpha(2)MR/LRP and u-PAR immunoreactivities were intense in macrophages, but apart from these cells, alpha(2)MR/LRP was found only in fibroblasts, and u-PAR only in tumor cells located peripherally in tumor-cell clusters and glands and some myofibroblasts in the adjacent stroma. Lymph-node metastases showed staining for u-PA and PAI-1 both of cancer cells and of stromal fibroblasts, also staining for u-PA of lymphocytes. Similarly to some of the poorly differentiated primary tumors, approximately half of the metastases showed very strong staining of stromal fibroblasts, and extracts of these metastases had higher u-PA and PAI-1 levels, as determined by ELISA, than extracts of metastases without this staining pattern. alpha(2)MR/LRP was present only in fibroblasts and u-PAR only in some tumor cells. The presence of u-PA, PAI-1, alpha(2)MR/LRP and u-PAR was controlled biochemically by immunoblotting analyses, ligand-blotting analyses, and direct and reverse zymography. The spatial distribution and the variation in concentration of the various components of the plasminogen-activation system point to a complex, multifunctional role for the 4 proteins in and/or during the development and spread of breast cancer.
Christensen
L
L
Department of Pathology, Glostrup Hospital, Denmark.
Wiborg Simonsen
A C
AC
Heegaard
C W
CW
Moestrup
S K
SK
Andersen
J A
JA
Andreasen
P A
PA
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008207:Lymphatic Metastasis; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; C524898:PLAUR protein, human; D017395:Plasminogen Activator Inhibitor 1; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator