Human breast adenocarcinoma cell lines promote angiogenesis by providing cells with uPA-PAI-1 and by enhancing their expression.
During angiogenesis, endothelial cells use uPA and PAI-1 to migrate and degrade the basement membrane surrounding capillary blood vessels. Invasive tumor cells produce a large amount of uPA that could bind uPAR present at the endothelial cell surface to facilitate their invasion. To verify this hypothesis, endothelial cells were incubated with conditioned medium (CM) from two breast cancer cell lines (MCF7 and MDA MB 231 cells). Within a short incubation period (30 min) with both CM, an increase of uPA, PAI-1 and uPA-PAI-1 complex was detected in endothelial cell layer as assessed by casein zymography, ELISA and uPA immunostaining. The extent of this enhancement was related to the levels of uPA secreted by tumor cells (high in MDA MB 231 cells and low in MCF7 cells). After 2 hr of incubation, the CM from both tumor cells upregulated uPA and PAI-1 mRNA levels in endothelial cells in a time-dependent manner. The uPA increase in the cell layer could not be attributable to an increase of uPAR level. Only the CM from highly invasive MDA MB 231 cells increased the angiogenic morphotype of endothelial cells assessed in a collagen gel. A single addition of amino-terminal fragment of uPA (ATF) was able to abolish the angiogenic effect induced by MDA MB 231 cell CM. Our data demonstrate that the interactions occurring between breast tumor cells and endothelial cells can modulate tumor angiogenesis at least by two mechanisms: an increase of uPA and PAI-1 cell surface-binding and of their expression by endothelial cells.
Laboratory of Tumor and Development Biology, University of Liège, Tour de Pathologie (B23), Sart Tilman, Liège, Belgium.
Khalid
K
Bajou
Jean-Marc
JM
Lewalle
Christian Rodriguez
CR
Martinez
Claudine
C
Soria
He
H
Lu
Agnès
A
Noël
Jean-Michel
JM
Foidart
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D017077:Culture Media, Conditioned; D017395:Plasminogen Activator Inhibitor 1; D014568:Urokinase-Type Plasminogen Activator