Thrombospondin-1 and transforming growth factor-beta l promote breast tumor cell invasion through up-regulation of the plasminogen/plasmin system.
BACKGROUND
Pericellular proteolysis is crucial in tumor cell invasion. The plasminogen/plasmin system is one of the main protease systems involved in cancer progression. Thrombospondin-1 (TSP-1), through activation of transforming growth factor-beta 1 (TGF-beta 1), up-regulates the main plasminogen activator, the urokinase-type plasminogen activator (uPA). The objectives of this study were to determine the role of TSP-1 and TGF-beta 1 in the localization of the plasminogen/plasmin system to the tumor cell surface by the uPA receptor (uPAR) and to determine its effect in breast tumor cell invasion.


METHODS
The effect of TSP-1 and TGF-beta 1 in uPAR expression was determined in MDA-MB-231 human breast cancer cells by enzyme-linked immunosorbent assay and Western blot analysis. Their effect and the role of the plasminogen/plasmin system in breast tumor cell invasion were studied with a Boyden Chamber assay.


RESULTS
uPAR expression was up-regulated more than twofold by both TSP-1 and TGF-beta 1. The effect of TSP-1 involved its receptor and the activation of TGF-beta 1 by TSP-1. Breast tumor cell invasion was up-regulated sevenfold to eightfold by both TSP-1 and TGF-beta 1 compared with the control group. Antibodies against uPA or uPAR neutralized the TSP-1- and TGF-beta 1-promoted breast tumor cell invasion.


CONCLUSIONS
TSP-1, through the activation of endogenous TGF-beta 1, up-regulates the plasminogen/plasmin system and promotes tumor cell invasion in breast cancer cells.
Albo
D
D
Department of Surgery, Allegheny University of the Health Sciences, Philadelphia, Pa. 19102, USA.
Berger
D H
DH
Wang
T N
TN
Hu
X
X
Rothman
V
V
Tuszynski
G P
GP
D001943:Breast Neoplasms / Q000473:pathology*; D015815:Cell Adhesion Molecules; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D010958:Plasminogen / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D055293:Receptors, Urokinase Plasminogen Activator; D019699:Thrombospondins; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D015815:Cell Adhesion Molecules; D008562:Membrane Glycoproteins; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019699:Thrombospondins; D016212:Transforming Growth Factor beta; D010958:Plasminogen; D005341:Fibrinolysin