Thrombospondin-1 and transforming growth factor-beta l promote breast tumor cell invasion through up-regulation of the plasminogen/plasmin system.

Abstract

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. 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. 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. 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.