Thrombospondin and transforming growth factor‐beta 1 increase expression of urokinase‐type plasminogen activator and plasminogen activator inhibitor‐1 in human MDA‐MB‐231 breast cancer cells

Juan P. Arnoletti, Daniel Albo, Mark S. Granick, Mark P. Solomon, Analia Castiglioni, Vicki L. Rothman, George P. Tuszynski

Research output: Contribution to journalArticle

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Abstract

Background. Thrombospondin is a high molecular weight adhesive glycoprotein that has been shown to function in mechanisms of tumor progression. The authors' previous studies have shown that thrombospondin promotes human lung carcinoma invasion by up‐regulation of the plasminogen activator system through a mechanism involving the activation of transforming growth factor‐beta 1 (TGF‐beta 1). In this study, a similar throm‐bospondin‐mediated mechanism operative in breast carcinoma cells is described. Methods. The effect of thrombospondin and TGF‐beta 1 on the capacity of a line of breast carcinoma cells to activate plasminogen was measured as well as the physiologic consequences of these activities on cell adhesion and proliferation. Plasminogen activation was assessed by measuring the plasmin activity and plasminogen activator inhibitor‐1 (PAI‐1) levels in cell‐conditioned media and the cell‐associated urokinase‐type plasminogen activator (uPA) levels. Results. Treatment of MDA‐MB‐231 breast carcinoma cells with either thrombospondin or TGF‐beta 1 caused increased secretion of PAI‐1 with a concomitant decrease in plasmin activity, whereas cell‐associated uPA expression was increased with respect to controls. Thrombospondin (40 μMg/ml) or TGF‐beta 1 (5 ng/ml) stimulated the cells to secrete 5.5‐ and 6.7‐fold more PAI‐1 than controls, respectively, and caused decreased plasmin activity in the cell culture medium. Conversely, either thrombospondin (40 μg/ml) or TGF‐beta 1 (5 ng/ml) caused the cells to express 4.55‐ and 5.38‐fold more uPA than controls, respectively. Thrombospondin and TGF‐beta 1 induced a more flattened and spread appearance in the cells with no effect on proliferation. These effects could be reversed with antibodies to either thrombospondin or TGF‐beta 1 and were not due to contamination of thrombospondin with active TGF‐beta 1. Conclusions. Thrombospondin and TGF‐beta 1 function similarly to increase cell‐associated uPA and cell‐secreted PAI‐1. These data suggest that thrombospondin may not only function as an adhesive molecule, but through a mechanism involving the activation of TGF‐beta 1, may modulate cell surface protease expression. In addition, these observations suggest that thrombospondin and TGF‐beta 1 could promote metastasis by increasing uPA‐mediated cell invasion, whereas through the action of PAI‐1, also protect blood‐born tumor emboli from destruction by host fibrinolytic enzymes. Cancer 1995;76:998–1005.

Original languageEnglish (US)
Pages (from-to)998-1005
Number of pages8
JournalCancer
Volume76
Issue number6
DOIs
StatePublished - Sep 15 1995
Externally publishedYes

Keywords

  • breast cancer
  • plasminogen activator inhibitor‐1
  • thrombospondin
  • transforming growth factor‐beta 1
  • tumor invasion
  • urokinase‐type plasminogen activator

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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