Role of urokinase plasminogen activator receptor in thrombospondin 1- mediated tumor cell invasion

Daniel Albo, David H. Berger, Vicki L. Rothman, George P. Tuszynski

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

We previously showed that thrombospondin 1 (TSP-1) upregulates the plasminogen/plasmin system and promotes breast tumor cell invasion. Preliminary data from our laboratory using neutralizing antibodies suggested that the upregulation in breast tumor cell invasion seen in response to TSP-1 involved the urokinase plasminogen activator receptor (uPAR). To confirm these findings in MDA-MB-231 breast cancer cells, we developed three other strategies to study the role of uPAR in tumor cell adhesion and TSP-1- mediated tumor cell invasion: (a) enzymatic cleavage of uPAR with glycosylphosphatidylinositol-specific phospholipase C; (b) inhibition at the mRNA level with a uPAR antisense construct (cells named LKAS-MDA); (c) inhibition of plasminogen binding with the lysine analogue ε-aminocaproic acid. Adhesion to laminin and type I and type IV collagen with and without the addition of ε-aminocaproic acid was studied. Tumor cell invasion was studied in a modified Boyden chamber collagen invasion assay. Antisense uPAR inhibition decreased uPAR expression by 48-66% and cell-associated urokinase plasminogen activator (uPA) by 30-68%. Additionally, antisense uPAR inhibition induced a 68-70% reduction in uPA and plasmin activities. Antisense uPAR transfection increased tumor cell adhesion by 46-53%. A similar effect was observed in ε-aminocaproic acid-treated MDA-MB-231 cells. TSP-1-mediated tumor cell invasion was almost completely inhibited by either antisense uPAR inhibition or treatment with phospholipase C or ε- aminocaproic acid. We conclude that uPAR plays a crucial role in the regulation of tumor cell adhesion and TSP-1-mediated tumor cell invasion.

Original languageEnglish (US)
Pages (from-to)331-338
Number of pages8
JournalJournal of Surgical Research
Volume82
Issue number2
DOIs
StatePublished - Jan 1 1999
Externally publishedYes

Fingerprint

Urokinase Plasminogen Activator Receptors
Thrombospondin 1
Aminocaproic Acid
Neoplasms
Cell Adhesion
Plasminogen Activators
Plasminogen
Fibrinolysin
Urokinase-Type Plasminogen Activator
Breast Neoplasms
Glycosylphosphatidylinositol Diacylglycerol-Lyase
Up-Regulation
Collagen Type IV
Type C Phospholipases
Laminin
Collagen Type I
Neutralizing Antibodies
Lysine
Transfection
Collagen

Keywords

  • Thrombospondin 1 (TSP-1)
  • Urokinase plasminogen activator (uPA)
  • Urokinase plasminogen activator receptor (uPAR)

ASJC Scopus subject areas

  • Surgery

Cite this

Role of urokinase plasminogen activator receptor in thrombospondin 1- mediated tumor cell invasion. / Albo, Daniel; Berger, David H.; Rothman, Vicki L.; Tuszynski, George P.

In: Journal of Surgical Research, Vol. 82, No. 2, 01.01.1999, p. 331-338.

Research output: Contribution to journalArticle

Albo, Daniel ; Berger, David H. ; Rothman, Vicki L. ; Tuszynski, George P. / Role of urokinase plasminogen activator receptor in thrombospondin 1- mediated tumor cell invasion. In: Journal of Surgical Research. 1999 ; Vol. 82, No. 2. pp. 331-338.
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