Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling

Julio A. Aguirre Ghiso, Katherine Kovalski, Liliana Ossowski

Research output: Contribution to journalArticlepeer-review

464 Scopus citations

Abstract

Mechanisms that regulate the transition of metastases from clinically undetectable and dormant to progressively growing are the least understood aspects of cancer biology. Here, we show that a large (~70%) reduction in the urokinase plasminogen activator receptor (uPAR) level in human carcinoma HEp3 cells, while not affecting their in vitro growth, induced a protracted state of tumor dormancy in vivo, with G0/G1 arrest. We have now identified the mechanism responsible for the induction of dormancy. We found that uPA/uPAR proteins were physically associated with α5β1, and that in cells with low uPAR the frequency of this association was significantly reduced, leading to a reduced avidity of α5β1 and a lower adhesion of cells to the fibronectin (FN). Adhesion to FN resulted in a robust and persistent ERK1/2 activation and serum-independent growth stimulation of only uPAR-rich cells. Compared with uPAR-rich tumorigenic cells, the basal level of active extracellular regulated kinase (ERK) was four to sixfold reduced in uPAR-poor dormant cells and its stimulation by single chain uPA (scuPA) was weak and showed slow kinetics. The high basal level of active ERK in uPAR-rich cells could be strongly and rapidly stimulated by scuPA. Disruption of uPAR-α5β1 complexes in uPAR-rich cells with antibodies or a peptide that disrupts uPAR- β1 interactions, reduced the FN-dependent ERK1/2 activation. These results indicate that dormancy of low uPAR cells may be the consequence of insufficient uPA/uPAR/α5β1 complexes, which cannot induce ERK1/2 activity above a threshold needed to sustain tumor growth in vivo. In support of this conclusion we found that treatment of uPAR-rich cells, which maintain high ERK activity in vivo, with reagents interfering with the uPAR/β1 signal to ERK activation, mimic the in vivo dormancy induced by downregulation of uPAR.

Original languageEnglish (US)
Pages (from-to)89-103
Number of pages15
JournalJournal of Cell Biology
Volume147
Issue number1
DOIs
StatePublished - Oct 4 1999
Externally publishedYes

Keywords

  • Fibronectin
  • Integrin activation
  • Mitogen-activated protein kinase
  • Tumor dormancy
  • uPAR

ASJC Scopus subject areas

  • Cell Biology

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