TY - JOUR
T1 - Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling
AU - Aguirre Ghiso, Julio A.
AU - Kovalski, Katherine
AU - Ossowski, Liliana
PY - 1999/10/4
Y1 - 1999/10/4
N2 - 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.
AB - 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.
KW - Fibronectin
KW - Integrin activation
KW - Mitogen-activated protein kinase
KW - Tumor dormancy
KW - uPAR
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UR - http://www.scopus.com/inward/citedby.url?scp=0002460807&partnerID=8YFLogxK
U2 - 10.1083/jcb.147.1.89
DO - 10.1083/jcb.147.1.89
M3 - Article
C2 - 10508858
AN - SCOPUS:0002460807
SN - 0021-9525
VL - 147
SP - 89
EP - 103
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 1
ER -