| pubmed-article:10508858 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:10508858 | lifeskim:mentions | umls-concept:C0027651 | lld:lifeskim |
| pubmed-article:10508858 | lifeskim:mentions | umls-concept:C0086418 | lld:lifeskim |
| pubmed-article:10508858 | lifeskim:mentions | umls-concept:C0007097 | lld:lifeskim |
| pubmed-article:10508858 | lifeskim:mentions | umls-concept:C0021701 | lld:lifeskim |
| pubmed-article:10508858 | lifeskim:mentions | umls-concept:C0071216 | lld:lifeskim |
| pubmed-article:10508858 | lifeskim:mentions | umls-concept:C0678686 | lld:lifeskim |
| pubmed-article:10508858 | lifeskim:mentions | umls-concept:C0013081 | lld:lifeskim |
| pubmed-article:10508858 | lifeskim:mentions | umls-concept:C2611831 | lld:lifeskim |
| pubmed-article:10508858 | lifeskim:mentions | umls-concept:C0205263 | lld:lifeskim |
| pubmed-article:10508858 | lifeskim:mentions | umls-concept:C1314939 | lld:lifeskim |
| pubmed-article:10508858 | pubmed:issue | 1 | lld:pubmed |
| pubmed-article:10508858 | pubmed:dateCreated | 1999-11-4 | lld:pubmed |
| pubmed-article:10508858 | pubmed:abstractText | 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 ( approximately 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 G(0)/G(1) arrest. We have now identified the mechanism responsible for the induction of dormancy. We found that uPA/uPAR proteins were physically associated with alpha5beta1, and that in cells with low uPAR the frequency of this association was significantly reduced, leading to a reduced avidity of alpha5beta1 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-alpha5beta1 complexes in uPAR-rich cells with antibodies or a peptide that disrupts uPAR-beta1 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/alpha5beta1 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/beta1 signal to ERK activation, mimic the in vivo dormancy induced by downregulation of uPAR. | lld:pubmed |
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| pubmed-article:10508858 | pubmed:language | eng | lld:pubmed |
| pubmed-article:10508858 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:10508858 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:10508858 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:10508858 | pubmed:month | Oct | lld:pubmed |
| pubmed-article:10508858 | pubmed:issn | 0021-9525 | lld:pubmed |
| pubmed-article:10508858 | pubmed:author | pubmed-author:OssowskiLL | lld:pubmed |
| pubmed-article:10508858 | pubmed:author | pubmed-author:Aguirre... | lld:pubmed |
| pubmed-article:10508858 | pubmed:author | pubmed-author:KovalskiKK | lld:pubmed |
| pubmed-article:10508858 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:10508858 | pubmed:day | 4 | lld:pubmed |
| pubmed-article:10508858 | pubmed:volume | 147 | lld:pubmed |
| pubmed-article:10508858 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:10508858 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:10508858 | pubmed:pagination | 89-104 | lld:pubmed |
| pubmed-article:10508858 | pubmed:dateRevised | 2009-11-19 | lld:pubmed |
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