Urokinase-Receptor/Integrin Complexes Are Functionally Involved in Adhesion and Progression of Human Breast Cancer in Vivo
| Autor: | Marcel Karperien, Paul H.A. Quax, Clemens W.G.M. Löwik, Bianca Sijmons, Gabri van der Pluijm, Chris van der Bent, Socrates E. Papapoulos, J. W. Drijfhout, Jan H. Verheijen, H. J. M. Vloedgraven |
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| Jazyk: | angličtina |
| Rok vydání: | 2001 |
| Předmět: |
medicine.medical_specialty
Integrins Integrin Bone Neoplasms Breast Neoplasms Receptors Cell Surface Pathology and Forensic Medicine Receptors Urokinase Plasminogen Activator Plasminogen Activators Internal medicine medicine Cell Adhesion Humans Fibrinolysin Cell adhesion skin and connective tissue diseases biology Cell adhesion molecule Middle Aged medicine.disease Metastatic breast cancer Urokinase receptor Fibronectin Endocrinology Tumor progression Cancer research biology.protein Disease Progression Vitronectin Female Regular Articles |
| Popis: | Interactions between specific cell-surface molecules, which include the urokinase receptor (uPAR) and integrins, are crucial to processes of tumor invasion and metastasis. Here we demonstrate that uPAR and beta1-integrins may cluster at distinct sites at the cell surface of metastatic MDA-MB-231 breast cancer cells and form functional complexes. Attachment assays performed in the presence of a synthetic peptide (p25), which interferes with the formation of uPAR-integrin complexes, reveal that uPAR is able to regulate the adhesive function of integrins in breast cancer cells. On dissociation of the uPAR-integrin complexes by p25, tumor cell attachment to the extracellular matrix was either decreased (vitronectin) or increased (fibronectin). Moreover, the tumor cells display remarkable morphological changes when cultured on fibronectin in the continuous presence of p25, leading to increased cell spreading and attachment. In marked contrast to control conditions, increased cellular adhesion to fibronectin after p25 treatment was entirely beta1-integrin-mediated. The role of uPAR-integrin complexes in tumor progression was studied in an in vivo bone xenograft model. Stably transfected MDA-MB-231 cells that overexpress p25 showed a significant reduction in tumor progression in bone (Por = 0.0001 versus mock-control). In line with these observations, continuous administration of p25 (25 microg/mouse/day, osmotic minipumps) for 28 days resulted in significantly reduced tumor progression of MDA-MB-231 cells in bone (Por = 0.005) when compared to scrambled control peptide. In conclusion, our data demonstrate that uPAR can act as an adhesion receptor in breast cancer and is capable of regulating integrin function. Our findings strongly suggest that adhesive and proteolytic events are tightly associated in metastatic breast cancer cells and that functional integrin-uPAR complexes are involved in tumor progression in vivo. |
| Databáze: | OpenAIRE |
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