Plasmin-Cellular Interactions in Breast Cancer Invasion and Metastasis.
Abstract
Invasion and metastasis of breast cancer cells requires a cell-surface proteinase cascade in which the protienase, plasmin, plays a prominent role. The tumor invasion proteinase cascade functions optimally only when plasmin is bound to the cell surface. Different cellular receptors may be responsible for plasmin-binding. The goal of this research program has been to identify macromolecules responsible for plasmin bindings in breast cancer cells and to characterize the function of these receptors. In the third year of this research program, we made substantial progress towards understanding the function of cell-surface cytokeratin-8 (CK8) as the major plasminogen receptor in three different breast cancer cell lines. Our studies have demonstrated that CK8 promotes plasminogen activation by tPA through the formation of a tetramolecular complex which may also involve CKl 8. Using genetic constructs, we characterized the binding sites for tPA and plasminogen in the cytokeratins and we have determined that these binding sites are non- identical. While CK8 serves as the principal binding site for plasminogen in MCF-7 cells, a separate macromolecule is apparently responsible for binding the plasminogen which serves as substrate for uPA in the protease cascade. We have also learned that highly aggressive breast cancer cell lines, which metastasize in animal model systems, do not express CK8 on the cell surface, probably due to the lack of desmosome structures. We have thus proposed a new model regarding plasminogen receptors and the tumor invasion proteinase cascade in breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1997
- Accession Number
- ADA344976
Entities
People
- Steven L. Gonias
Organizations
- University of Virginia