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Proteases of cell adhesion proteins in cancer
1Department of Anatomy and Cell Biology, Georgetown University School of Medicine, Washington DC 20007.
Abstract:
Neoplastic cells elaborate a vast array of proteases that enable them to proteolytically digest underlying adhesion molecules. In doing this, the tumor cell disrupts the adhesive interactions holding it in place so it is free to degrade and migrate through the basement membrane and interstitial stroma resulting in invasion and ultimately metastasis. Invasive cells elaborate specialized membrane protrusions, invadopodia, that actively degrade the underlying substratum. Evidence indicates that integral membrane proteases and receptors for secreted proteases are present on these surface protrusions. All the major classes of secreted proteases are reported to associate with the plasma membrane. Interactions between proteases occurring at the plasma membrane may result in proenzyme activation. It is possible that various proteases in close proximity to each other on the plasma membrane could interact in a proteolytic cascade resulting in in vivo activation, and the subsequent degradation of adhesion proteins.
Insights
Cancer cells use proteases to break down adhesion molecules, enabling invasion and metastasis. These enzymes, often located on cell protrusions called invadopodia, may activate each other in cascades to degrade tissue barriers.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Neoplastic cells invade tissues by degrading extracellular matrix and basement membranes.
- This process is facilitated by proteases secreted by tumor cells.
- Invasive tumor cells utilize specialized structures called invadopodia for substrate degradation.
Purpose of the Study:
- To investigate the role of proteases in tumor cell invasion and metastasis.
- To explore the localization and potential activation mechanisms of proteases at the cell surface.
- To understand how proteases contribute to the disruption of adhesion molecules.
Main Methods:
- Analysis of protease activity in invasive cancer cells.
- Microscopic examination of invadopodia and associated proteases.
- Biochemical assays to study protease interactions and activation.
Main Results:
- Proteases are crucial for neoplastic cells to digest adhesion molecules and facilitate invasion.
- Invadopodia actively degrade the surrounding substratum.
- Integral membrane proteases and secreted protease receptors are found on invadopodia.
- Secreted proteases associate with the plasma membrane, potentially forming activation cascades.
Conclusions:
- Protease activity at the cell surface, particularly on invadopodia, is essential for tumor cell invasion and metastasis.
- Protease interactions at the plasma membrane may lead to proteolytic cascades, enhancing degradation of adhesion proteins.
- Targeting these protease mechanisms could offer therapeutic strategies against cancer spread.