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Multiple pathways of cell invasion are regulated by multiple families of serine proteases
Mario Del Rosso1, Gabriella Fibbi, Marco Pucci
1Department of Experimental Pathology and Oncology, Florence University, Italy. delrosso@unifi.it
Abstract:
The complex process of tumor invasion requires the coordinated expression and activity of cell-substratum adhesive interactions and of cell-associated protease systems, which destroy the extracellular matrix (ECM), in order to enable the invading cells to simultaneously grip and destroy the anatomical barriers that control cell spreading. A number of data indicate that such a 'grip and go' process may be performed by an enlarging series of cell membrane-associated serine proteases and serine protease receptors, which provide the invasive cells with a functional unit (the protease and its receptor), able to mediate cell-substratum adhesion through specific receptor domains, to proteolytically degrade ECM and to deliver into the cell signals that up-regulate the expression either of the protease/receptor complex, or of other adhesion molecules, such as integrins. There is evidence that some proteases and protease receptor expression are under the control of tumor hypoxia, which is the result of an imbalance in oxygen supply and demand. The urokinase-type plasminogen activator (u-PA) receptor (u-PAR) is under hypoxic control and cooperates with other serine proteases of the blood coagulation pathways that may extravasate in the tumor milieu as a result of hypoxia-simulated increase of vessel permeability. Other serine proteases and their receptors cooperate with the cell-associated fibrinolytic system to promote cell invasion. Among these, tissue factor and its ligand coagulation factor VII, thrombin and its protease-activated receptors, and type II trans-membrane serine proteases seem to play a crucial role. This Review takes into consideration the complex scenario of the single serine proteases and related receptors that are involved in cell invasion, as well as the protease receptor/adhesion molecule interplay which is necessary to focus the cell surface-driven proteolysis where adhesion provides a grip to the invading cell.
Insights
Tumor invasion relies on cell adhesion and proteases that degrade the extracellular matrix. Hypoxia influences urokinase plasminogen activator receptor (u-PAR) and coagulation factors, crucial for cancer cell spread.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Tumor invasion is a complex process involving cell adhesion and extracellular matrix (ECM) degradation.
- Cell-membrane-associated serine proteases and their receptors form functional units for cell invasion.
- Tumor hypoxia, an imbalance of oxygen supply and demand, influences the expression of proteases and receptors.
Purpose of the Study:
- To review the role of serine proteases and their receptors in tumor invasion.
- To explore the interplay between protease receptors and adhesion molecules in facilitating cell invasion.
- To discuss the impact of tumor hypoxia on the expression and function of invasion-related proteases.
Main Methods:
- Review of existing scientific literature on serine proteases, their receptors, and their involvement in tumor cell invasion.
- Analysis of the functional cooperation between proteases, receptors, and adhesion molecules like integrins.
- Consideration of the regulatory role of tumor hypoxia on the expression of urokinase-type plasminogen activator receptor (u-PAR) and other proteases.
Main Results:
- Serine proteases and their receptors mediate a 'grip and go' process, enabling cell adhesion, ECM degradation, and intracellular signaling.
- Urokinase-type plasminogen activator receptor (u-PAR) is under hypoxic control and interacts with coagulation factors.
- Tissue factor, thrombin, and type II transmembrane serine proteases are identified as key players in promoting cell invasion.
Conclusions:
- The coordinated action of serine proteases, their receptors, and adhesion molecules is essential for tumor cell invasion.
- Hypoxia significantly influences the expression of key proteases and receptors involved in cancer cell spread.
- Understanding these complex interactions provides insights into targeting tumor invasion and metastasis.