Urokinase Plasminogen Activation in Cancer Metastasis

The urokinase plasminogen activation system plays a pivotal role in tumour cell invasion and dissemination by converting the inactive zymogen plasminogen into the broad-acting serine protease plasmin. Binding of urokinase‐type plasminogen activator (uPA) to its cell‐surface receptor (uPAR) focusses proteolytic activity at the pericellular environment, initiating a proteolytic cascade that degrades extracellular matrix (ECM) components and releases matrix‐bound growth factors. Beyond its proteolytic function, uPA–uPAR engagement triggers intracellular signalling networks—often via co-receptors such as integrins and receptor tyrosine kinases—that promote cell migration, survival, epithelial–mesenchymal transition and establishment of secondary lesions. Dysregulation of this system has been documented across a wide spectrum of malignancies, correlating with poor prognosis and resistance to therapy. Therapeutic strategies targeting uPA, uPAR or their interaction with ECM partners are under development both as prognostic biomarkers and as means to impede metastasis.

Research from Nature Portfolio

Recent work has clarified the link between oncogenic RAS mutations and uPAR overexpression, demonstrating that RAS‐driven cancers co‐opt uPA–uPAR interactions to facilitate adhesion, migration and metastatic colonisation. Functional studies reveal that heightened uPAR levels in RAS‐mutant cells amplify crosstalk with vitronectin and receptor tyrosine kinases, shifting the balance from dormancy to proliferation at distant sites. Importantly, novel small-molecule inhibitors that disrupt the uPAR–vitronectin interface have shown efficacy in preclinical models, attenuating metastatic spread in vitro and in vivo. These findings underscore the value of uPAR as both a mechanistic node in RAS-driven tumour progression and as a viable target for anti-metastatic drug development.

Urokinase Plasminogen Activation in Cancer Metastasis publication trend

The graph below shows the total number of articles in urokinase plasminogen activation in cancer metastasis across all publications each year (not limited to Nature Index journals).

Technical terms

Urokinase‐type plasminogen activator (uPA): A serine protease that converts plasminogen into plasmin upon binding to uPAR.

Urokinase plasminogen activator receptor (uPAR): A glycosylphosphatidylinositol-anchored membrane protein that localises uPA activity to the cell surface and initiates downstream signalling.

Plasminogen: The inactive precursor of plasmin, circulating in blood and activated by specific proteases.

Plasmin: A potent serine protease that degrades fibrin and ECM proteins, and activates other proteolytic enzymes.

Extracellular matrix (ECM): The complex network of proteins and glycoproteins providing structural support to tissues and regulating cell behaviour.

Epithelial–mesenchymal transition (EMT): A phenotypic conversion whereby epithelial cells acquire mesenchymal traits, enhancing motility and invasiveness.

References

1. Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications. Frontiers in Oncology (2018).
2. Urokinase-type plasminogen activator receptor (uPAR) expression enhances invasion and metastasis in RAS mutated tumors. Scientific Reports (2017).
3. A dual role for ERK-1/2 in the regulation of plasmin activity and cell migration in metastatic NSCLC-H1299 cells. Archives of Toxicology (2023).
4. Redrawing Urokinase Receptor (uPAR) Signaling with Cancer Driver Genes for Exploring Possible Anti-Cancer Targets and Drugs. Pharmaceuticals (2023).
5. Plasmin and Plasminogen System in the Tumor Microenvironment: Implications for Cancer Diagnosis, Prognosis, and Therapy. Cancers (2021).
6. Identification of the urokinase receptor as an adhesion receptor for vitronectin.. Journal of Biological Chemistry (1994).