Protease Inhibition Mechanisms in Cancer Metastasis

Cancer metastasis involves a complex interplay between tumour cells and their surrounding stroma, with proteolytic enzymes mediating the degradation of extracellular barriers and facilitating invasion. Proteases such as serine proteases and matrix metalloproteinases (MMPs) cleave structural components of the extracellular matrix, enabling tumour cell migration and dissemination. In response, endogenous protease inhibitors—particularly the serine protease inhibitor (serpin) family—act as critical regulators of pericellular proteolysis. By forming covalent complexes with target enzymes, serpins modulate protease activity, thereby influencing cell adhesion, migration and the formation of metastatic niches. Dysregulation of the protease–inhibitor balance can either suppress or, paradoxically, promote metastasis through effects on matrix remodelling, angiogenesis and interactions with immune cells. Recent work has illuminated how specific serpins, notably those targeting urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), exert pleiotropic roles in shaping the tumour microenvironment. Understanding these inhibitory mechanisms has yielded insights into potential therapeutic strategies aimed at restoring proteolytic homeostasis to limit metastatic spread.

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Protease Inhibition Mechanisms in Cancer Metastasis publication trend

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

Technical terms

Protease: An enzyme that cleaves peptide bonds in proteins, often facilitating tissue remodelling and cell migration.

Serine protease inhibitor (serpin): A family of proteins that inhibit serine proteases through a suicide-substrate mechanism, regulating extracellular proteolysis.

Urokinase-type plasminogen activator (uPA): A serine protease that converts plasminogen to plasmin, promoting degradation of extracellular matrix components.

Matrix metalloproteinase (MMP): A class of zinc-dependent endopeptidases involved in the breakdown of extracellular matrix proteins during tissue remodelling and tumour invasion.

Extracellular matrix (ECM): A complex network of proteins and polysaccharides surrounding cells, providing structural support and regulating cell behaviour.

Metastasis: The process by which cancer cells spread from a primary tumour to establish secondary growths in distant organs.

References

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3. LHX2 Enhances the Malignant Phenotype of Esophageal Squamous Cell Carcinoma by Upregulating the Expression of SERPINE2. Genes (2022).