The Plasminogen Activator Inhibitor 1 (PAI-1) paradox in cancer: From tumor microenvironment remodeling to therapeutic targeting.

Abstract

Plasminogen activator inhibitor-1 (PAI-1), encoded by the SERPINE1 gene, is a key regulator of the fibrinolytic system through inhibition of the plasminogen activators urokinase (uPA) and tissue-type plasminogen activator (tPA). Although this canonical function would be expected to limit extracellular matrix degradation and tumor invasion, elevated PAI-1 expression is consistently associated with tumor progression and poor clinical outcomes across multiple cancer types. This apparent contradiction, known as the "PAI-1 paradox," highlights the diverse biological functions of PAI-1 beyond fibrinolysis. Within the tumor microenvironment, PAI-1 regulates several hallmarks of cancer through interactions with extracellular matrix components and receptors such as LRP1, uPAR, and integrins. These interactions influence angiogenesis, apoptosis resistance, tumor cell migration, and extracellular matrix remodeling. Emerging evidence also indicates that PAI-1 shapes the immune microenvironment by modulating immune cell recruitment and macrophage polarization, although the underlying mechanisms remain incompletely understood. Clinically, SERPINE1 overexpression correlates with poor prognosis in numerous malignancies, including colorectal, lung, breast, and gastric cancers. Pharmacological targeting of the PAI-1 axis with small-molecule inhibitors or neutralizing antibodies shows antitumor activity in preclinical models, and the oral inhibitor TM5614 has reached phase III clinical trial in chronic myeloid leukemia and melanoma. This narrative review summarizes current knowledge of PAI-1 regulation and function in cancer and discusses therapeutic strategies targeting this pathway.

Abstract as supplied by the indexing source. © the authors / publisher.