Revisiting the biological roles of PAI2 (SERPINB2) in cancer

Tumour expression of the urokinase plasminogen activator correlates with invasive capacity. Consequently, inhibition of this serine protease by physiological inhibitors should decrease invasion and metastasis. However, of the two main urokinase inhibitors, high tumour levels of the type 1 inhibitor actually promote tumour progression, whereas high levels of the type 2 inhibitor decrease tumour growth and metastasis. We propose that the basis of this apparently paradoxical action of two similar serine protease inhibitors lies in key structural differences controlling interactions with components of the extracellular matrix and endocytosis–signalling co-receptors. Of the two main urokinase plasminogen activator inhibitors, high tumour levels of the type 1 inhibitor promote tumour progression, whereas high levels of the type 2 inhibitor decrease tumour growth and metastasis. What might be the basis of this paradoxical action?