Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and plasminogen activator inhibitors in patients with renal cell carcinoma: correlation with tumor associated macrophage and prognosis.

Abstract

Urokinase-type plasminogen activator (uPA) has an important role in tumor progression through the degradation of extracellular matrix. In addition, uPA receptor (uPAR) and plasminogen activator inhibitors (PAIs), composed of PAI-1 and 2, are also known to affect such activities. Tumor associated macrophage (TAM) is an important regulator of tumor progression that is associated with the uPA system in various cancers. However, to our knowledge the clinical significance of PAI-2 and the relationship between the uPA system and TAM in human renal cell carcinoma (RCC) tissues have not been investigated. We investigated and clarified these issues. The subjects of the current study were 106 consecutive surgically resected specimens from patients with RCC. The expression of uPA, uPAR, PAI-1 and PAI-2 was determined by immunohistochemistry. We also examined the relationships among these molecules, survival and TAM. The mean immunoreactive scores (range 0 to 6) of uPA, uPAR, PAI-1 and PAI-2 were 3.09, 2.22, 1.99 and 0.56, respectively. These scores correlated with the grade and presence of metastasis. The expression of uPA, uPAR and PAI-1 but not PAI-2 correlated negatively with cause specific survival. Of uPA family members multivariate analysis showed that PAI-1 independently influenced cause specific survival. TAM counts correlated with PAI-1 only (p <0.001). Our results suggest that PAI-1 is an important regulator of tumor progression and survival, and PAI-1 may modulate them via TAM. On the other hand, PAI-2 has a minimum role in survival. Our results may help discussions of treatment strategy in patients with RCC.