Type‐1 Plasminogen Activator Inhibitor in Human Renal Cell Carcinoma

Abstract

In experimental models, plasminogen activator-mediated degradation of the extracellular matrix is inhibited by type-1 plasminogen activator inhibitor (PAI-1). PAI-1 has also been shown to protect tumour stromal tissue from autoproteolytic activities and may thus substantially promote tumour growth and metastasis formation. Human renal cell carcinoma (RCC) cells express significant amounts of plasminogen activator activity. In the present study, the expression of its specific inhibitor PAI-1 has been investigated in 32 cases of RCC and compared with adjacent non-tumour renal tissues. RCC tissue exhibited higher levels of PAI-1, determined at both the antigen and the mRNA level by ELISA and Northern blot analysis respectively. Immunohistochemical analysis showed that PAI-1 antigen was primarily confined to tumour cells and vascular endothelium, a distribution similar to that previously reported for plasminogen activator activity in RCC. The close co-localization with endogenous plasminogen activator activity may be important in the regulation of RCC-associated proteolysis. The increased expression of PAI-1 and its predominant localization within the tumour may help to conserve tumour tissue integrity and may thus promote RCC progression and metastasis formation.

Urokinase gene expression indicates early invasive growth in squamous cell lesions of the uterine cervix

“…uPA, tPA, and PAI-1 expression has been attributed to various cell types, and carcinoma cells, stromal cells, or both of these cell types have been described as sources of uPA, tPA, and PAI-1. [31][32][33][34][35][36][37] In our study, at variance with observations in other tumour entities and with other techniques, uPA and tPA expression was rarely detectable in stromal cells of uterine SCCs. Expression of PAI-1, on the other hand, predominated in stromal cells and was additionally observed in endothelial cells.…”

The urokinase plasminogen activator system in angiosarcoma, Kaposi's sarcoma, granuloma pyogenicum, and angioma: an immunohistochemical study

“…Very different approaches which interfere with the expression and reactivity of uPA, uPA‐R, and PAI‐1 at the gene or protein level were successfully tested, including antisense oligonucleotides, antibodies, inhibitors, and recombinant or synthetic uPA and uPA‐R analogs. 8–21 Our results suggest that specific proteinase inhibitors may represent a new therapeutic strategy in order to inhibit neoangiogenesis in both KS and AS. Up to now, only a very small percentage of patients with AS, usually those with lesions less than 10 cm in diameter at presentation, can be successfully treated by surgery and radical wide‐field radiotherapy.…”

“…It has been demonstrated that elevated tumor antigen levels of uPA, uPA‐R, and/or PAI‐1 are associated with tumor invasion, metastasis, and poor prognosis in different types of tumor. For example, in breast cancer, 7–8 gastric cancer, 9 squamous cell carcinoma of the oropharnyx, 10 lung cancer, 1 and renal cell carcinoma, 11 uPAS plays an important role in tumor progression.…”

The multi‐functional serpin, protein C inhibitor: beyond thrombosis and hemostasis

“…u‐PA plays important roles in various extracellular proteolytic processes. Although PAI‐1 and PAI‐2, the primary physiological inhibitors of u‐PA, are expressed in human renal cell carcinoma (RCC) tissue [91], they are not normally expressed in the kidneys [92]. In normal human urine, there are high levels of u‐PA–PCI complexes, suggesting that these complexes might be formed in the kidneys.…”