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centration of tPA in plasma amounts to 5–10 ng/ml, but varies strongly under different physiological and pathological conditions. Although it was already known before 1970 that plasminogen activator activity may be increased in tumour tissues over non-neoplastic tissue, for some time, interest was turned away from the possible role of plasminogen activators in cancer progression [15–20], particularly because the techniques used then did not distinguish between the two types of plasminogen activators, uPA and tPA [21, 22]. In the years following Astedt and Holmberg’s observation that uPA is released by human ovarian cancer cells, several other authors reported elevated uPA concentrations in tumour tissues compared to non-neoplastic tissues [23–26]. These observations prompted several investigators to restart detailed analyses of plasminogen activators, especially uPA, in tumour tissue and blood samples from cancer patients. Due to refined analytical tools and instruments, the structure of uPA, its proteolytic activation and role in the pathophysiology of tumour stroma degradation and tumour spread was investigated. This was also enhanced by the fact that, in 1985, a cell surface receptor for uPA (uPAR; CD87) was detected and it also became clear that the proteolytic activity of uPA and tPA in thrombolysis and fibrinolysis is counterbalanced by inhibitors of tPA and uPA and that uPAR is a focal adhesion point for localised uPA-mediated proteolysis in the physiological and malignant state [27, 28]. In 1966, Brakman et al. [29] described the presence of a plasminogen activator inhibitor in a group of patients with an impaired plasma fibrinolytic system, but it took another 18 years before the inhibitor PAI-1 was isolated [30]. The PAI-1 concentration in plasma is about 20 ng/ml. The other inhibitor, PAI-2, was first detected in human placental tissue [31] and was therefore named placenta-type plasminogen activator inhibitor. Later it became clear that PAI-2 is also present in various types of white blood cells and in tumour tissue [32]. The PAI-2 concentrations in plasma are usually low, but can be high (above 35 ng/ml) in pregnant women. |
