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Background: Plasminogen activators (PA) may be released by the gut and eliminated by the liver. Patients with liver disorders or malignancy often have abnormal plasma levels of PAs. Some tumours may produce PAs., Methods: In patients undergoing gastric surgery for malignant (n = 18) or benign (n = 21) disorders., blood drawn from the portal vein and a peripheral vein was analysed for tissue-type plasminogen activator antigen and activity (tPA: Ag, tPA: Act), single-chain urokinase-type plasminogen activator activity (scuPA: Act), and plasminogen activator inhibitor antigen and activity (PAI: Ag, PAI: Act)., Results and Conclusions: In both groups tPA: Act and scuPA: Act levels were significantly higher in portal blood than in peripheral blood, but tPA: Ag and PAI: Act levels did not differ. PAI: Act levels were significantly lower in patients with malignant disease, but levels of the other markers did not differ in the two groups.

Colorectal tumorigenesis is associated with remarkable changes in the plasminogen activation system at the tissue level. The sequence of normal mucosa-adenomatous polyp-adenocarcinoma-metastasis is accompanied by an increase in the urokinase-type of plasminogen activator, the urokinase receptor and the inhibitors type-1 and type-2, with a concurrent decrease in the tissue-type plasminogen activator. Overall survival analysis of colorectal cancer patients, with a follow-up of more than 5 years, revealed that several of these components, in both the carcinomas and their corresponding normal mucosa, are of prognostic value independent of major clinicopathological parameters. Therefore, the plasminogen activation cascade not only contributes to the invasive and metastatic growth of colorectal tumours, but might also have a clinical impact with respect to adjuvant and intervention therapy.

In tumour development, proteases such as plasminogen activators (PAs) play a role in degradation of the extracellular matrix and other tissue barriers. Recently, we demonstrated that plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of cutaneous melanocytic tumour progression. In this study we investigated the expression and distribution of the various components of the PA system and the presence of PA enzyme activity in 45 freshly frozen primary uveal melanoma with known follow-up (14 spindle and 31 non-spindle type) and in metastases (n = 5). Tissue-type PA (t-PA) was found in endothelium of blood vessels and in tumour cells in almost all lesions, and was markedly present at the invasive front (towards the sclera and Bruch's membrane), but no correlation with tumour-related death could be established. Urokinase PA (u-PA) was expressed focally, by only five non-spindle cell melanomas but in all metastases. u-PA expression correlated with occurrence of metastasis. u-PA receptor (u-PAR) was present in one-third of all the tumours examined. Plasminogen activator inhibitors (PAI-1 and PAI-2) were found only focally in approximately 10 per cent of the lesions. Staining of t-PA, u-PA, and PAI was observed in all the metastases. We conclude that in uveal melanoma, u-PA expression may be associated with metastatic disease and accordingly with a poor prognosis. Further research on a larger group of tumours with known follow-up is needed to establish whether u-PA positivity is of additional prognostic value in uveal melanoma.

We quantitated urokinase and tissue plasminogen activator (u-PA, t-PA), plasminogen activator inhibitor 1 and 2 (PAI-1, PAI-2), and fibrinolytic activity in peripheral blood (PB), tumour blood (TB), peritoneal/ascitic fluid (PAF) and cystic fluid (CF) from 104 patients with benign and 36 patients with malignant ovarian tumours, and in peripheral blood from 62 healthy controls. PB levels of u-PA were higher in patients with benign and malignant tumours than in controls. High concentrations of u-PA were found in CF, but not in TB, suggesting that u-PA is released by the tumour tissue, but not by the tumour vasculature. PB levels of t-PA were higher in both tumour groups than in controls. Increased levels of t-PA were found in TB, but not in CF, indicating that t-PA is released by the tumour vasculature, but not by the tumour tissue. PB levels of PAI-1 were higher in patients with both benign and malignant tumours than in controls. High levels of PAI-1 were present in both TB and CF from malignant tumours, suggesting that PAI-1 is released from the tumour vasculature as well as the tumour tissue. Elevated concentrations of PAI-2 were found in CF, but not in TB, indicating release from the tumour tissue, but not from the vasculature. High levels of t-PA, PAI-1 and PAI-2 were found in PAF of malignant tumours, and resorption from this compartment may explain elevated PB levels in patients with ascites. None of the PAs/PAIs proved useful as a PB marker for detection of early stage ovarian cancer. However, an index based on PAF levels of t-PA and PAI-1 discriminated between malignant and benign ovarian cysts in the absence of ascites. In addition, our study stresses the importance of including patients with benign tumours as well as healthy controls when markers for malignant tumours are evaluated.

The content of PAI-I was measured in carcinoma tissues from the stomach and colorectum divided macroscopically into 3 portions: the central part of the carcinoma, the marginal part of the carcinoma containing some normal mucosa, and the normal mucosa. Among these tissues, the highest levels of PAI-I antigen were found in the central part of the carcinoma. On the other hand, no PAI-I antigen or activity was observed in the normal mucosae. The PAI-I produced in the stomach and colorectal carcinoma tissues showed a non-lytic zone with a molecular weight of 54 kDa by reverse fibrin autography, and this 54-kDa band reacted with anti-PAI-I IgG on an immunoblotted nitrocellulose membrane by the avidin-biotin complex method. The contents of PAI-2 in the carcinoma tissues were not significantly different from those in the normal mucosa of the stomach and colorectum. In both the stomach and colorectal carcinomas, the highest value of u-PA/total PA (sum of u-PA and t-PA) was observed in the central part of the carcinoma, followed by the marginal part of the carcinoma, and was lowest in the normal mucosa. We conclude that increased levels of PAI-I in malignant tissue of the stomach and colorectal tract may serve to modulate extra-cellular proteolysis by u-PA.