Differential biological significance of tissue-type and urokinase-type plasminogen activator in human breast cancer

Abstract

Summary Plasminogen activator (PA) is a serine protease existing in two forms known as tissue-type (t-PA) and urokinase-type (u-PA). To examine whether PA is related to the postoperative clinical course of human breast cancer, total PA activity, t-PA activity, u-PA activity, and immunoreactive t-PA were determined in tissue extracts from 144 breast cancer specimens. The patients were initially divided into four groups according to the postoperative clinical course: Group I (83 patients who are disease-free), Group II (20 patients whose first metastases were found only in bone), Group III (19 patients whose first metastases were found in both bone and lung), and Group IV (22 patients whose first metastases were found only in lung). Total PA activity was significantly lower in Groups, II, III and IV than in Group I. Both t-PA activity and t-PA antigen levels were also significantly lower in Groups II, III and IV than in Group I, while no significant difference was found in u-PA activity among these groups, indicating that low activity of total PA in Groups II, III and IV was due to a decrease in t-PA but not in u-PA. In the multivariate analyses, t-PA activity was found to be an independent prognostic factor for relapse-free survival. When four groups of patients were further analysed in terms of nodal status, both t-PA activity and antigen levels were markedly decreased in the node-negative Group II compared with the node-negative Groups III and IV or with the node-positive Groups II, III and IV. Of additional interest, u-PA activity was significantly higher in node-positive patients than in nodenegative patients with any group. The clinico-pathologic analyses of the patients in this series showed that node involvement and lymphatic invasion were more frequently positive in Groups III and IV than in Groups I and II. When 144 breast cancers were categorised in terms of combinations of oestrogen receptor (ER) and progesterone receptor (PgR) status, breast cancers which were positive for both receptors were found to contain the highest t-PA activity and antigen. This study provides provocative evidence suggesting a possible differential significance of t-PA and u-PA expression in human breast cancer.Many transformed or malignant tumour cells are known to produce plasminogen activator (PA), a serine-type protease converting plasminogen to plasmin (Unkeless et al., 1975;Howett et al., 1978;Orenstein et al., 1983). It is widely accepted that PA is intimately involved in the metastatic spread of tumour cells (Dano et al., 1985;Colombi et al., 1986;Mignatti et al., 1986;Reich et al., 1988;Ossowski et al., 1988;Markus et al., 1988;Yu et al., 1990;Testa et al., 1990;Hollas et al., 1991). There are two main forms of PA: urokinase type (u-PA) and tissue-type (t-PA). While both catalyse cleavage of the peptide bond between Arg-Val in plasminogen, thus converting the proenzyme to plasmin, they differ in many aspects such as their molecular weight, immunological reactivity and amino acid sequence (Ny et al., 1984;Riccio et al.,...

In vivo Evaluation Method of the Effect of Nattokinase on Carrageenan-Induced Tail Thrombosis in a Rat Model

“…Consequently, the increased levels of plasmin and nattokinase itself dissolve the fibrin clot [24,25]. Major plasminogen activators are mainly divided into t-PAs and urokinase-type plasminogen activators [26,27]. Nattokinase stimulates t-PA, and plasmin is produced from plasminogen [28].…”

Production of immunoreactive polymorphonuclear leucocyte elastase in human breast cancer cells: possible role of polymorphonuclear leucocyte elastase in the progression of human breast cancer

“…Furthermore, elastase is reported to potentiate the conversion of plasminogen to plasmin by urokinase-type plasminogen activator (Machovich & Owen, 1989), which is also synthesised by a number of tumour cells, including breast cancer cells (Cajot et al, 1986;Stump et al, 1986). Recently, a direct correlation has been found between levels of urokinase plasminogen activator activity and/or concentration and 'metastatic potential in human and rodent mammary carcinoma (Duffy et al, 1988;Janicke et al, 1990;Yamashita et al, 1992;1993b). Collagenase, which may play a role in tumour cell invasion at a neutral pH, can be activated through plasminogen activator (Paranjpe et al, 1980).…”

Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer

“…Both uPA and PAI-1 are established prognostic factors in several types of cancer, a high tissue level of both components generally being associated with tumour progression and with poor disease-free and/or overall survival (reviewed by Duffy, 1996;Schmitt et al, 1997). Furthermore, several investigators have reported on the potential diagnostic and prognostic relevance of tPA analysed either in plasma or in tumour tissues from patients, including those afflicted with breast or colon cancer (Layer et al, 1987;De Bruin et al, 1988;Duffy et al, 1988;Needham et al, 1988;Grøndahl-Hansen et al, 1990;Jänicke et al, 1990Jänicke et al, , 1991Rella, et al, 1993;Yamashita et al, 1993Yamashita et al, , 1995Duggan et al, 1997). In addition, some studies even have examined the presence of complexes between tPA and PAI-1 in plasma from healthy individuals and patients with various diseases (Niwano et al, 1992;Hansson et al, 1994;Maser et al, 1997).…”