The Relevance of Plasminogen Activators to Neoplastic Growth

Markus, Gabor

doi:10.1159/000469158

Cited by 89 publications

(31 citation statements)

References 45 publications

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“…Elevated levels of proteases are present in solid tumors of the breast, ovary, colon, stomach, prostate and lung [1][2][3][4][5][6][7][8]. Collagenases, cathepsins, plasmin and plasminogen activators are found at various locations; in the cytoplasma, on the cell surface or released into the extracellular space [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…protease activity, growth factors, steroid hormones, immunogenicity, cell adhesion, attachmeat factors). Elevated levels of the cysteine proteases, cathepsin B, L and uPA, have been correlated with increased malignancy [3,4,5,8,[17][18][19][20][21][22]. This may be due to the fact that cysteine proteases efficiently convert soluble or tumor cell receptor-bound pro-uPA to catalytically active two-chain HMW-uPA [16].…”

Section: Introductionmentioning

confidence: 99%

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Effective activation of the proenzyme form of the urokinase‐type plasminogen activator (pro‐uPA) by the cysteine protease cathepsin L

et al. 1992

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Increased levels of both the cysteine protease, cathepsin L, and the serinc protease, uPA (urokinase-typc plasminogen activator), are present in solid tumors and are correlated with malignancy, uPA is released by tumor cells as an inactive single.chain proenzyme (pro-uPA) which has to be activated by proteolytic cleavage. We analyzed in detail the action of the cysteine protcase, cathepsin L, on recombinant human pro-uPA. Enzymatic assays, SDS-PAGE and Western blot analysis revealed that cathepsin L is a potent activator of pro.uPA, As determined by N-terminal amino acid sequence analysis, activation of pro-uPA by cathepsin L is achieved by cleavage of the Lys~K-lle~9 peptidc bond, a common activation site of serine proteases such as plasmin and kallikrcin. Similar to cathepsin B (Kobayashi et al,, J. Biol, Chem, (1991) 266, 5147-5152) cleavage of pro-uPA by cathepsin L was most efl'~ctive at acidic pH (molar ratio ofcathepsin L to pro-uPA of 1:2,000), Nevertheless, even at pH 7,0, pro-uPA was activated by cathepsin L, althougla a 10-fold higher concentration of cathep~in L was required, As tumor cells may produce both pro-uPA and cathepsin L, implications for the activation of tumor cell-derived pro-uPA by cathepsin L may be considered. Different pathways of activation of pro-uPA in tumor tissues may coexist: (i) autoeatalytic intrinsic activation of pro-uPA; (it) activation by serine protcases (plhsmin, kallikrein, Factor Xlla); and (iii) activation by cysteine proteases (cathepsin B and L), Pro-uPA; Urokiuase: Cysteine protease; Cathepsin B; Cathepsin L; N-Terminal amino acid sequence analysis

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effective activation of the proenzyme form of the urokinase‐type plasminogen activator (pro‐uPA) by the cysteine protease cathepsin L

et al. 1992

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“…The remodelling it involves requires the coordinated action of cell-secreted proteolytic enzymes and their inhibitors. Elevated levels of urokinase-type plasminogen activator (uPA) have been implicated in these invasive processes (Dano et al, 1985;Duffy, 1987;Layer et al, 1987;Markus et al, 1988;Pyke et al, 1991b), and plasminogen activator inhibitor type 1 (PAI-1) has been found in many types of malignant tissue (Kruithof et al, 1988;Cubellis et al, 1990;Foucre et al, 1991;Tanaka et al, 1991;Reilly et al, 1992). Plasminogen activator inhibitor type 2 (PAI-2) is one of the primary physiological inhibitors of uPA.…”

mentioning

confidence: 99%

Prognostic value of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in breast carcinomas

Bouchet

Spyratos²,

Pm³

et al. 1994

Br J Cancer

147

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Summary It is now clearly established that proteolytic enzymes, including plasminogen activator (uPA), play an important role in breaking down the extracellular matrix, which is considered to be a step in metastasis formation. Plasminogen activators are controlled at various levels. Two inhibitors, PAI-1 and PAI-2, have been identified, the latter being more specific for uPA. In attempts to determine their prognostic value, it is essential to investigate the relative importance of these parameters and their interactions. We used an immunoenzymatic method to assay uPA, PAI-I and PAI-2 antigens in cytosols prepared from 314 primary breast tumours. The patients were followed up for a minimum of 6 years and all relevant clinical and laboratory findings were recorded. Univariate analysis confirmed the poor outcome of patients whose tumours contained large amounts of uPA and PAI-1. In addition, low levels of PAI-2 correlated with shorter disease-free survival in the overall population (P= 0.02), post-menopausal women (P= 0.02) and women without lymph node involvement (P = 0.02). Multivariate analysis in the 'main effects' Cox model identified node involvement, macroscopic tumour size and PAI-2 as significant variables. The 'interactive' model, taking into account interactions between uPA and its two inhibitors, identified a first subgroup with a very poor prognosis associating either high levels of PAI-I with low levels of PAI-2 in the overall population and the women with no node involvement or high levels of uPA with low levels of PAI-2 in the group of menopausal women. We conclude that PAI-I provides the same prognostic information as uPA, and does not appear to play a role as an inhibitor. In contrast, PAI-2 increases the prognostic value of uPA, particularly in post-menopausal women, and PAI-1 in patients with no node involvement.

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“…Stimulation of human peripheral blood granulocytes by N·formyl chemotactic peptide CHO·NLPNTL Granulocytes were isolated essentially as described.13) Briefly, 50 ml of fresh human blood obtained from four healthy donors was anticoagulated with 5,000 units of heparin and immediately centrifuged througb Ficoll-Hypaque. The cell pellet was resuspended and residual erythrocytes were lysed by using 0.16 M NH 4 Cl containing 12 mM NaHCO J , 0.1 mM EDTA, pH 7.3. Granulocytes were washed with PBS.…”

Section: Methodsmentioning

confidence: 99%

Inactivation of Human Tumor Cell Pro‐urokinase by Granulocyte Elastase

Kanayama

Terao

1990

Japanese Journal of Cancer Research

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Supernatant obtained from granulocytes stimulated in the presence of cytochalasin B by the chemotactic peptide N-formyl-norleucyl-Ieucyl-phenylalanyl-norleucyl-tyrosyl-lysine displayed an inhibitory effect on the plasmin-dependent conversion of tumor urokinase-type plasminogen activator proenzyme (pro-uPA) to the active form of uPA. Moreover, the supernatant was also found to inhibit the fibrinolytic activity of human vulva (A431) and breast (MCF7) carcinoma cell lines, which contain large amounts of pro-uPA, by 87% and 96%, respectively. By using eglin C (elastase inhibitor) and a monoclonal antibody to elastase (proteolytic activity blocker of the enzyme), elastase was identified as the key enzyme of the supernatant in these phenomena. Purified elastase converted pro-uP A to an enzymatically inactive molecule composed of two polypeptide chains of Mr = 33,000 and 22,000 linked to each other by a disulfide bond. Elastase-containing granulocytes were identified by immunohistochemistry techniques in the tissues of squamous cell carcinoma and adenocarcinoma of uterus. The cells were found close to the tumor cells and in the stroma surrounding the tumor nests. By immunohistochemical staining, uP A was also found in the tumor cells. Evidently, elastase released by chemotactically activated granulocytes, which are attracted into tumor tissues, may inhibit the conversion of pro-uP A to enzymatically active uP A in the tumor cells.

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The Relevance of Plasminogen Activators to Neoplastic Growth

Cited by 89 publications

References 45 publications

Effective activation of the proenzyme form of the urokinase‐type plasminogen activator (pro‐uPA) by the cysteine protease cathepsin L

Effective activation of the proenzyme form of the urokinase‐type plasminogen activator (pro‐uPA) by the cysteine protease cathepsin L

Prognostic value of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in breast carcinomas

Inactivation of Human Tumor Cell Pro‐urokinase by Granulocyte Elastase

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