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PubMed1993

Modulation by endothelin-1 of tissue plasminogen activator and plasminogen activator inhibitor-1 release from cultured human vascular endothelial cells: interaction of endothelin-1 with cytokines.

The interaction of endothelin-1 (ET-1) with either interleukin-1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF alpha) on the release of tissue plasminogen activator antigen (t-PA:Ag) and plasminogen activator inhibitor-1 antigen (PAI-1:Ag) was investigated in a culture system of vascular endothelial cells derived from human umbilical vein. The t-PA:Ag release was significantly decreased by either IL-1 beta or TNF alpha; ET-1 intensified the suppressive effect of the cytokines. In contrast, PAI-1:Ag release was significantly increased by either IL-1 beta or TNF alpha; ET-1 significantly reduced the stimulatory effect of the cytokines. The data suggest that endothelial cell-mediated fibrinolysis may be modulated by ET-1.

Cells, Cultured↗
PubMed1997

Changes in ovarian expression of tissue-type plasminogen activator and plasminogen activator inhibitor type-1 messenger ribonucleic acids during ovulation in rat.

We investigated the time course and localization of ovarian tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAI-1) expression during the ovulatory period in rat by RNase protection assay and in situ hybridization. Immature female Wistar rats were injected with 25 IU pregnant mare serum gonadotropin (PMSG), followed 50 h later by 25 IU human chorionic gonadotropin (hCG). Levels of tPA mRNA were low before hormone treatment and after PMSG treatment. After hCG treatment, tPA mRNA levels increased rapidly, the first peak at 4 h after hCG treatment and reached a maximum just prior to ovulation, 12 h later, before declining again. PAI-1 mRNA was barely detectable before hormone treatment but was transiently induced by hCG treatment, reaching peak levels after 4 h. Subsequently, PAI-1 mRNA levels decreased until early luteinization. The expression of tPA mRNA 4 h after hCG treatment occurred mainly in the follicular thecal-interstitial cells, but was barely detectable in the granulosa cells, whereas 12 h after hCG treatment it was maximal in the granulosa cells of the large follicles destined to ovulate. PAI-1 mRNA was expressed mainly in ovarian stromal tissue and in the thecal external interstitial cells encapsulating the follicles at 4 h after hCG treatment. These results suggest that the temporal regulation of tPA biosynthesis after hCG induction depends on the cell types and size classes in the various ovarian compartments. PAI-1 may be produced by the stormal tissue and the thecal external interstitial cells and is perhaps implicated in structural changes during follicular growth, ovulation and luteinization.

Animals↗
PubMed1990

Detection of cathepsin B, plasminogen activators and plasminogen activator inhibitor in human non-small lung cancer cell lines.

Human non-small lung cancer cell lines HS-24 (established from a primary squamous cell carcinoma) and SB-3 (established from a metastasis of a primary adenocarcinoma of the lung into the adrenal gland) were analysed for the proteinases tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator inhibitor (PAI-1). The proteinases were characterized by activity measurements, inhibition studies, enzyme-linked immunosorbent assay (ELISA), and Western blot analysis. Cell-associated proteinases were determined in cell lysates, secreted proteinases in cell conditioned culture media. Both cell lines were found to secrete uPA and PAI-1, whereas tPA could be detected only in HS-24 conditioned media. No cathepsin B activity could be detected in media of both cell lines. However, activation experiments and western blot analysis showed, that at least HS-24 secrete an inactive precursor. Cell lysates of HS-24 and SB-3 show PA activity, but on a low level. Cathepsin B activity was also found to be low in HS-24 lysates. However, SB-3 lysates show high cathepsin B activity. Further characterization of the proteinases by their sensitivity against several inhibitors suggests that they are similar to the corresponding proteinases of normal, nonmalignant cells.

Adenocarcinoma↗
PubMed2005

Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina.

OBJECTIVE: In women, sex hormones cause increased morbidity and mortality in patients with coronary heart disease (CHD) and adversely affect the coagulation profile. We have studied the effect of physiological testosterone replacement therapy in men on coagulation factor expression, to determine if there is an increased risk of thrombosis. METHODS: Double-blind, randomized, placebo-controlled trial of testosterone in 46 men with chronic stable angina. Measurements of free, total and bioavailable testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH), estradiol, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, tissue plasminogen activator (tPA) and full blood count were made at 0, 6 and 14 weeks. RESULTS: Bioavailable testosterone levels were: 2.58 +/- 0.58 nmol/l at baseline, compared with 3.35 +/- 0.31 nmol/l at week 14 (P < 0.001) after treatment compared with 2.6 +/- 0.18 nmol/l and 2.44 +/- 0.18 nmol/l in the placebo group (P was not significant). There was no change in fibrinogen (3.03 +/- 0.18 g/l at baseline and 3.02 +/- 0.18 g/l at week 14, P = 0.24), tPA activity (26.77 +/- 4.9 Iu/ml and 25.67 +/- 4.4 Iu/ml, P = 0.88) or PAI-1 activity (0.49 +/- 0.85 Iu/ml and 0.36 +/- 0.06 Iu/ml, P = 0.16) with active treatment and no differences between the groups (at week 14, P value 0.98, 0.59 and 0.8 for fibrinogen, PAI-1 and tPA respectively). Haemoglobin concentration did not change over time, in the testosterone group (1.44 +/- 0.02 g/l and 1.45 +/- 0.02 g/l, P = 0.22). CONCLUSION: Physiological testosterone replacement does not adversely affect blood coagulation status.

Administration, Cutaneous↗
PubMed2001

Circulating levels of plasminogen activator inhibitor type-1, tissue plasminogen activator, and thrombomodulin in hemodialysis patients: biochemical correlations and role as independent predictors of coronary artery stenosis.

This study investigated the relationship between the circulating levels of the endothelial cell glycoproteins plasminogen activator inhibitor type 1 (PAI-1), tissue plasminogen activator (TPA), and thrombomodulin (TM) and the major vascular risk factors described in dialysis patients. In addition, the role of these endothelial cell products as independent predictors of coronary artery disease (CAD) was analyzed. Levels of TM, TPA antigen (Ag), TPA activity, PAI-1 Ag, PAI-1 activity, TPA/PAI complexes, thrombin-antithrombin complexes, fibrinopeptide A, C-reactive protein (CRP), interleukin-1beta and tumor necrosis factor-alpha, lipids, apoproteins A1 and B, and albumin were measured in a group of 200 nondiabetic dialysis patients and 100 healthy matched volunteers. When compared with healthy controls, dialysis patients showed increased levels of CRP, TM, TPA, and PAI-1 and evidence of increased thrombin-dependent fibrin formation. Increased levels of active PAI-1 were associated to a great extent with major classic vascular risk factors and to a lesser extent with CRP and serum triglycerides. Forty-six patients (23%) had evidence of CAD. Variables associated with CAD in the univariate analysis included age, time on dialysis, male gender, number of packs of cigarettes per year, high BP, fibrinogen, apolipoprotein B, albumin, PAI-1 activity, CRP, thrombin-antithrombin complexes, and fibrinopeptide A. Logistic regression analysis found age, high-density lipoprotein cholesterol, gender, high BP, CRP, time on dialysis, and PAI-1 activity to be independent predictors of CAD. This model classified correctly 85% of patients as having CAD and showed adequate goodness of fit for all risk categories. Our data support a pathogenic link among activated inflammatory response, endothelial injury, and CAD in hemodialysis patients and suggest that assessment of circulating PAI-1 levels could be an additional tool to identify dialysis patients who are at risk for developing atheromatous cardiovascular disease.

Case-Control Studies↗
PubMed1995

Plasma von Willebrand factor, tissue plasminogen activator, plasminogen activator inhibitor, and antithrombin III levels in Behçet's disease.

Sixty-three patients with Behçet's disease (BD), 30 patients with recurrent oral ulcer and 30 healthy individuals as control group were included in the study. ISG criteria was used for the diagnosis of BD and patients were classified as active and inactive and evaluated accordingly. In the patient and control groups, von Willebrand factor (vWF), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI) levels were determined using ELISA method and antithrombin III (AT-III) by nephelometric methods. High levels of endothelial product, vWF in the active Behçet patient group (p < 0.005) supports endothelial destruction due to vasculitis related with BD. In the active patient group tPA levels were significantly lower (p < 0.05) than the inactive and control groups with higher levels of PAI (p < 0.05 and p < 0.01) respectively. In Behçet disease, besides the decrease in tPA synthesis, high PAI levels also can affect tPA decrease and lead to inhibition of fibrinolytic activity. In active Behçet group, levels of AT-III were low and no significant difference was observed in recurrent oral ulcer and control groups. This situation may arise from the excessive use of AT-III in active disease. In conclusion, high levels of vWF in Behçet patients is thought to arise from vasculitis and high levels of PAI from the accumulation of thrombocytes on the damaged surface of endothelium leading to a decrease in tPA levels and inhibition of fibrinolytic activity.

Adolescent↗
PubMed1990

[The correlation between the activity of tissue plasminogen activator (TPA), levels of tissue plasminogen activator inhibitor (PAI-1) antigen and serum lipids in healthy subjects].

It is well known that abnormality of the coagulation-fibrinolytic system and serum lipids plays an important role in the development of thrombi and atherosclerotic disease. In the present study, the correlation between the activity of tissue plasminogen activator (TPA), the levels of tissue plasminogen activator inhibitor (PAI-1) and serum lipids (TC, TG, beta-Lp, HDLC, LDLC and apolipoproteins) were studied in 102 healthy subjects. The activity of TPA showed negative correlation with the obesity rate (r = 0.21, p less than 0.05) but levels of PAI-1 antigen showed a positive correlation with the obesity rate (r = 0.182, p less than 0.1). The activity of TPA showed no correlation with serum lipids including apolipoproteins, while the levels of PAI-1 antigen showed a positive correlation between TG and beta-Lp (r = 0.292, p less than 0.01, r = 0.211, p less than 0.05). The levels of PAI-1 antigen showed a negative correlation with HDLC (r = -0.286, p less than 0.01). These results indicate that TPA and PAI-1 play an important role in the development of thrombotic disease and atherosclerotic disease.

Adult↗
PubMed1995

Relationship between tissue plasminogen activator, plasminogen activator inhibitor and CT image in chronic subdural hematoma.

The present study was performed to investigate the relationship between the concentrations of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) and the CT images in 23 cases of chronic subdural hematomas (SDHs). The concentrations of t-PA and PAI-1 were quantified by enzyme-linked immunosorbent assay (ELISA). Chronic SDHs were divided into five groups according to their appearance on computed tomography: high-density (n = 4), isodensity (n = 8), low-density (n = 5), mixed-density (n = 3), layering (n = 3) types. The volume of hematoma was measured with an image analyzing software program. The concentrations of t-PA were higher in layering (41.2 +/- 0.3 ng/ml, mean +/- standard error of the mean) and high-density (40.0 +/- 1.1 ng/ml) types compared to those of low-density (23.3 +/- 4.1 ng/ml) and iso-density (25.1 +/- 3.7 ng/ml) types. The concentrations of PAI-1 were lower in layering (95.9 +/- 1.0 ng/ml) and high-density (103.4 +/- 34.5 ng/ml) types compared to that of low-density (192.5 +/- 2.6 ng/ml) type. So the ratio between t-PA and PAI-1 (t-PA/PAI) was greater in layering and high-density types. The volume of hematoma was larger in mixed-density and layering types but statistically insignificant. These results presumably suggest that the ratio between t-PA and PAI concentration may contribute to the pathogenesis of the chronic SDH.

Adult↗
PubMed1997

Increased expression of urokinase type plasminogen activator(u-PA), plasminogen activator inhibitor-1(PAI-1), and collagenases in Caco-2 cells infected by Salmonella typhimurium.

Salmonella penetrates the basement membrane of intestinal epithelial cells into deeper tissues, in which process extracellular matrix proteases should be required. Hypothesizing that the proteases might be provided by host cells, we investigated the changes of expression of urokinase type plasminogen activator(u-PA), plasminogen activator inhibitor-1(PAI-1), and collagenases in epithelial cells(Caco-2) infected with Salmonella typhimurium. The change of mRNA levels, amount of the enzyme secretion and functional activity were analyzed by Northern blot, ELISA, and Zymography. The mRNA level of u-PA was elevated by Salmonella infection itself without any exogenous transcription regulators. u-PA was actively secreted into the medium and was enzymatically active. The synthesis and secretion of PAI-1 was increased over time from 2 hrs post infection(pi) to 8 hrs pi. Zymographic assay revealed that the secretion of collagenases (type IV, type V and interstitial collagenase) were also increased. Taken together, S. typhimurium infection might induce accumulation of pericellular proteolytic activity and consequently degrade the extracellular matrix surrounding the infected cells. These in turn might enable Salmonella to invade into deeper tissues.

Caco-2 Cells↗
PubMed2003

Tissue plasminogen activator and plasminogen activator inhibitor type 1 gene polymorphism in patients with gastric ulcer complicated with bleeding.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) may be involved in the pathogenesis of peptic ulcers through suppression of fibrinolysis. This study was designed to investigate associations of t-PA and PAI-1 genes with clinical features of the patients with bleeding gastric ulcers. Eighty-four patients with peptic ulcers and 100 controls were studied between January 1998 and April 2000. We used polymerase chain reaction and endonuclease digestion to genotype for 4G/5G polymorphism in the promoter region of the PAI-1 gene and the Alurepeat insertion/deletion (I/D) polymorphism in intron h of the t-PA gene. Various clinical features, including lesion site, bleeding event, recurrence of ulcer, and rebleeding, were assessed using a multiple logistic regression model. The genotype distributions of both the t-PA and PAI-1 genes did not differ between the patient and control groups. The occurrence of the I/D or D/D genotype of t-PA was significantly higher in cases of duodenal ulcer (adjusted OR=4.39, 95% CI=1.12-17.21). When a dominant effect (i.e., 4G/4G or 4G/5G versus 5G/5G) of the 4G allele was assumed, the PAI-1 4G/4G genotype was independently associated with rebleeding after hemostasis (adjusted OR=5.07, 95% CI=1.03-24.87). Our data suggest that t-PA gene polymorphism is associated with duodenal ulcers, and that the PAI-1 gene may be a risk factor leading to recurrent bleeding after initial hemostasis.

Adult↗
PubMed2000

Tissue plasminogen activator and plasminogen activator inhibitor-1 in human choledochal bile.

Fibrinolytic properties have been detected in animal and human gallbladder (GB) bile. Plasminogen activator inhibitor-1 (PAI-1) has been reported in greater concentration in GB stone bile and may be a nucleating factor in the pathogenesis of GB stone formation. It is unknown whether or not human choledochal bile has similar properties, which could have a role in choledocholithiasis. The aims of this study were to determine the presence of fibrinolytic properties of human choledochal bile and to compare those properties among normal, acalculous, and calculous-infected choledochal bile. Tissue plasminogen activator (t-PA) and PAI-1 of choledochal bile were measured by enzyme linked immunosorbent assay in patients with cholangitis due to acalculous bile duct obstructions (n = 9), choledocholithiasis with cholangitis (n = 20), and normal bile (n = 7). The t-PA concentration of choledochal bile was no different among the three groups (acalculous-infected bile, median 4.61 ng/ml, and calculous-infected bile, 4.61 ng/ml, versus normal bile, 7.33 ng/ml). PAI-1 was detected in choledochal bile in significantly greater concentrations in patients with acalculous cholangitis due to bile duct obstructions and choledocholithiasis with cholangitis (acalculous-infected bile, median 0.36 ng/ml, and calculous-infected bile, 0.1 ng/ml, versus normal bile, 0.02 ng/ml, p < 0.05), but the bile concentration of PAI-1 was no different between the acalculous and calculous-infected choledochal bile. Human choledochal bile possesses t-PA and PAI-1. PAI-1 was present in greater concentrations in both acalculous and calculous-infected choledochal bile. Increased levels of PAI-1 may be an epiphenomenon of cholangitis rather than a factor in the pathogenesis of choledocholithiasis.

Aged↗
PubMed2002

Clinical utility of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 determination in primary breast cancer tissue for individualized therapy concepts.

Invasion factors urokinase-type plasminogen activator (uPA) and its plasminogen activator inhibitor (PAI-1) are the only novel tumor biological prognostic factors validated at the highest level of evidence with regard to their clinical utility in breast cancer. Antigen levels of both factors present in extracts of primary tumor tissue are determined by standardized, quality-assured enzyme-linked immunosorbent assays. Numerous studies showed that patients with low levels of uPA and PAI-1 have a significantly better survival than patients with high levels of either factor. Recently, these data have been validated by a European Organization for Research and Treatment of Cancer pooled analysis comprising more than 8000 breast cancer patients. The particular combination of both factors, uPA/PAI-1 (both low vs. either or both factors high), outperforms the single factors as well as other traditional prognostic factors with regard to risk group assessment, particularly in node-negative breast cancer. Node-negative breast cancer patients with low levels of uPA and PAI-1 have a very good prognosis and, as such, may be candidates for being spared the burden of adjuvant chemotherapy. In contrast, node-negative patients with high uPA/PAI-1 are at a substantially increased risk of relapse, comparable to that of patients with > or = 3 involved axillary lymph nodes. First results from a multicenter prospective randomized therapy trial in node-negative breast cancer (Chemo N(0)) as well as recent retrospective analyses indicate that these high-risk patients benefit from adjuvant chemotherapy. Thus, combined determination of the invasion factors uPA and PAI-1 supports risk-adapted individualized therapeutic strategies in patients with primary breast cancer, particularly in those with node-negative breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

[Tissue type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in transplanted kidneys].

We have studied the involvement of fibrinolysis in acute rejection after kidney transplantation by analyzing changes in urinary levels of substances such as FDP, D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI). Fibrinolytic activity was found to be low (that is, PAI is dominant) during acute rejection, and it was elevated (that is, PA became dominant) as acute rejection subsided. It appears that the dominance of PA leads to an increase in the products of fibrinolysis and an elevation in the D-dimer/FDP ratio, resulting in disappearance of the acute rejection. Based on these findings, we thought it necessary to administer t-PA to kidney recipients so that PA becomes dominant earlier and the acute rejection can be reduced. It is necessary for us to directly study the phenomena within the kidneys. Therefore, we recently conducted a histochemical study of the distribution of t-PA, Urokinase type PA (u-PA) and PAI in transplanted kidneys. Transplanted kidney, which functioned well or showed signs of acute or chronic rejection, were biopsied. These renal samples as well as control samples (biopsied from normal nongrafted kidney) were examined as to distribution of t-PA, u-PA and PAI by the indirect enzyme complement method. In conclusion, t-PA, u-PA and PAI were detected in the glomeruli, arterioles, tubule and interstices of the control kidneys, well functioning grafts, acutely rejected grafts chronically rejected grafts. All samples showed intense chromatic responses in the arterioles and part of the tubules. On the whole, the chromatic response tended to be more intense in the acute rejection group than in the other group.

Fibrinolysis↗
PubMed1999

Sex-related differences in plasminogen activator and plasminogen activator inhibiting activities in young and aged rats.

The purpose of this study was to determine whether aging influences the sex-related differences in fibrinolytic activity in rats. We measured plasminogen activator (PA) activity and plasminogen activator inhibiting (PAI) activity in 5-, 12-, 45-, and 60-week-old male and female rats. We also examined the effects of gonadectomy and sex hormone-treatments in adult male and female rats. The increase in age did not influence the PA activity in the male or female rats. However, the PA activity was higher in the female rats than in the males in all four age groups. Orchidectomy caused a significant increase in PA activity in the male rats. Estradiol treatment induced a significant increase of PA activity in ovariectomized female rats. Testosterone treatment resulted in a decrease of PA activity in orchiectomized male rats. The increase in age had an effect on PAI activity; the activity level in the 45- and 60-week-olds was stronger than that in the 12-week-old rats. The PAI activity was not significantly different between the normal rats of each sex. Gonadectomy did not influence the PAI activity in male or female rats, and testosterone and estradiol treatments also did not affect PAI activity in gonadectomized male and female rats. We found that the increase in age induced a decrease in the fibrinolytic system in the rats, and that there were sex-related differences in the fibrinolytic system in even 60-week-old rats.

Aging↗
PubMed2000

Effects of N-(4-hydroxyphenyl) retinamide on urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in prostate adenocarcinoma cell lines.

Previous investigations have demonstrated that a synthetic retinoid, N-(4-hydroxyphenyl) retinamide (4-HPR), inhibits the invasion of prostate adenocarcinoma in vitro. Urokinase-type plasminogen activator (uPA) is a prerequisite for tumor invasion. The purpose of this study was to evaluate the effects of 4-HPR on uPA and plasminogen activator inhibitor-1 (PAI-1) in prostate cancer. Human prostate adenocarcinoma cell lines, TSU-PR1 and PC3, were grown in serum-free media containing 4-HPR. Cellular mRNA and protein were subsequently extracted. Northern blot analysis, enzyme-linked immunosorbent assay (ELISA) and chromogenic functional analysis were performed on the samples. Administration of 10(-6) M 4-HPR for 3 days resulted in an increase in uPA mRNA expression (TSU-PR1: 391%, PC3: 356%), and a simultaneous increase in PAI-1 mRNA expression (TSU-PR1: 217%, PC3: 235%) was observed. ELISA concomitantly demonstrated a significant increase (p < 0.05) in uPA protein in the conditioned media (TSU-PR1: 134%, PC3: 139%) and cell lysates (TSU-PR1: 284%, PC3: 255%). Both cell lines demonstrated a significant increase (p < 0.05) in PAI-1 protein in the conditioned media (TSU-PR1: 152%, PC3: 167%) and cell lysates (TSU-PR1: 170%, PC3: 222%). Concentrations below 10(-6) M failed to alter the protein production of either uPA or PAI-1. The functional uPA assay demonstrated a reduction of the proteolytic activity of uPA (TSU-PR1: 13%, PC3: 7%) in cell lysates of 10(-6) M 4-HPR (p < 0.05), while there was minimal uPA activity in the conditioned media. 4-HPR stimulates a paradoxical increase in uPA and PAI-1, but the anti-invasive effects of 4-HPR are consistent with the increase in both uPA and PAI-1, resulting in an overall reduction of functional uPA activities.

Adenocarcinoma↗
PubMed2000

Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells.

The effects of fluvastatin, a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) inhibitor, on the biosynthesis of tissue plasminogen activator (t-PA) and of its major physiological inhibitor (plasminogen activator inhibitor type 1, PAI-1) were investigated in cultured human umbilical vein endothelial cells (HUVEC). Fluvastatin (0.1 to 2.5 microM), concentration-dependently reduced the release of PAI-1 antigen by unstimulated HUVEC, subsequent to a reduction in PAI-1 steady-state mRNA levels and de novo protein synthesis. In contrast, it increased t-PA secretion. The drug also reduced PAI-1 antigen secreted in response to 10 microg/ml bacterial lipopolysaccharide (LPS), 100 U/ml tumour necrosis factor alpha (TNFalpha) or 0.1 microM phorbol myristate acetate (PMA). Mevalonate (100 microM), a precursor of isoprenoids, added to cells simultaneously with fluvastatin, suppressed the effect of the drug on PAI-1 both in unstimulated and stimulated cells as well as on t-PA antigen. Among intermediates of the isoprenoid pathway, all-transgeranylgeraniol (5 microM) but not farnesol (10 microM) prevented the effect of 2.5 microM fluvastatin on PAI-1 antigen, which suggests that the former intermediate of the isoprenoid synthesis is responsible for the observed effects.

Cells, Cultured↗
PubMed2000

Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1.

In vivo tumor progression in mice with targeted deficiencies in urokinase-type plasminogen activator (UPA-/-) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1-/-), was studied using a fibrosarcoma tumor model. Murine T241 fibrosarcoma cells were s.c. implanted into three groups of mice with the following genotypes, wild-type (WT), UPA-/-, and PAI-1-/-. A significantly diminished primary tumor growth in UPA-/- and PAI-1-/- mice occurred, relative to WT mice. Tumors in UPA-/- and PAI-1-/- mice displayed lower proliferative and higher apoptotic indices and displayed a different neovascular morphology, as compared with WT mice. These results are consistent with the decreased growth rates of this tumor in these gene-deleted mice. Immunohistochemical analyses of the tumors revealed a decrease in vascularity and vascular endothelial growth factor expression only in tumors in PAI-1-/- mice. Analyses of the relative extents of corneal angiogenesis in these same animals, induced by basic fibroblast growth factor, corroborated the resistance of PAI-1-/- mice to neovascularization. The results obtained suggest that the host fibrinolytic system plays an important role in tumor growth in this model. Alterations in host expression of components of this system may alter tumor growth and dissemination by affecting the balance between tumor cell death and proliferation, as well as extracellular matrix changes needed for invasiveness and angiogenesis.

Animals↗
PubMed2001

Prognostic impact of proteolytic factors (urokinase-type plasminogen activator, plasminogen activator inhibitor 1, and cathepsins B, D, and L) in primary breast cancer reflects effects of adjuvant systemic therapy.

PURPOSE: Prognostic and predictive impact of five proteolytic factors associated with tumor invasion and metastasis in primary breast cancer were evaluated after long-term follow-up. EXPERIMENTAL DESIGN: Antigen levels of urokinase-type plasminogen activator, plasminogen activator inhibitor-1 (PAI-1), Cathepsins B, D, and L were determined using immunochemical assays in primary tumor tissue of 276 patients. RESULTS: During follow-up (median 109 months), 119 (43%) patients relapsed, and 117 (42%) died. In the whole collective, lymph node status (P < 0.001; RR 3.8), Cathepsin L (P < 0.001; RR 2.6), and PAI-1 (P = 0.027; RR 1.7) were the only independent significant factors in multivariate analysis for disease-free survival (DFS). For overall survival (OS), lymph node status (P < 0.001; RR 2.9), Cathepsin L (P = 0.017; RR 1.9), PAI-1 (P = 0.01; RR 1.9), and grading (P = 0.026; RR 1.7) were significant. In the node-negative subgroup, PAI-1 was the only significant factor for DFS (P = 0.004; RR 3.7) and the strongest factor (P = 0.004; RR 3.7) for OS next to grading (P = 0.017; RR 3.1). In node-positive patients, Cathepsin L was the only significant factor for both DFS (P < 0.001; RR 3.2) and OS (P = 0.003; RR 2.5). For all proteolytic factors but Cathepsin L, the univariate prognostic impact on DFS was substantial in patients without adjuvant systemic therapy but was diminished if adjuvant therapy had been administered. Cathepsin L maintained its strong prognostic impact on DFS even in patients with adjuvant endocrine therapy (P = 0.01; RR 2.8). CONCLUSIONS: The observed effect of adjuvant systemic therapy on their prognostic strength suggests that the assessed proteolytic factors supply predictive information on therapy response.

Adult↗