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PubMed1992

Tissue-type plasminogen activator, plasminogen activator inhibitor, and histidine-rich glycoproteins in stressed human newborns.

Normal newborns have reduced levels of tissue-type plasminogen activator (tPA). Stressed newborns have an increased prevalence of thrombotic diseases. An impaired release of tPA and/or increased plasminogen activator inhibitor (PAI) is associated with thrombotic risk in the adult patient. The purpose of this study was to assay the plasma levels of tPA, PAI, histidine-rich glycoprotein (HRG), and other fibrinolytic proteins in 15 severely stressed newborns. The stressed babies showed significantly higher (p less than .001) levels of tPA antigen compared with normal newborns. Also, PAI activity and PAI-1 antigen levels were increased. Levels of both HRG and plasminogen were higher in the stressed group but the ratio of HRG to plasminogen was the same as that in the normal control newborns (1:3), suggesting an insignificant effect of HRG. D-dimers were significantly elevated in the stressed newborns. However, 8 patients died and 4 of these were found to have massive thrombotic disease on autopsy. These results show that the newborn when stressed will increase tPA levels and activate the lytic system. However, the activity is suboptimal inasmuch as PAI activity did not decrease and thrombotic disease was observed.

Female↗
PubMed1990

A plasminogen activator inhibitor-2 from a promyelocytic leukemia cell line, PL-21, binds to the carboxy-terminal chain of plasminogen activators.

A promyelocytic leukemia cell line, PL-21, was found to produce an inhibitor of plasminogen activators (PAI). The PAI reacted to anti-PAI-2 but not anti-PAI-1 anti-serum and had an apparent molecular weight of 43 kDa on unreduced SDS-PAGE. The PAI inhibited not only urokinase-type plasminogen activator (u-PA) but single- and two-chain tissue-type plasminogen activators (t-PAs) on plasminogen-containing fibrin plate. It formed SDS-stable complexes with both t-PA and u-PA but not with prourokinase as demonstrated by both fibrin zymography and immunoblotting using anti-PA and anti-PAI-2 antisera after SDS-PAGE. These complexes were still present even after reduction with dithiothreitol. The PAI appears to bind to the carboxy-terminal chain of both PAs, because the part of the band corresponding to the carboxy-terminal chain of PAs moved to an upper position as a result of complex formation when two-chain form of PAs were incubated with the PAI and analyzed by SDS-PAGE followed by immunoblotting.

Amino Acid Sequence↗
PubMed1990

Expression of heterogeneous profiles of plasminogen activators and plasminogen activator inhibitors by human glioma lines.

Expression of plasminogen activator (PA) enzyme activity is believed to be one of the mechanisms by which malignant cells cause pericellular proteolysis of stromal structures during implantation and tissue invasion. In this study, four cell lines derived from human gliomas were studied to ascertain which PA enzymes and PA inhibitors determine the level of secreted PA activity. A plasminogen-dependent esterolytic assay was used, and two lines (U251 and U373) were found to secrete high levels of PA activity, while PA activity was undetectable in the conditioned media from the remaining two lines (U138 and LM). The PA produced by U251 and U373 resolved as single bands comigrating with high molecular weight urokinase (Mr 54,000) on casein-plasminogen zymography. Northern blot analysis demonstrated high levels of mRNA for urokinase-type PA (uPA) in U251 and U373, as well as a considerably lower level of uPA message in LM. U251 and U373 also contained mRNA for tissue-type PA (tPA), although secreted tPA activity was not demonstrated by zymography. The U138 line contained essentially undetectable levels of mRNA for either uPA or tPA. U138 was also unique in secreting PA inhibitor activity and contained high levels of mRNA for PA inhibitor 2, which was not seen in any other line. All cell lines contained PA inhibitor 1 mRNA, with substantially more expression in the U138 and LM lines than in U251 and U373. None of the lines secreted measureable anti-plasmin activity. We conclude that there is considerable heterogeneity among human glioma cells in expression of PA enzymes and PA inhibitors. The coordinated regulation of these proteins likely determines secreted PA activity and the resultant role of plasminogen activation in tumor implantation and invasion.

Blotting, Northern↗
PubMed1989

Vascular origin determines plasminogen activator expression in human endothelial cells. Renal endothelial cells produce large amounts of single chain urokinase type plasminogen activator.

Positioned at the boundary between intra- and extravascular compartments, endothelial cells may influence many processes through their production of plasminogen activators (PA). Available data have shown that tissue-type plasminogen activator (t-PA) is the major form produced by human endothelial cells. We have compared the molecular forms of PA produced by human endothelial cells from different microvascular and large vessel sources including two different sites within the circulation of the kidney. Using combined immunoactivity assays specific for u-PA and t-PA activity and antigen, we found that both human renal microvascular and renal artery endothelial cells produced high levels of u-PA antigen (60.48 ng/10(5) cells/24 h and 50.42 ng/10(5) cells/24 h, respectively) and corresponding levels of u-PA activity after activation with plasmin. Activity was not evident before plasmin activation, showing that the u-PA produced is almost exclusively as single chain form U-PA. In contrast, human omental microvascular endothelial cells and human umbilical vein endothelial cells produced exclusively t-PA (8.80 ng/10(5) cells/24 h and 2.17 ng/10(5) cells/24 h, respectively). Neither endothelial cell type from human kidney produced plasminogen activator inhibitor, as determined by reverse fibrin autography and titration assays. Agents including phorbol ester, thrombin, and dexamethasone were shown to regulate the renal endothelial cell production and mRNA expression of both u-PA and t-PA. Among the macro- and microvascular endothelial cells tested, only those from the renal circulation produced high levels of single chain form U-PA, suggesting the vascular bed of origin determines the expression of plasminogen activators.

Cells, Cultured↗
PubMed1988

The effect of human recombinant tissue-type plasminogen activator on clinical and laboratory parameters of hemostasis and systemic plasminogen activation in the dog and the rat.

The effect of human recombinant tissue-type plasminogen activator (rt-PA) on parameters of hemostasis and systemic plasminogen activation was studied in the dog and rat. Effects on screening coagulation times, fibrinogen concentration, fibrin/fibrinogen degradation products, and plasminogen and alpha 2-antiplasmin (alpha 2-AP) activities in plasma were examined following single bolus injections of 0.5-5.0 mg/kg, single and repeated 3 hr infusions of 0.75-7.5 mg/kg and 24 hr infusions of 6.0 and 30.0 mg/kg administered intravenously to dogs. Rats receiving single or 14 daily injections of 5.0-30.0 mg/kg i.v. were similarly monitored. Systemic fibrinogenolysis (greater than 50% decrease in fibrinogen, plasminogen or alpha 2-AP values) was observed in dogs receiving greater than or equal to 1.0 mg/kg as a bolus, greater than or equal to 3.75 mg/kg (20.8 micrograms or 1.19 x 10(4) IU kg-1min-1) as a 3 hr infusion and greater than or equal to 6 mg/kg (4.2 micrograms or 2.42 x 10(3) IU kg-1min-1) as a 24 hr infusion; and in rats treated with bolus injections of 30 mg/kg rt-PA. Clinical and laboratory indications of impaired hemostasis and bleeding (anemia, prolonged coagulation times and post-mortem evidence of hemorrhage) were associated with these effects, which together were dose-dependent and influenced by the rate of infusion. The incidence of major hemorrhage was variable and limited to animals receiving prolonged (24 hr) or repeated infusions.

Animals↗
PubMed1986

Purification of an active plasminogen activator inhibitor immunologically related to the endothelial type plasminogen activator inhibitor from the conditioned media of a human melanoma cell line.

24 established melanoma cell cultures were screened for their secretion of plasminogen activators and plasminogen activator inhibitors into the culture medium by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by conventional and reverse fibrin autography. Among the cell lines investigated, 22 cell lines predominantly secreting tissue type plasminogen activator (t-PA) and four cell lines additionally secreting urokinase were found. The conditioned media of two cell lines (KRFM and MJZJ) were found to contain plasminogen activator inhibitor (PAI) activity at a Mr position of approximately 50,000. The PAI of one of the two melanoma cell (MJZJ)-conditioned media found to contain PAI activity was purified to apparent homogeneity employing concanavalin A-Sepharose chromatography, gel filtration on Sephadex G-150, chromatography on Affi-Gel blue, and affinity chromatography on a Sepharose 4B immobilized monoclonal anti-t-PA IgG column. The purified melanoma PAI was found to be a single chain protein, acid stable, immunologically related to the endothelial derived PAI. In contrast to endothelial PAI, melanoma PAI presented itself in the conditioned media of the melanoma cells and in the purified preparation to an appreciable extent in its active form.

Cell Line↗
PubMed1994

Both the cytosols and detergent extracts of breast cancer tissues are suited to evaluate the prognostic impact of the urokinase-type plasminogen activator and its inhibitor, plasminogen activator inhibitor type 1.

The serine protease urokinase-type plasminogen activator (uPA) plays a key role in tumor-associated proteolysis in malignant solid tumors. Proteolytic activity of uPA is controlled by its naturally occurring plasminogen activator inhibitor type 1. As an initial observation, a correlation of enzymatic uPA activity in breast cancer cytosols with prognosis was described in 1988 (Duffy et al., Cancer (Phila.), 62: 531-533, 1988). A pronounced prognostic impact of uPA, independent of classical risk parameters, was then first demonstrated in detergent-extracted (Triton X-100) breast cancer tissues by applying enzyme-linked immunosorbent assay techniques (Jänicke et al., Lancet, 2: 1049, 1989; Fibrinolysis, 4:69-78, 1990; Duffy et al., Cancer Res., 50: 6827-6829, 1990). In addition, not only uPA but also plasminogen activator inhibitor type 1 were shown to be of prognostic value in breast cancer (Jänicke et al., Semin. Thromb. Hemostasis, 17: 303-312, 1991; Breast Cancer Res. Treat., 24: 195-208, 1993). Subsequently, the prognostic value of uPA and plasminogen activator inhibitor type 1 was also confirmed in studies using archived "cytosol fractions" of breast cancer tissues (Foekens et al., Cancer Res., 52: 6101-6105, 1992; Spyratos et al., J. Natl. Cancer Inst., 84: 1266-1272, 1992; Grondahl-Hansen et al., Cancer Res., 53: 2513-2521, 1993; Sumiyoshi et al., Int. J. Cancer, 50: 345-348, 1992). A direct comparison of both methods with regard to prognosis, however, was lacking. We therefore prepared both the detergent-treated tissue extracts and the cytosol fractions from the same breast cancer specimens to allow a direct comparison of both methods. In 247 breast cancer patients investigated, the Triton X-100-extracted tissues revealed about twice as much uPA antigen (uPATx: median, 2.32 ng/mg protein) than the cytosol fractions (uPAcyt: median, 1.07 ng/mg protein). In contrast, the presence of Triton X-100 did not result in an increase of PAI-1 (PAI-1Tx: median, 6.34 ng PAI-1/mg protein) compared to the cytosol fractions (PAI-1cyt: median, 7.15 ng PAI-1/mg protein). Good correlations between uPATx and uPAcyt (R = 0.72) and between PAI-1Tx and PAI-1cyt (R = 0.88) were observed. Furthermore, PAI-1 and uPA are moderately correlated with each other (uPATx versus PAI-1Tx: R = 0.40; uPAcyt versus PAI-1cyt: R = 0.39). The prognostic power of uPA showed its best advantage in Triton X-100-extracted tissues (RR = 3.22), most pronounced in the subgroups of node-negative and premenopausal patients, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Breast Neoplasms↗
PubMed1996

Evaluation of tissue plasminogen activator and plasminogen activator inhibitor-I levels in acute myocardial infarction.

Fluctuations in tissue plasminogen activator (t-PA) activity, t-PA antigen, and plasminogen activator inhibitor-I (PAI-1) antigen levels were evaluated in blood samples obtained from 84 patients with initial uneventful acute myocardial infarction (AMI) and 35 patients with reinfarction and fatal infarction (patients with bad prognoses). Patients with initial AMI had significantly higher levels of t-PA activity than those of 14 patients with angina pectoris. Tissue plasminogen activator activity peaked between day 7 and 19 after the initial attack of AMI. Plasminogen activator inhibitor-I antigen level decreased significantly between day 2 and 19, then returned to the baseline levels of patients with angina pectoris nearly 4 weeks later. The t-PA activity levels of patients with reinfarction were significantly lower than those in patients without events between day 0 and 3 and between day 7 and 19. The percentage stenosis in the coronary arteries measured by coronary angiography was negatively correlated with t-PA activity. This information may help in selecting aggressive treatments such as thrombolysis by recombinant t-PA and predicting the prognosis for patients with AMI.

Aged↗
PubMed1993

Plasminogen activators, plasminogen activator inhibitors and markers of intravascular coagulation in pre-eclampsia.

In pre-eclampsia (PE), reduced levels of plasma urokinase-like plasminogen activator (u-PA) and plasminogen activator inhibitor-2 (PAI-2), and increased levels of plasma tissue-type plasminogen activator (t-PA) antigen were seen. The majority of moderate and severe pre-eclamptic women (7 out of 10) ended up with pre-term delivery as compared with 2 out of 11 who went on to term. Patients with moderate and severe PE had significantly lower levels (mean +/- SD, ng/ml) of PAI-2 (58.4 +/- 34.9) and u-PA antigen (1.61 +/- 0.62) as compared to those with mild PE (95.6 +/- 39.3 and 1.61 +/- 0.62 and 2.12 +/- 0.61, respectively). Significantly raised t-PA antigen (14.6 +/- 5.7 ng/ml) was seen in moderate and severe PE as compared with mild PE (9.9 +/- 3.4 ng/ml). PAI-1 activity was significantly raised only in moderate and severe PE as compared with normal pregnancy. There were no significant differences in thrombin-antithrombin-III complexes, D-dimer and beta-thromboglobulin levels between the PE group and normal pregnancy, although these parameters were above the non-pregnant levels. Platelets in PE were within the range found in normal pregnancy. It appears that measurements of plasma u-PA and PAI-2 levels in patients with PE may have prognostic value in determining the outcome of pregnancy in this pregnancy disorder.

Antithrombin III↗
PubMed1997

Plasminogen activator inhibitor-1 represses integrin- and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation.

Cell migration involves the integrins, their extracellular matrix ligands, and pericellular proteolytic enzyme systems. We have studied the role of plasminogen activator inhibitor-1 (PAI-1) in cell migration, using human amnion WISH cells and human epidermoid carcinoma HEp-2 cells in an assay measuring migration from microcarrier beads and a modified Boyden-chamber assay. Active, but not latent or reactive center-cleaved, PAI-1 inhibited migration. A PAI-1 mutant without ability to inhibit plasminogen activation was as active as wild-type PAI-1 as a migration inhibitor, showing that inhibition of plasminogen activation was not involved. PAI-1 specifically interfered with intergrin- and vitronectin-mediated migration: Migration onto vitronectin-coated but not onto fibronectin-coated surfaces was inhibited by PAI-1, a cyclic RGD peptide inhibited migration, and both cell lines expressed vitronectin-binding alpha v-integrins. In addition, active PAI-1, but not latent or reactive center-cleaved PAI-1, inhibited vitronectin binding to integrins in an in vitro binding assay, without affecting binding of fibronectin. Monoclonal antibodies against the urokinase receptor, another vitronectin binding protein, did not affect cell migration in the beads assay, while some inhibitory effect was observed in the Boyden-chamber assay. We conclude that PAI-1, independently of its role as a proteinase inhibitor, inhibits cell migration by competing for vitronectin binding to integrins, while the interference of PAI-1 with binding of vitronectin to the urokinase receptor may play a secondary role. These data define a novel function for the serpin PAI-1, enabling it to regulate cell migration over vitronectin-rich extracellular matrix in the body.

Amnion↗
PubMed1989

Tumor necrosis factor-alpha regulates mRNA for urokinase-type plasminogen activator and type-1 plasminogen activator inhibitor in human neoplastic cell lines.

Tumor necrosis factor-alpha (TNF-alpha) was found to induce type-1 plasminogen activator inhibitor (PAI-1) antigen in the human fibrosarcoma cell line HT-1080, and PAI-1 and urokinase-type plasminogen activator (u-PA) antigens in the human carcinoma cell line T-CAR1; tissue-type plasminogen activator (t-PA) antigen was not affected or slightly decreased. The effects in HT-1080 and T-CAR1 cells were preceded by increases in the cellular levels of the corresponding mRNAs. Cycloheximide caused an increase of PAI-1 mRNA in T-CAR1 cells, but not in HT-1080 cells; during this increase the relative abundance of the two PAI-1 mRNA species, of 2.3 kb and 3.4 kb, respectively, changed strongly in favor of the longer transcript. We conclude that TNF-alpha may affect proteolytic activity in the microenvironment of cells in malignant tumors by affecting gene expression of u-PA and PAI-1.

Cycloheximide↗
PubMed1999

Inhibition of B16BL6 melanoma invasion by tyrosine and phenylalanine deprivation is associated with decreased secretion of plasminogen activators and increased plasminogen activator inhibitors.

We previously found that dietary tyrosine (Tyr) and phenylalanine (Phe) limitation significantly decreased the metastatic phenotype of B16BL6 melanoma cells in vivo and decreased the in vitro invasion of these cells. To more specifically characterize the effects of Tyr and Phe deprivation we examined the three steps involved in invasion: attachment to host cells and components, elaboration of proteases that degrade basement membranes, and migration of invading tumor cells. Here we report that B16BL6 melanoma cell invasion through growth factor reduced (GFR) Matrigel is significantly decreased by Tyr and Phe deprivation. Tyr and Phe deprivation in vitro decreased the attachment of B16BL6 melanoma cells to GFR Matrigel, heparin sulfate proteoglycans (HSPG), neonatal murine epidermal (NME) cells and the extracellular matrix (ECM) from these cells. These cells also exhibited a decrease in chemotactic response to fetal bovine serum (FBS). Deprivation of these two amino acids decreased the secretion of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) while plasminogen activator inhibitor (PAI)-1 and -2 were increased in these cells. These observations suggest that Tyr and Phe deprivation decreases the in vitro chemotactic and invasive ability of B16BL6 melanoma cells by decreasing attachment and secreted PA activity and by increasing secreted PAIs in these cells.

Animals↗
PubMed1998

Transforming growth factor beta1 in the human endometrium. Cyclic variation, increased expression by estradiol and progesterone, and regulation of plasminogen activators and plasminogen activator inhibitor-1.

The purpose of this study was to identify cyclic variations and hormonal regulation of endometrial transforming growth factor beta1 (TGFbeta1) mRNA. Regulation of the plasminogen-activating system was also examined, since it is involved in activation of latent TGFbetas. We measured TGFbeta1 mRNA in 51 normal endometrial samples by Northern blot and densitometric scanning of autoradiograms. Each value was related to the corresponding beta-actin value to allow quantitative evaluation. TGFbeta1 mRNA was higher in the mid and late secretory and menstrual phases than in the earlier parts of the cycle. This pattern implies progesterone dependence. The content of TGFbeta1 mRNA in endometrial tissue explants obtained in the proliferative phase was significantly increased after stimulation for 4 days with estradiol + progesterone in vitro. Both TGFbeta1 and estradiol + progesterone increased the content of plasminogen activator inhibitor-1 mRNA and protein in primary cultures of endometrial stromal cells. Conditioned-medium concentrations of urokinase plasminogen activator (u-PA) were increased by TGFbeta1, but decreased by estradiol + progesterone. This effect of estradiol + progesterone results from increased internalization and degradation of u-PA secondary to up-regulation of the cell surface receptor for u-PA by progesterone (Casslén et al., JCEM 1995; 80: 2776-2784). Increased extracellular u-PA in response to TGFbeta1 exposure was thus in concordance with an unchanged amount of available u-PA receptors on the cell surface. The activation mechanism of latent TGFbeta involves u-PA activity; since u-PA activity is reduced in the secretory endometrium, we suggest that although TGFbeta1 mRNA is increased in the mid and late secretory phase, TGFbetas are mainly in their latent form until the premenstrual rise in u-PA activity stimulates activation. TGFbeta may promote capillary growth during endometrial regeneration.

Adult↗
PubMedDate not supplied

Chromosomal localization of the human urokinase plasminogen activator receptor and plasminogen activator inhibitor type-2 genes: implications in colorectal cancer.

Activation of the proenzyme of urokinase (uPA) on the surface of cancer cells has been implicated in the initiation of focal proteolytic mechanisms that permit invasion and metastasis by colon cancers. The activity of uPA on the cell surface appears to be a function of the number of uPA-specific receptors (uPAR) and the extent of inhibition of uPA by plasminogen activator inhibitors (PAI). The mapping of the genes coding for uPAR, and for PAI-2, was performed to determine whether their chromosomal localization suggested their involvement in the genetic alterations associated with cancer cell DNA. This study confirms the localization of the human urokinase plasminogen activator receptor gene to chromosome 19q and, using in situ hybridization, provides a precise localization to chromosome 19q13.2. In addition, our results confirm the previous allocation of the human plasminogen activator inhibitor-2 gene to a location 18q21.3-->18q22.1, a location that corresponds to the commonest (> 70%) somatic deletions found in colorectal carcinomas. The mapping of the uPAR and PAI-2 genes enables the elucidation of their possible involvement in the genetic alterations that determine the invasive and metastatic phenotypes in colorectal cancer.

Chromosome Mapping↗
PubMed1993

Immunohistochemical study of tumor cell-associated plasminogen activators and plasminogen activator inhibitors in lung carcinomas.

STUDY OBJECTIVE: To compare the expression of plasminogen activators (PA) and plasminogen activator inhibitors (PAI) in normal lung mucosa and lung carcinomas. DESIGN: Immunohistochemical localization of urokinase-type PA (uPA), tissue-type PA (tPA), type 1 PAI (PAI-1), and type 2 PAI (PAI-2) in four normal lung biopsy specimens and in four adenocarcinomas (AC), four squamous carcinomas (SC), two large-cell carcinomas (LCC), and ten small-cell carcinomas (SCC) biopsy specimens. Qualitative immunostaining scoring system. RESULTS: tPA and uPA immunostaining scores from all specimens were statistically similar. The cellular staining for uPA and tPA was generally constant (normal epithelial layers, AC cells, SC cells) except for LCC cells (inconstant uPA staining, p < 10(-3). Both PAIs were detected in cells of the normal epithelial layer. The four carcinoma cell types stained for PAI in a statistically different pattern (p < 10(-3)). Cells of the peripheral cords of SCC were inconstantly PAI-1 and PAI-2 positive (p < 10(-3)). LCC were PAI-2 negative and inconstantly stained for PAI-1. SCC cells were PAI-1 and PAI-2 negative. CONCLUSION: Lung carcinomas of worst clinical prognosis no longer express PAI reactivity. The imbalance of the plasminogen activation pathway may favor the spreading of the more invasive histologic types of bronchogenic carcinomas.

Adenocarcinoma↗
PubMed1999

Characterization of cell-associated plasminogen activation catalyzed by urokinase-type plasminogen activator, but independent of urokinase receptor (uPAR, CD87).

The 55-kD urokinase (uPA) receptor (uPAR, CD87) is capable of binding uPA and may be involved in regulating cell-associated plasminogen activation and pericellular proteolysis. While investigating the relationship between uPAR levels and plasmin generation, we found that uPA-catalyzed plasminogen activation is stimulated by cells which do not express uPAR. This uPAR-independent mechanism appears to be at least as effective in vitro as uPAR-dependent stimulation, such that stimulation on the order of 30-fold was observed, resulting from improvements in both apparent kcat and apparent Km. The mechanism depends on simultaneous binding of both uPA and plasminogen to the cell and requires the presence of the amino-terminal fragment (ATF), available in single chain and two chain high-molecular-weight uPA, but not low-molecular-weight uPA. Stimulation was observed in all leukemic cell lines investigated at similar optimum concentrations of 10(6) to 10(7) cells/mL and may be more general. A mechanism is proposed whereby uPA can associate with binding sites on the cell surface of lower affinity, but higher capacity than uPAR, but these are sufficient to stimulate plasmin generation even at subphysiologic uPA concentrations. This mechanism is likely to operate under conditions commonly used for in vitro studies and may have some significance in vivo.

Humans↗
PubMed1995

Expression of plasminogen activators and plasminogen activator inhibitors in cutaneous melanomas of transgenic melanoma-susceptible mice.

The Tyr-SV40E transgenic mouse model of malignant skin melanoma has been used here to generate melanomas in genetically identical (C57BL/6) mice for analysis of the plasminogen activator (PA) system during tumor development and progression. Twenty-two melanocytic lesions were examined by in situ zymography for PA activity and by immunohistochemistry for concomitant visualization of PA proteins; these lesions encompassed 3 nevi and 19 primary melanomas ranging from melanotic through mixed tumors to amelanotic tumors. Although urokinase-type plasminogen activator (u-Pa) activity was not detected at premalignant stages, it began to appear early in tumorigenesis and became more prominent in later stages of a majority of the tumors. The activity was largely attributable to the endothelium of sprouting capillaries and to a lesser degree to granulocytes, fibroblastic cells, and occasional melanoma cells within tumors. Tissue-type plasminogen activator (t-PA) was undetectable or low in all cases. Of the inhibitors (PAI), PAI-1 was seen in endothelial and fibroblastic cells and in the extracellular matrix, whereas PAI-2 occurred in only one case and was melanoma cell associated. Eleven additional melanomas were analyzed by reverse transcription-PCR for PA expression in RNA extracts from relatively large tumor samples. These were obtained from eight primary melanomas and three metastases, again spanning melanotic, mixed, and amelanotic cases. From four of the mixed primary tumors with distinct melanotic and amelanotic zones, the respective components were propagated separately in transgenic hosts as s.c. transplants to obtain data for clearly identifiable melanotic versus amelanotic parts. u-PA and PAI-1 mRNAs were expressed in all. t-PA expression varied greatly and was notably high in several amelanotic tumors or tumor components, possibly as a result of large blood vessels, as such vessels were seen to be t-PA positive in normal tissue. The u-PA activity in sprouting capillaries may indicate a role in neoangiogenesis. Therefore, according to these mouse models, u-PA may indirectly be a potential therapeutic target against melanoma progression.

Animals↗
PubMed1995

Effects of suramin on metastatic ability, proliferation, and production of urokinase-type plasminogen activator and plasminogen activator inhibitor type 2 in human renal cell carcinoma cell line SN12C-PM6.

Effects of suramin, a polysulfonated naphthylurea compound, on metastatic ability, proliferation, and production of plasminogen activators and plasminogen activator inhibitors were studied using the highly metastatic human renal cell carcinoma cell line, SN12C-PM6. After renal subscapular implantation of tumor cells in nude mice, suramin significantly inhibited metastasis of tumor cells to the lungs and liver. In vitro growth of tumour cells was inhibited by suramin in a dose-dependent manner, at relatively low doses (ID50 = 105 micrograms/ml). Plasminogen activator inhibitor type 2 (PAI-2) production by tumor cells was enhanced by suramin (100 micrograms/ml), whereas urokinase-type plasminogen activator (uPA) production was suppressed. Thus, the increase in PAI-2 and the decrease in uPA production correlated with the inhibitory effects on tumour growth and metastasis by suramin. Therefore suramin may be beneficial for the treatment of patients with an early stage of renal cancer with potential risk of metastasis.

Animals↗