The urokinase-type plasminogen activator and inhibitors in resectable lung adenocarcinoma

BackgroundThe urokinase-type plasminogen activator (uPA) system is closely related to the occurrence and progression of cancer in many aspects. Previous studies demonstrated that the conclusions about the prognosis value of uPA, plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) in lung cancer are controversial, so this study was performed for the exploration of the predictive effect of uPA, PAI-1 and PAI-2 on the overall survival (OS) of resectable pulmonary adenocarcinoma patients.MethodsUPA, PAI-1 and PAI-2 expression levels were assayed by immunohistochemical staining based on tissue microarray (TMA) that is composed of formalin-fixed paraffin-embedded specimens from 84 resectable lung adenocarcinoma patients from July 2004 to June 2009. The relationship of IHC, mRNA expression levels of three molecules were investigated respectively. The three molecules’ relationship with clinicopathologic parameters and OS was explored by Chi-square, Kaplan-Meier, and Cox regression analyses. The Cancer Genome Atlas (TCGA) database was used to analyze differential gene expressions of RNA-sequencing data of pulmonary adenocarcinoma and normal tissues, and Kaplan-Meier methods were adopted to confirm the prognostic value of uPA, PAI-1 and PAI-2 in resectable lung adenocarcinoma in TCGA database and the R package MethylMix was used to conduct an analysis integrating methylation data and gene expression of RNA-sequencing data based on TCGA.ResultsUPA, PAI-1 and PAI-2 had much higher IHC expression levels in tumor than those in the normal tissues (uPA, Z = -10.511; PAI-1, Z = -4.836; PAI-2, Z = -6.794; all P < 0.0001). High DNA methylation level of gene uPA resulted in the decrease of its expression. In addition, expression level of PAI-2 was positively associated with tumor size (χ² = 8.372, P = 0.004). Multivariate analyses showed TNM stage III was an independent adverse prognostic factor (hazard ratio = 3.736, 95 % confidence interval = 1.097–12.72, P = 0.035). Kaplan-Meier method revealed that uPA, PAI-1 and PAI-2 expression levels were not related to the OS for 84 resectable lung adenocarcinoma patients. According to TCGA data, PAI-1 expression level was identified as a potential adverse predictor for prognosis of resectable lung adenocarcinoma (Gehan-Breslow-Wilcoxon test, P = 0.025).ConclusionsOur data show that, the expression levels of uPA, PAI-1 and PAI-2 are significantly up-regulated in resectable lung adenocarcinoma. Besides, this study highlights PAI-1 as a latent adverse prognostic factor in resectable adenocarcinoma of lung.     

PAI-1在多囊卵巢综合征大鼠脂肪组织中的表达及意义

目的 探讨纤溶酶原激活物抑制因子-l(PAI-1)在多囊卵巢及正常大鼠脂肪组织中的表达及在多囊卵巢综合征(PCOS)发病中的作用.方法 应用脱氢表雄酮(DHEA)皮下注射23 d龄SD雌性大鼠20天,建立PcOS大鼠模型,应用免疫组织化学技术对PAI-1在大鼠脂肪组织的表达强度变化进行研究.结果 PCOS大鼠模型建立成功;PAI-1在PCOS组脂肪组织基质细胞上的表达明显增强.结论 PAI-1在多囊卵巢大鼠发病中起着重要作用.     

Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 and -2 in hepatocellular carcinoma

It has become more and more clear in recent decades that the plasminogen activation system, which includes urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), plasminogen activator inhibitor (PAI)-1 and PAI-2, plays a very important role in the aggressiveness of cancer. Using immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), the expression of these four components of the uPA system was analyzed in 19 cases of hepatocellular carcinoma (HCC) and 18 cases of the adjacent non-cancer tissues which all had chronic active hepatitis with liver fibrosis or liver cirrhosis. Four cases of normal liver tissues, as controls for immunohistochemical stains, were obtained from the hepatectomized liver of patients with metastatic cancer in the liver. The positive rates of uPA, uPAR, PAI-1 and PAI-2 for immunohistochemical stains in cancer tissues were 78.9, 68.4, 57.9 and 31.6%, respectively. Positive signals were mainly distributed in the cytoplasm of the cancer and in stromal cells. Moreover, the strong stains were chiefly located in the invasive front of the cancer cells. No specific stain was detected in four cases of normal liver tissues. In ELISA, there were significant differences between cancer and non-cancer tissues in concentration of uPA, uPAR and PAI-1 (P < 0.0003, 0.0024 and 0.01, respectively), but there was no significant difference in that of PAI-2 (P = 0.37). These results suggest that uPA, uPAR and PAI-1 are related to invasion of HCC.     

胃癌中uPA、PAI-1表达及其与血管生成的关系

目的 观察胃癌组织中uPA、PAI-1mRNA及蛋白的表达，并探讨它们与肿瘤分化、血管生成及临床病理因素之间的关系。方法 用原位杂交及免疫组化S-P法检测110例胃癌组织中uPA、PAI-1的表达，根据CD34阳性的血管内皮细胞计数肿瘤组织微血管密度（MVD）。结果 （1）胃癌组织中uPA mRNA和蛋白、PAI-1 mRNA和蛋白阳性表达定位于胞质；uPA的表达随分化程度的降低有逐渐升高的趋势，PAI-1的表达随分化程度的降低有逐渐降低的趋势。（2）110例uPA mRNA及蛋白表达阳性组MVD值显著高于阴性组，差异均具有显著性（P值均＜0．05）。（3）uPA mRNA及蛋白的表达与临床分期呈正相关（P＜0．05），PAI-1的表达与临床分期和淋巴结转移无相关性。（4）uPA mRNA／蛋白与PAI-1 mRNA／蛋白的表达无相关性。结论uPA与促进胃癌的血管生成密切相关，阻断uPA的分泌和作用途径有望对胃癌浸润转移起抑制作用；胃癌组织中PAI-1可能担当重要的调节剂或者是肿瘤细胞防止自身降解的保护剂而不是这个系统的单纯抑制剂。     

Expression of urokinase-type plasminogen activator,its receptor,and its inhibitor in gastric adenocarcinoma tissues.

The plasminogen and plasmin system, which is mainly regulated by urokinase-type plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1), is generally believed to play a role in cancer invasion and metastasis. This study was conducted to investigate the role of uPA, uPAR and PAI-1 in the invasion and metastasis of gastric adenocarcinoma. The expression of mRNAs for uPA and PAI-1 was determined by Northern blot analysis in nine primary gastric cancer tissues, nine paired metastatic lymph nodes and normal gastric mucosa. The mRNA of uPA was not or faintly detected in normal mucosa, while the expression was increased in both primary gastric cancer tissues and metastatic lymph nodes to a similar degree. The mRNA expression for PAI-1 in the gastric cancer tissues was not different from that in the paired metastatic lymph nodes and normal mucosae. uPAR was determined by immunohistochemical staining, demonstrating that five (56%) and six (67%) out of nine primary gastric cancer tissues and nine paired metastatic lymph nodes were positive, respectively and the intensity was stronger in metastatic lymph nodes. The results support the concept that most gastric cancer cells may have an innately moderate level of uPA and uPAR, and that increase of uPAR expression can be considered to be closely associated with cancer invasion and metastasis.     

Mature breast adipocytes promote breast cancer cell motility

Adipocytes express substances involved in both normal physiology and pathological processes. One such adipocyte protein is the Serpin (serine protease inhibitor) plasminogen activator inhibitor-1 (PAI-1). PAI-1 functions to inhibit urokinase type plasminogen activator (uPA) though PAI-1 itself is also implicated in breast cancer progression. While the role of adipocytes in breast cancer development is not fully understood, obesity is a known risk factor associated with breast cancer. Thus, we characterized adipocytes from breast and omental tissues for PAI-1 and uPA, and the influence of adipocytes on breast cancer cell motility. Using preadipocyte cells from breast and omental adipose tissue, we differentiated each site into mature adipocytes. PAI-1 protein was found in breast adipocytes>omental preadipocytes>omental adipocytes>breast preadipocytes. Interestingly, uPA protein was not detected in any of these cell types. We then incubated breast adipocyte conditioned media (Adip-CM) and preadipocyte conditioned media (PreAdip-CM) on both normal (MCF-10A) and malignant (MCF-10CA1) breast epithelial cell lines. Adip-CM, but not PreAdip-CM, (a) increased cell motility in both MCF-10A and MCF-10CA1 cells; (b) increased cell-associated uPA activity in both cell lines; (c) increased phosphorylated-Akt levels in MCF-10CA1 cells; and (d) gene array profiles show altered expression of several genes associated with cancer adhesion, metastasis and signaling. Our results suggest that mature breast adipocytes are capable of altering the epithelial cell phenotype, producing a more motile cell type and further provide a potential link between obesity and risk of breast cancer.     

Expression of matrix metalloproteinases-1, -2, and -9; tissue inhibitors of matrix metalloproteinases-1 and -2; cathepsin B; urokinase plasminogen activator; and plasminogen activator inhibitor, type I in skull base chordoma

Little is known about proteinase expression in skull base chordoma, a rare bone tumor exhibiting local invasiveness. Using immunohistochemical techniques, we investigated the expression of matrix metalloproteinases (MMPs)-1, -2, and -9; tissue inhibitors of matrix metalloproteinases (TIMPs)-1 and -2; cathepsin B (CatB); urokinase plasminogen activator (uPA); and plasminogen activator inhibitor, type I (PAI1), in 45 patients with skull base chordoma (45 primary and 25 autologous recurrent lesions). We compared these data with clinicopathologic parameters and the expression of cell differentiation markers. MMP-1, MMP-2, TIMP-1, CatB, uPA, and PAI1 were frequently expressed, and there was a significant correlation in the expression of some proteinases. Immunoreactivity for MMP-1, MMP-2, CatB, and uPA was significantly higher in lesions exhibiting tumor infiltration of host bone than in those without such components. Expression of MMP-1, TIMP-1, CatB, and uPA was associated with that of low-molecular-weight cytokeratin (CAM5.2). There were no differences in proteinase expression in 25 pairs of primary and their recurrent lesions, and proteinase expression did not predict local recurrences. However, patients with higher expression of both MMP-1 and uPA showed worse prognosis compared with the others. In conclusion, expression of some proteinases correlated with CAM5.2 expression and seemed to play an important role in a synergistic manner in the invasion process in skull base chordoma. The authors believe that elevated expression of MMP-1 and uPA can be used to identify patients with a worse prognosis in skull base chordoma.     

Plasminogen activator inhibitor-1 as a measure of vascular remodelling in breast cancer

The generation of urokinase plasminogen activator (uPA) by tumours is an important pathway for neoplastic cell invasion and metastasis. Indeed in several tumour types, elevated levels of uPA, its receptor (uPAR) or its inhibitor plasminogen activator inhibitor-1 (PAI-1) is associated with a poorer prognosis. Since endothelial cells also use this proteolytic system to remodel the extracellular matrix during angiogenesis and since angiogenesis, as assessed by microvessel density, is also a predictor of patient survival, this study was designed to investigate the relationship between angiogenesis and the urokinase system in breast tumours. The aims were to assess whether the uPA, uPAR and/or PAI-1 correlates with angiogenic activity and could therefore be a useful objective clinical measure of tumour neovascularization; and to clarify whether the poor outcome associated with high levels of the urokinase system is due to its association with angiogenesis. The study also sought to examine the relationship between the uPA system and vessel remodelling using loss of a basement membrane epitope (LH39) normally associated with established capillaries. The cytosolic levels of uPA, PAI-1 and uPAR were therefore measured by enzyme linked immunoabsorbent assay, together with tumour vascularity, in 136 well-characterized invasive breast carcinomas. There were significant relationships between uPA and uPAR (Spearman r=0.37, p<0.0001), uPA and PAI-1 (Spearman r=0.19, p=0.03) and between uPAR and PAI-1 (Spearman r=0.23 p=0.01). A significant correlation was also observed between PAI-1 and vessel remodelling (Spearman r=0.34, p=0.04), patient age (p=0.01), nodal status (p=0.047) and tumour grade (p=0.04), but no association between tumour vascularity and PAI (p=0.96), uPA (p=0.69) or uPAR (p=0.81) was present. No significant association was seen between any of the urokinase variables and expression of the angiogenic factor thymidine phosphorylase. Furthermore, no significant associations were found between any of the studied parameters and overall survival in a univariate analysis of the cancer patients. A multivariate Cox proportional hazard model of overall survival showed that uPA (p=0.15), but not uPAR (p=0.52) or PAI-1 (p=0.61), gave no additional prognostic information. These findings show that uPA may work via an independent pathway to angiogenesis and therefore combined blockade of uPA and angiogenesis may have additional therapeutic benefits. It also shows, as recently demonstrated in animal models, that PAI-1 may be a key regulator of vascular remodelling in human cancer.     

uPA和PAI-1在人脑胶质瘤的表达及其与肿瘤血管生成的关系

目的探讨uPA、PAI鄄1和VEGF与人脑胶质瘤病理分级和侵袭行为的关系及各因子间的相互联系。方法采用免疫组化SP方法检测42例人脑胶质瘤和8例正常脑组织uPA、PAI鄄1和VEGF蛋白的表达。结果12例中低度恶性胶质瘤中,uPA、PAI鄄1和VEGF阳性表达率分别为58.3%、50.0%、33.3%,30例高度恶性胶质瘤的阳性率分别为96.7%、86.7%、93.3%,两组间各指标相比较,uPA和VEGF差异有极显著性(P<0.01),PAl鄄1差异有显著性(P<0.05)。uPA、PAI鄄1和VEGF阳性染色主要定位于血管内皮细胞和瘤细胞胞浆,以肿瘤侵袭边缘和坏死组织周围多见。uPA与VEGF、PAI鄄1与VEGF之间均呈明显正相关(P<0.05)。8例正常脑组织除1例有PAl鄄1微弱表达外,其余均为阴性。结论随脑胶质瘤恶性度增高,uPA、PAl鄄1和VEGF表达增强,三者协同作用,可作为胶质瘤恶性度高和侵袭能力强潜在的分子生物学指标。     

多囊卵巢综合征患者血PAI-1和uPA含量的变化

目的观察多囊卵巢综合征(PCOS)患者外周血纤溶酶原激活抑制物1(PAI-1)和尿激酶型纤溶酶原激活物(uPA)的水平。方法实验分PCOS组和对照组,PCOS组又分为肥胖组和正常体重组,用酶联免疫吸附法(ELISA)测定PCOS组与对照组患者血浆PAI-1及血清uPA水平,并测定体重指数(BMI)、腰臀比(WHR)、空腹血糖(FPG)、空腹胰岛素及胰岛素释放试验(IRT),以稳态模型公式评估胰岛素抵抗(IR),并计算胰岛素曲线下面积(AUC)。结果PCOS组与对照组相比,黄体生成素/卵泡刺激素(LH/FSH)、睾酮(T)、空腹血糖、稳态(HOMA)指数、AUC及PAI-1含量均显著升高(P<0.05)。其中,PCOS肥胖组与正常体重组相比,HOMA指数、AUC及PAI-1含量也显著升高(P<0.05)。在相关性分析中,PAI-1与HOMA指数、PAI-1与AUC、PAI-1与BMI、HOMA-IR与BMI均有显著相关性(P<0.0001)。结论胰岛素抵抗和肥胖是影响PCOS患者PAI-1水平升高的一个很重要因素,抗PAI-1的研究可能为多囊卵巢综合征的治疗提供一个新的方法。     

胃癌组织中尿激酶型纤溶酶原激活剂及其受体基因表达和临床意义

目的：研究尿激酶型纤溶酶原激活剂（ｕＰＡ）及其特异受体（ｕＰＡＲ）与胃癌的关系及其在胃癌浸润转移中的作用。方法：采用ｃＤＮＡ－ｍＲＡＮ原位分子杂交技术,分别检测了６４例胃癌及其癌旁组织中ｕＰＡ和ｕＰＡＲｍＲＮＡ表达情况,同时结合病人的临床生物学指征进行分析。结果：癌与癌周比较,ｕＰＡ和ｕＰＡＲｍＲＮＡ阳性表达率明显升高,Ｐ〈０．００１。在伴有淋巴结转移的病例中,ｕＰＡ和ｕＰＡＲ阳性例数分别为１９／２９和２４／２９,与无转移的１０／３５和１３／３５相比,Ｐ分别〈０．０１和〈０．００１。在浸润到肌层、浆膜层的病例中ｕＰＡ和ｕＰＡＲ阳性例数分别为２５／３８和３０／３８,与浸润到粘膜和粘膜下层的４／２６例和７／２６相比,Ｐ均〈０．００１。在ｕＰＡ和ｕＰＡＲ同时阳性的病例中,伴有淋巴结转移和浸润到肌层以下的分别占１５／２     

Signalling networks associated with urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in breast cancer tissues: new insights from protein microarray analysis

The urokinase-type plasminogen activator (uPA) and the main uPA inhibitor PAI-1 play important roles in cell migration and invasion in both physiological and pathological contexts. Both factors are clinically applicable predictive markers in node-negative breast cancer patients that are used to stratify patients for adjuvant chemotherapy. In addition to their classical functions in plasmin regulation, both factors are key components in cancer-related cell signalling. Such signalling cascades are well described in cell culture systems, but a better understanding of uPA- and PAI-1-associated signalling networks in clinical tissues is needed. We examined the expression of uPA, PAI-1, and 21 signalling molecules in 201 primary breast cancer tissues using protein microarrays. Expression of uPA was significantly correlated with the expression of ERK and Stat3, while expression of PAI-1 was correlated with the uPA receptor and Akt activation, presumably via integrin and HER-receptor signalling. Analysis of uPA expression did not reveal any significant correlation with staging, grading or age of the patients. The PAI-1 expression was correlated with nodal stage. Network monitoring for uPA and PAI-1 in breast cancer reveals interactions with main signalling cascades and extends the findings from cell culture experiments. Our results reveal possible mechanisms underlying cancer development.     

Urokinase plasminogen activator expression by primary and HPV 16-transformed keratinocytes

The molecular events underlying progression of human papillomavirus (HPV) 16-associated intraepithelial neoplasia to invasive cancer have not been studied in detail. Penetration of the basement membrane is an early, but poorly understood step in this process and probably involves the action of one or more metallo- and serine proteinases. Urokinase-type plasminogen activator (uPA) is a serine proteinase that has been implicated in the pathogenesis of several epithelial tumors, but its role in HPV-associated tumors is not known. To examine uPA expression by HPV 16-transformed keratinocytes in vitro, primary foreskin keratinocyte cultures were transfected by HPV 16 DNA. The primary parental cells and the HPV 16-transformed keratinocytes were studied using substrate gel zymography, Western blot analysis and an in vitro assay measuring penetration of a Matrigel artificial basement membrane. Both uPA and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), were overexpressed in the HPV 16-transformed cells relative to the parental cell line. The transformed cells, but not the parental cells, were able to degrade and penetrate the Matrigel membrane and penetration was blocked by both PAI-1 and by antibodies to uPA. Our data suggest that HPV 16-induced transformation of keratinocytes is associated with upregulation of uPA expression. In conjunction with other proteinases, uPA plays an important role in the ability of HPV 16-transformed keratinocytes to penetrate artificial basement membranes.     

The plasminogen activator inhibitor "paradox" in cancer

Proteolysis in general and specifically the plasminogen activating system regulated by urokinase (uPA) its specific receptor, the GPI membrane anchored urokinase receptor (uPAR) and the specific plasminogen activator inhibitor 1 (PAI-1) plays a major role in tumorigenesis, tumor progression, tumor invasion and metastasis formation. This is exemplified by a body of published work showing a positive correlation between the expression of uPA or uPAR in several tumors and their malignancy. It is generally assumed that such a "pro-malignant" effect of the uPA-uPAR system is mediated by increased local proteolysis thus favoring tumor invasion, by a pro-angiogenic effect of this system and also by uPA-uPAR signaling towards the tumor thereby shifting the tumor phenotype to a more "malignant" one. However, when tumor patients are analyzed for long term survival, those with high levels of the inhibitor of the system, PAI-1 have a much worse prognosis than those with lower PAI-1 levels. This indicates that increased overall proteolysis alone cannot be made responsible for the adverse effects of the plasminogen activating system in tumors. Moreover, it becomes increasingly evident that components of the fibrinolytic system secreted by the tumor cells themselves are not solely responsible for a correlation between the plasminogen activating system and tumor malignancy; components of the plasminogen activating system secreted by stroma cells or cells of the immune system such as macrophages contribute also to the impact of fibrinolysis on malignancy. This review summarizes the evidence for the role of plasminogen activator inhibitor-1 in mediating the malignant phenotype and possible mechanism thereby trying to explain the "PAI-1 paradox in cancer" on a molecular level.     

Urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 mRNA assessment in breast cancer by means of NASBA: correlation with protein expression

Urokinase plasminogen activator (uPA) and its main inhibitor, plasminogen activator inhibitor type-1 (PAI-1) determined in tumor tissue by means of enzyme-linked immunosorbent assay (ELISA) can discriminate patients with primary breast cancer at high risk vs low risk for recurrence. The aim of this study was to analyze uPA and PAI-1 messenger RNA (mRNA) expression by means of quantitative nucleic acid sequence-based amplification (NASBA) on 77 primary breast tumor samples and to correlate this expression with the uPA and PAI-1 protein content. We observed that the 2 markers were significantly overexpressed (uPA, P < .0001; PAI-1, P = .0042) in mRNA in the ELISA+ group. The receiver operating characteristic (ROC) curves demonstrated high concordance between NASBA and ELISA (area under the ROC curve of 0.84 and 0.70 for uPA and PAI-1, respectively) and showed that uPA and PAI-1 status could be predicted by using the molecular assay with sensitivity and specificity values of 80.8% and 82.4% and sensitivity and specificity values of 66.7% and 74.0%, respectively.     

Effects of black cohosh on the plasminogen activator system in vascular smooth muscle cells

Objective

The rhizome of the Cimicifuga racemosa plant (commonly known as black cohosh) has been used for menopausal complaints. Studies regarding the cardiovascular effects of black cohosh are lacking. We investigated the effect of black cohosh on the plasminogen activator system in cultured vascular smooth muscle cells (VSMCs).

Methods

VSMCs were isolated from rat aortae. Expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) proteins were evaluated by Western blot analysis and enzyme-linked immunosorbent assay, respectively. The activities of PAI-1 and t-PA in the conditioned media were assessed by fibrin overlay zymography. A 40% 2-propanol extract of black cohosh was used.

Results

Black cohosh extract (BcEx) stimulated the protein expression of PAI-1, but it did not affect that of t-PA. Vitamin E, a potent antioxidant, inhibited the BcEx-induced increase in PAI-1 expression, while ICI 182,780, an estrogen receptor antagonist, had no effect. Fibrin overlay zymography revealed that BcEx increased the activity of PAI-1 in the conditioned media, while concurrently decreasing that of free t-PA by inducing a binding to PAI-1.

Conclusions

BcEx induces PAI-1 protein expression in the VSMCs likely via an oxidant mechanism. It also stimulates the enzyme activity of PAI-1 and reduces that of free t-PA. These findings suggest that black cohosh might exert a negative influence on fibrinolysis.     

Urokinase-type plasminogen activator receptor in gastric cancer: tissue expression and prognostic role

The urokinase-type plasminogen activator (UPA) and its inhibitor PAI-1 are thought to play an important part in gastric cancer (GC) invasion and metastasis. Little is known about the behavior and prognostic impact of the receptor for UPA (UPAR). The aims of the present study were: (1) to measure UPAR, UPA and PAI-1 levels in GC and in non-malignant tissue distant from the tumor (NORM); (2) to evaluate their relationship with histomorphological parameters; and (3) to determine their prognostic value. UPAR, UPA and PAI-1 levels were determined by ELISA in GC and NORM samples from 20 patients with GC undergoing surgery. The GC was also examined in terms of the presence (n=10) or absence (n=10) of metastasis, differentiation (five differentiated, 15 undifferentiated) and histotype. Survival was analysed using life table analysis. UPAR, UPA and PAI-1 were significantly higher in GC vs NORM, in the presence of metastasis (UPAR, UPA) and in undifferentiated GC (UPAR, PAI-1). UPAR significantly correlated with UPA and PAI-1. Low levels of UPAR (P=0.04), UPA (P=0.007) and PAI-1 (P=0.02) were associated with a better survival. Our results demonstrate a sharp increase in UPAR in GC and suggest a prognostic role for it. The concomitant activation of UPAR, UPA and PAI-1 in GC confirm the important role of the plasminogen activator system in the process of invasion and metastasis.     

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 µg/ml). Plasminogen activator inhibitor type 2 (PAI-2) production by tumor cells was enhanced by suramin (100 µg/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.