The urokinase plasminogen activator system as a target for prognostic studies in breast cancer

The identification of patients at high risk of relapse is currently one of the most important issues in breast cancer research. However, the selection of high-risk patients continues to be difficult due to the unpredictable course of this disease. Axillary lymph node status is currently recognized as the best clinical discriminant between good and poor prognosis, yet almost 30% of node- negative patients and 65% of node-positive patients will experience a relapse. Additional prognostic markers are therefore urgently needed.Since metastatic disease is the main cause of cancer patient morbidity and mortality, the measurement of molecules functionally involved in the regulation of tumor invasion and metastasis is attractive as a means to predict prognosis.Cancer invasion is a complex process in which degradation of the extracellular matrix plays a crucial role. This degradation is accomplished by the concerted action of several proteolytic enzyme systems, including generation of plasmin by the urokinase pathway of plasminogen activation, matrix metallo-proteases, and other extracellular proteases. Increased expression and secretion of urokinase plasminogen activator (uPA) strongly correlates with the malignant phenotype of many types of cells, and the central role of uPA in tumor invasion is now well established.This review will focus on the prognostic impact of components of the urokinase plasminogen activation system in breast cancer with emphasize on methodological issues.     

尿激酶型纤溶酶原激活物在乳腺癌中的表达及意义

目的 研究尿激酶型纤溶酶原激活物（ｕＰＡ）在乳腺癌组织中的表达及其临床意义。方法 应用免疫组化ＳＡＢＣ法检测１００例原发性乳腺癌患者中的ｕＰＡ的表达。结果 １０例乳腺癌患者中,ｕＰＡ高表达５５例,占５５．０％;低表达者４５例,占４５．０％;ｕＰＡ表达与ＴＮＭ分期、淋巴结状况及肿瘤大小相关,与年龄、月经状况、ＷＲ无关。ｕＰＡ高表达者的无病生存期和总生存期低于ｕＰＡ低表达者。单因素分析显示,ｕＰＡ的预     

子宫内膜腺癌组织中尿激酶型纤溶酶原激活系统的表达及其临床意义

目的:研究尿激酶型纤溶酶原激活系统在子宫内膜腺癌的发生、发展及浸润转移中的规律及其对临床的指导意义.方法:应用免疫组织化学方法测定24例正常子宫内膜、30例子宫内膜增生过长及62例子宫内膜腺癌组中uPA、uPAR、PAI-1的表达,并分析与良恶性、临床分期、组织学分级、基层浸润深度及淋巴结转移的关系.结果:uPA、uPAR、PAI-1在子宫内膜腺癌组中的表达较正常子宫内膜组和子宫内膜增生过长组中的表达显著升高(P均<0.05),而正常子宫内膜组和子宫内膜增生过长组中的表达无显著性差异(P>0.05).uPA、uPAR、PAI-1的高表达与肿瘤分化、临床分期、肌层浸润深度和淋巴结转移有关(P<0.05).结论:uPA、uPAR、PAI-1的表达与子宫内膜腺癌的发生、发展及浸润转移密切相关,可作为判断预后的重要指标.     

UPA，PA1-1在结直肠癌血浆中的测定及其临床意义

目的：探讨UPA,PA1-1在结直肠癌血浆中的浓度变化,及其作为肿瘤指标的临床应用价值。方法：使用ELISA方法测定20名健康人群血浆UPA,PA1-1浓度,以及48例结直肠癌患者治疗前血浆UPA,PA1-1浓度（其中22例追踪测定术后血样浓度）。同时期测定血清CEA浓度。结果：UPA、PA1—1在48例结直肠癌患者血浆中的浓度明显高于对照组（P〈0．05）。追踪22例患者根治术前后血浆UPA、PAI-1浓度变化,其浓度显著下降。血浆UPA在DukesC、D期,以及转移的患者中浓度较高。而PA1-1在DukesD期患者中明显升高。血浆UPA,PA1-1浓度有微弱的相关（r=0．523）。在早期诊断中,UPA、PA1-1的敏感性分别为78．17％、39．58％。特异度分别为90％、95％。多个指标联合检测时敏感度明显上升,其中UPA和CEA联合检测效果最佳,敏感度83．33％。结论：UPA、PAI-1在结直肠肿瘤进展中起重要作用。作为早期诊断指标,UPA好于CEA和PA1-1。联合检测UPA与CEA,准确性更好。     

淋巴结阴性乳腺癌PAI-Ⅰ表达及预后价值

Objective:To investigate the expressions of plasminogen activator inhibitor type 1(PAI-1),C-erbB-2,VEGF and Ki-67 by immunohistostaining and then to evaluate the prognostic value of PAJ-1 in node-negative breast cancer,Methods:The study included a retrospective series of 62 female patients with axillary lymph node-negative breast cencer.Expressions of PAI-1,C-erbB-2,VEGF and Ki-67 were determined by immunohistostaining on formalin-fixed paraffin-embedded tissue sections from these patients after a median follow-up of 69 months(range 22-117 months).Correlations with well known clinicopathologic factors were assessed and multivariate survival analyses were performed.Results:High PAI-1 level was positively associated with high histologic grade of the tumors.Disease-free survival(DFS)was significantly shorter for the patients with moderate to intensive expression of PAI-1 lban for those with negative(X2=25.46,P＜0.001:X2=23.07,P＜0.001)to mild expression(X2=19.75,P＜0.001:X2=17.40.P＜0.001).Although on univariate analysis of the prognostic factors,tumor size,location of primary tumor and age as well as expressions of PAI-1,VEGF and Ki-67 were all significantly prognostic factors for DFS(P＜0.05),PAI-1 was the only independent prognostic factor on multivariate analysis(P＜0.0001;hazard ratio[HR].4.041:95% confidence intewal[CI],1.928-8.468).Conclusion:These results of the current study indicate that intermediate or high expression of PAI-1 represents a strong and independent unfavorable prognostic factor for the development of recurrence or metastases in axillary node-negative breast cancer.     

The miR-143/-145 cluster regulates plasminogen activator inhibitor-1 in bladder cancer

Background:

Upregulation of the proto-oncogene plasminogen activator inhibitor-1 (PAI-1) is a common hallmark of various solid tumours, but the mechanisms controlling its expression are not fully understood.

Methods:

We investigate microRNAs (miRNAs) regulating PAI-1 in a panel of normal bladder urothelial biopsies, superficial Ta bladder tumours and invasive T1–T4 tumours using expression microarrays and qRT–PCR. The prognostic implications of PAI-1 deregulation are established by tissue microarray staining of non-muscle-invasive bladder tumours. MicroRNA repression of PAI-1 is assayed by ectopic miRNA expression, argonaute immunoprecipitation and luciferase assays.

Results:

We found that the miR-143/-145 cluster is downregulated in all stages of bladder cancer and inversely correlated with PAI-1 expression. Mature miR-143 and miR-145 are coordinately expressed, and both directly target the PAI-1 3′UTR, leading to reduced PAI-1 mRNA and protein levels. Furthermore, we show that PAI-1 and miR-145 levels may serve as useful prognostic markers for non-muscle-invasive bladder tumours for which accurate progressive outcome is currently difficult to predict.

Conclusion:

This report provides the first evidence for direct miRNA regulation of PAI-1 in bladder cancer. We also demonstrate mRNA co-targeting by a cluster of non-family miRNAs, and suggest miR-145 and PAI-1 as clinically relevant biomarkers in bladder cancer.     

Physiological and pathological changes of plasma urokinase-type plasminogen activator, plasminogen activator inhibitor-1, and urokinase-type plasminogen activator receptor levels in healthy females and breast cancer patients

The plasma urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and urokinase-type plasminogen activator receptor (uPAR) levels were measured in healthy volunteers and breast cancer patients. In pre-menopause healthy females, blood was sampled weekly during one menstruation cycle and menstruation phases (follicular, ovulatory, luteal) were determined by FSH/LH levels. uPA, PAI-1, and uPAR levels were at the nadir during ovulatory phase. uPA level was highest at follicular phase while PAI-1 level was highest at luteal phase. In comparison between pre- and post-menopause states, uPA and uPAR levels were higher in post-menopause state while PAI-1 level was higher in pre-menopause state. In breast cancer patients, uPA, PAI-1, and uPAR positive rates were low when we use the menopause-state-unmatched cut-off points. As we adjusted the cut-off points by menopause states, the PAI-1 positivity increased mainly in post-menopause cancer patients. These findings suggest that there is a minor but possible sequential change of these molecules during menstruation cycle which might blur the pathological positivity in pre-menopause cancer patients. The pathological elevation of PAI-1 was well detected in post-menopause cancer patients, but this elevation did not correlate with tumor burden such as number of metastatic sites or metastatic location. In conclusion, adjustment of physiological changes of uPA, PAI-1, and uPAR is required in determining pathological elevation of the plasma levels in cancer patients, especially in females.This revised version was published online in October 2005 with corrections to the Cover Date.     

Urokinase plasminogen activator and its inhibitor, PAI-1, in association with progression-free survival in early stage endometrial cancer

Components of the urokinase plasminogen activator (u-PA) system are involved in the metastatic process, and have accordingly been associated with clinical outcome in a variety of malignant tumours. We investigated the prognostic importance of u-PA and plasminogen activator inhibitor type 1 (PAI-1) in endometrial cancer, analysed with luminometric immunoassay (LIA) and enzyme-linked immunosorbent assay (ELISA), respectively. Two different cut-off levels were used: the median and the 80th percentile—the latter because of the low progression rate for patients with early stage (I-II) endometrial cancer. After a median follow-up time of 6.8 years, univariate analysis of patients with stage I–II disease (n=188) showed that high u-PA and high PAI-1 content was associated with a shorter progression-free survival (PFS), but at different cut-off levels, uPA at the median (P=0.003), and PAI-1 at the 80th percentile (P<0.001). Among the other factors, DNA ploidy status was most strongly correlated to PFS, followed by age (continuous), International Federation of Gynaecology and Obstetrics (FIGO) grade of differentiation, S-phase fraction and progesterone receptor (PgR) status. Bivariate analyses, including ploidy and one of the factors u-PA or PAI-1, showed that both add significant prognostic information. We conclude that u-PA and PAI-1 are promising prognostic factors in early stage endometrial cancer.     

Two distinct expression patterns of urokinase,urokinase receptor and plasminogen activator inhibitor‐1 in colon cancer liver metastases

Metastatic growth and invasion by colon cancer cells in the liver requires the ability of the cancer cells to interact with the new tissue environment. Plasmin(ogen) is activated on cell surfaces by urokinase‐type PA (uPA), and is regulated by uPAR and plasminogen activator inhibitor‐1 (PAI‐1). To compare the expression patterns of uPA, uPAR and PAI‐1 in colon cancer with that in their liver metastases, we analysed matched samples from 14 patients. In all 14 primary colon cancers, we found upregulation of uPAR, uPA mRNA and PAI‐1 in primarily stromal cells at the invasive front. In 5 of the 14 liver metastases, we found intense expression of uPAR, uPA‐mRNA and PAI‐1 in primarily stromal cells at the metastases periphery, and in an expression pattern similar to that found in the primary tumours. In the remaining 9 liver metastases, uPAR and uPA‐mRNA were only seen associated with the presence of necrosis within the liver metastases. In addition, PAI‐1‐immunoreactivity was in all liver metastases seen in hepatocytes at the metastases periphery. Interestingly, the former 5 liver metastases positive for uPAR, uPA mRNA and PAI‐1 at the metastasis periphery all had a predominantly desmoplastic reaction, whereas 8 of the remaining 9 showed direct contact between the cancer cells and the liver parenchyma. We conclude that there are 2 distinct patterns of expression of uPAR, uPA and PAI‐1 in colon cancer liver metastases and that these correlate closely with 2 morphological growth patterns. These findings may have implication for the treatment of patients with metastatic disease. © 2008 Wiley‐Liss, Inc.     

Spred2 inhibits TGF‐β1‐induced urokinase type plasminogen activator expression,cell motility and epithelial mesenchymal transition

TGF‐β1 is a potent inductor of malignance in cancer cells. TGF‐β1 stimulates the expression of extracellular matrix degrading proteases, cell migration and it is also involved in the epithelial‐mesenchymal transition (EMT). In the present work, we analyzed the role of Spred2 in the urokinase‐type plasminogen activator (uPA) stimulation, EMT and cell migration by TGF‐β1. We found that both the expression of mRNA and the protein level of Spred2 were lower in transformed keratinocytes PDV compared with immortalized keratinocytes MCA‐3D. The transient ectopic expression of Spred2 in PDV cells inhibited the TGF‐β1‐transactivated SRE‐Luc reporter which is related with the ERK1,2 signal. The stable ectopic expression of Spred2 in PDV cells (SP cells) led to the loss of ERK 1,2 activation by TGF‐β1, although Smad2 activation was not affected, and the knockdown of Spred2 enhanced the activation of ERK1,2 signal by TGF‐β1. The increment of uPA expression induced by TGF‐β1 was suppressed in SP cells. In contrast, the stimulus on PAI‐1 expression was not affected and comparable to parental PDV cells. SP cells under TGF‐β1 treatment were unable to display the EMT, since the overexpression of Spred2 abolished the TGF‐β1‐induced disruption of the E‐cadherin cell to cell interactions, reorganization of the actin cytoskeleton and upregulation of the mesenchymal marker vimentin. Finally, SP cells could not respond to the TGF‐β1 stimulus on cell migration. Taken together, the data in the present study suggests that Spred2 is a regulator of TGF‐β1‐induced malignance in transformed keratinocytes.     

The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy

Cancer dissemination and metastasis is synonymous with invasive cell migration; a process in which the extracellular matrix (ECM) plays the dual role of the substratum on which the cells move as well as the physical obstacle that the cells have to surpass. To degrade the physical obstacle, which the ECM poses in the direction of migration, cells use proteolytic enzymes capable of degrading the ECM components. A major protease system responsible for ECM degradation is the plasminogen activation system, which generates the potent serine protease plasmin. The subject of this review, the urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plays an impressive range of distinct, but overlapping functions in the process of cancer invasion and metastasis: Firstly, uPA/uPAR promotes extracellular proteolysis by regulating plasminogen activation. Secondly, uPA/uPAR regulates cell/ECM interactions as an adhesion receptor for vitronectin (Vn) and through its capacity to modulate integrin function. Thirdly, uPA/uPAR regulates cell migration as a signal transduction molecule and by its intrinsic chemotactic activity. This review is focused on recent insight into the cancer related biology of the uPA/uPAR system as well as its implications for clinical cancer diagnosis, prognosis and therapy.     

Tissue extraction procedures for investigation of urokinase plasminogen activator (uPA) and its inhibitors PAI-1 and PAI-2 in human breast carcinomas

Urokinase type plasminogen activator (uPA) and its inhibitors, plasminogen activator inhibitor type I (PAI-1) and type II (PAI-2), are supposed to be involved in the expression of the invasive and metastatic phenotype of cancer cells. However, clinical investigations on the prognostic significance of their levels in tumor tissue are difficult to realize because of the absence of a convenient method of measurement of these parameters.The aim of the present investigation was to set up a method allowing the measurement of these enzymes and of sex steroid receptor status in appropriate subcellular fraction(s) in conditions easily reproducible in routine.We found that a tissue homogenate prepared according to the method recommended [5] for current measurement of sex steroid receptors is appropriate for further distinct preparations. One aliquot is used for cytosol preparation; another can be treated by 2% Triton X-100 (vol/vol) and provide an extract containing the totality of uPA and PAI-1.The advantage of this procedure is that appropriate subcellular fractions can be derived from a unique homogenization step. Total uPA and PAI-1 are measured in a Triton extract with good performance as compared to previous investigations [4]. PAI-2 is measured in the same cytosol fraction used for sex steroid receptors and other parameters.Because of its simplicity and its high reliability, this method could be a useful tool in the investigation of uPA family proteases and analysis of their prognostic significance in early breast tumors.     

Novel inhibitors of urokinase-type plasminogen activator and matrix metalloproteinase expression in metastatic cancer cell lines

The plasminogen-activating (PA) and matrix metalloproteinase (MMP) enzyme systems are implicated in proteolytic turnover of the extracellular matrix (ECM) associated with biologic processes including wound healing, inflammation and angiogenesis. Aberrant expression of components of the PA and MMP enzyme systems occurs in the pathogenesis of metastatic cancer. Oxamflatin (Ox), a novel hydroxamic acid derivative, inhibits u-PA mRNA expression and proteolytic activity while simultaneously upregulating the expression of the natural inhibitor of u-PA, plasminogen activator inhibitor type 2 (PAI-2) in metastatic cancer cells. We have characterized the effects of Ox and a novel derivative, Metacept-1 (MCT-1), on PA and MMP-mediated proteolysis and invasion in several metastatic tumor lines. Both compounds are able to inhibit u-PA-, MMP-2- and MMP-9-mediated gene expression at low micromolar concentrations as well as u-PA- and MMP-mediated proteolysis as assessed by zymography, with MCT-1 being the more effective of the 2 agents in some assays. Cellular invasion assays correlate with gene expression and zymography experiments identifying both Ox and MCT-1 as able to inhibit invasion of metastatic cancer cell lines through matrigel at nanomolar concentrations, with MCT-1 more effective than Ox in 2 of the 3 cancer cell lines assessed.     

Influence of the extraction procedure on plasminogen activator inhibitor-2 (PAI-2) and urokinase receptor (uPAR) assays in breast cancer tissues

Summary The levels of uPA, its inhibitors PAI-1 and PAI-2, and the uPA receptor (uPAR) have prognostic value in breast cancer. However, different extraction methods and assays kits are used in different laboratories and may directly influence the levels observed. To define a buffer suitable for both PAI-2 and uPAR extraction from breast cancer tissue compatible with hormone receptors and other cytosolic prognosticator assays, we compared PAI-2 and uPAR values obtained by immunoenzymatic assays (American Diagnostica, Green-which, USA) in several extraction conditions: 1) cytosol obtained with the standard hormone receptor buffer; 2) solubilized pellets obtained by Triton X100 extraction of the pelleted membranes obtained with standard hormone receptor buffer; 3) cytosol obtained by direct extraction in the buffer (containing Triton X100) recommended by the manufacturer, after 2 hours or 12 hours of incubation. Cytosol extracts prepared using the standard procedure recommended for hormone receptors gave the highest PAI-2 values. The highest uPAR values were obtained in the subsequent detergent extraction of the pelleted membranes. PAI-2 levels obtained with the kit manufacturer's method after 12 hours of incubation were lower than those obtained after 2 hours of incubation, whereas uPAR levels were similar. We conclude that the most suitable extraction protocol employs standard hormone receptor extraction buffer to obtain a supernatant cytosol fraction for PAI-2 assay, and subsequent detergent extraction of the pelleted membranes to obtain an extract suitable for uPAR.     

Th1／Th2类细胞因子在卵巢癌患者检测的意义

 目的 探讨卵巢癌患者血浆中Th1／Th2类细胞因子的变化及其临床意义。方法 用流式细胞微球芯片捕获技术检测34例卵巢癌患者及14例健康妇女血浆中IL-2、IFN-γ、TNF-α、IL-4、IL-6、IL-10水平。结果 卵巢癌患者较健康妇女血浆中IL-2、IFN-γ、TNF-α水平明显降低，而IL-4、IL-6、IL-10明显升高（其中IL-10升高无统计学意义），且这种变化随临床期别的升高更加明显。结论 卵巢癌患者外周血中Th1／Th2类细胞因子平衡失调，检测Th1／Th2类细胞因子可作为评价卵巢癌临床进展及预后指标。     

宫颈癌患者Th1／Th2细胞因子表达水平的研究

  目的 检测宫颈癌患者外周血CD+4 T细胞分泌细胞因子的水平变化，分析Th1和Th2细胞的细胞因子免疫活动，为肿瘤的免疫治疗提供实验依据。方法 用刺激物刺激细胞，增加细胞内细胞因子的表达，再加入荧光标记的特异性抗细胞因子单克隆抗体，特异性抗原抗体结合，以流式细胞仪分析特异性细胞因子表达水平。结果 宫颈癌患者Th1型细胞因子白细胞介素-2（IL-2）表达水平较正常对照组降低，差异有统计学意义，而Th1 型细胞因子干扰素-γ（IFN-γ）表达水平较正常对照组差异无统计学意义。Th2型细胞因子白细胞介素-4（IL-4）、白细胞介素-6（IL-6）、白细胞介素-10（IL-10）表达水平较正常对照组显著升高，差异有显著性意义。结论 宫颈癌患者Th1型反应模式处于弱势状态，Th2型反应模式处于优势状态，Th1／Th2平衡失调，Th1／Th2平衡向Th2方向漂移，这可能是肿瘤细胞发生免疫逃逸，从而导致肿瘤的发生或者转移的原因之一。     

uPA、PAI-1在食管癌发生、发展不同阶段的表达及意义

目的：探讨尿激酶型纤溶酶原激活物（uPA）、纤溶酶原激活物抑制剂-1（PAI-1）在食管癌发生、发展中的作用及意义。方法：采用免疫组织化学SP法检测正常食管黏膜上皮组织（18例）、食管黏膜上皮不典型增生组织（23例）及食管癌组织（68例）中uPA、PAI-1蛋白的表达,并分析其和食管癌临床病理特征的关系。结果：uPA蛋白在正常食管黏膜上皮组织、食管黏膜上皮不典型增生组织及食管癌组织中的阳性率分别为27.8%、39.1%、70.6%,三者间有显著性差异（P〈0.05）;PAI-1蛋白在正常食管黏膜上皮组织、食管黏膜上皮不典型增生组织及食管癌组织中的阳性率分别为22.2%、34.8%、64.7%,三者间有显著性差异（P〈0.05）。uPA、PAI-1蛋白表达与年龄、性别、病理类型无关（P〉0.05）,在临床病理Ⅰ-Ⅱ期和Ⅲ-Ⅳ期间有升高的趋势,但差异无统计学意义（P〉0.05）,与分化程度和淋巴结有无转移有关（P〈0.05）。结论：uPA、PAI-1蛋白在食管癌发生、发展不同阶段的表达呈进行性上升的趋势,可能与食管癌的发生、发展相关,过度表达提示预后不良。     

ERK1/2和VEGF在非小细胞肺癌中的表达及相关性研究

目的:探讨细胞外信号调节激酶(ERK1/2)以及血管内皮生长因子(VEGF)在非小细胞肺癌(NSCLC)中的表达情况及两者之间的相关性,以及对非小细胞肺癌(NSCLC)预后的影响。方法:应用免疫组化方法检测人NSCLC组织及其癌旁组织中ERK1/2和VEGF的表达情况。结果:ERK1/2及VEGF在NSCLC中的表达均高于癌旁组织,均与患者的年龄、性别、肿瘤类型没有相关性,而与肿瘤TNM分期、分化程度、淋巴结转移情况密切相关,两者阳性表达的患者预后差。两者的表达成正相关。结论:ERK1/2、VEGF与NSCLC的发生、发展密切相关。ERK1/2的过度激活在NSCLC的发生、发展中可能起到重要作用。     

Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR-beta1 integrin complex in colon cancer cells

Cancer invasion is regulated by cell surface proteinases and adhesion molecules. Interaction between specific cell surface molecules such as urokinase plasminogen activator receptor (uPAR) and integrins is crucial for tumour invasion and metastasis. In this study, we examined whether uPAR and beta1 integrin form a functional complex to mediate signalling required for tumour invasion. We assessed the expression of uPAR/beta1 integrin complex, Erk signalling pathway, adhesion, uPA and matrix metalloproteinase (MMP) expression, migration/invasion and matrix degradation in a colon cancer cell line in which uPAR expression was modified. Antisense inhibition of the cell surface expression of uPAR by 50% in human colon carcinoma HCT116 cells (A/S) suppressed Erk-MAP kinase activity by two-fold. Urokinase plasminogen activator receptor antisense treatment of HCT116 cells was associated with a 1.3-fold inhibition of adhesion, approximately four-fold suppression of HMW-uPA secretion and inhibition of pro-MMP-9 secretion. At a functional level, uPAR antisense resulted in a four-fold decline in migration/invasion and abatement of plasmin-mediated matrix degradation. In empty vector-transfected cells (mock), uPA strongly elevated basal Erk activation. In contrast, in A/S cells, uPA induction of Erk activation was not observed. Urokinase plasminogen activator receptor associated with beta1 integrin in mock-transfected cells. Disruption of uPAR-beta1 integrin complex in mock-transfected cells with a specific peptide (P25) inhibited uPA-mediated Erk-MAP kinase pathway and inhibited migration/invasion and plasmin-dependent matrix degradation through suppression of pro-MMP-9/MMP-2 expression. This novel paradigm of uPAR-integrin signalling may afford opportunities for alternative therapeutic strategies for the treatment of cancer.