Urokinase receptor and vascular endothelial growth factor are synergistically associated with the liver metastasis of colorectal cancer.

Considering recent findings that the urokinase plasminogen activation (PA) system is involved in invasion and vascular endothelial growth factor (VEGF) is involved in angiogenesis of colorectal cancer, we evaluated these factors in the liver metastasis of primary colorectal cancer. Cancer tissues from 71 colorectal cancer patients were assayed quantitatively for antigen levels of urokinase type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2), and were also assayed immunohistochemically for expression of VEGF protein. Among the PA system factors, both the levels of uPAR and PAI-1 were significantly higher in larger tumors than in smaller ones, and were also significantly higher in tumors that invaded subserosa, serosa or adjacent organs than in mucosal, submucosal tumors or in tumors that invaded the muscle layer. The uPAR levels were significantly higher in tumors with liver metastasis than in those without. VEGF overexpression was significantly more frequent in tumors with lymph node involvement or liver metastasis than in those without. Among the PA system factors, the uPAR levels were significantly higher in tumors with VEGF overexpression and a multivariate analysis revealed that high uPA level and VEGF overexpression were independent risk factors for liver metastasis. The combination of high uPAR level and overexpression of VEGF was associated with the worst prognosis in patients with colorectal cancer. These results suggest that uPAR and VEGF might contribute synergistically to the liver metastasis of colorectal cancer.     

Urokinase Receptor and Vascular Endothelial Growth Factor Are Synergistically Associated with the Liver Metastasis of Colorectal Cancer

Considering recent findings that the urokinase plasniinogen activation (PA) system is involved in invasion and vascular endothelial growth factor (VEGF) is involved in angiogenesis of colorectal cancer, we evaluated these factors in the liver metastasis of primary colorectal cancer. Cancer tissues from 71 colorectal cancer patients were assayed quantitatively for antigen levels of urokinase type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2), and were also assayed immunohistochemically for expression of VEGF protein. Among the PA system factors, both the levels of uPAR and PAI-1 were significantly higher in larger tumors than in smaller ones, and were also significantly higher in tumors that invaded subserosa, serosa or adjacent organs than in mucosal, submucosal tumors or in tumors that invaded the muscle layer. The uPAR levels were significantly higher in tumors with liver metastasis than in those without. VEGF overexpression was significantly more frequent in tumors with lymph node involvement or liver metastasis than in those without. Among the PA system factors, the uPAR levels were significantly higher in tumors with VEGF overexpression and a multivariate analysis revealed that high uPA level and VEGF overexpression were independent risk factors for liver metastasis. The combination of high uPAR level and overexpression of VEGF was associated with the worst prognosis in patients with colorectal cancer. These results suggest that uPAR and VEGF might contribute Synergistically to the liver metastasis of colorectal cancer.     

Evaluate the Expression of uPA, PAI-1 in Human Gastric Cancer and its Correlation with the Angiogenesis by the Application of Tissue Microarray

OBJECTIVE To investigate the expression of urokinase-type plasminogen (uPA), its inhibitor-1 (PAI-1) mRNA and its protein in human gastric cancer and to find out the relationship among the tumor differentiation, angiogenesis, and other clinical pathologic factors.METHODS In situ hybridization (ISH) was used to get the uPA, PAI-lmRNA in 110 cases with human gastric cancer in 2-tissue microarray (TMA). Immunohistochemical staining (S-P method) for uPA, PAI-1 protein and CD34 were performed in the 110 cases in 2 TMA.RESULTS The expression of the uPA, PAI-lmRNA and their protein happened in the cytoplasm of gastric cancer cells were induced by the poor differentiation of the GC, and the expression of uPA had an increasing trend while the expression of the PAI-1 had a decreasing trend. The microvessel density (MVD) had a positive correlation with the clinical stages and the significant relationship with the lymph node metastasis (P < 0.05). The MVD in uPA positive group was significantly higher than those in uPA negative group (P < 0.05). The expression of PAI-1 has no correlation neither with the clinical stages nor the lymph node metastasis.CONCLUSION The uPA play an important role in invasion and metastasis of GC through promoting angiogenesis. Interdicting the secretion and function of the uPA may allow the target therapy against the tumor invasion. As a new high-throughput technology the tissue microarray is a valuable way to be used in clinical treatment.     

Evaluate the expression of uPA, PAI-1 in human gastric cancer and its correlation with the angiogenesis by the application of tissue microarray

OBJECTIVE To investigate the expression of urokinase-type plasminogen （uPA）, its inhibitor-1 （PAI-1） mRNA and its protein in human gastric cancer and to find out the relationship among the tumor differentiation, angiogenesis, and other clinical pathologic factors. METHODS In situ hybridization （ISH） was used to get the uPA, PAI-lmRNA in 110 cases with human gastric cancer in 2-tissue microarray （TMA）. Immunohistochemical staining （S-P method） for uPA, PAI-1 protein and CD34 were performed in the 110 cases in 2 TMA. RESULTS The expression of the uPA, PAI-lmRNA and their protein happened in the cytoplasm of gastric cancer cells were induced by the poor differentiation of the GC, and the expression of uPA had an increasing trend while the expression of the PAI-1 had a decreasing trend. The microvessel density （MVD） had a positive correlation with the clinical stages and the significant relationship with the lymph node metastasis （P 〈 0.05）. The MVD in uPA positive group was significantly higher than those in uPA negative group （P 〈 0.05）. The expression of PAI-1 has no correlation neither with the clinical stages nor the lymph node metastasis. CONCLUSION The uPA play an important role in invasion and metastasis of GC through promoting angiogenesis. Interdicting the secretion and function of the uPA may allow the target therapy against the tumor invasion. As a new high-throughput technology, the tissue microarray is a valuable way to be used in clinical treatment.     

非小细胞肺癌淋巴结转移相关因素的研究

目的：检测尿激酶纤溶酶原激活物（uPA）、尿激酶纤溶酶原激活物抑制剂（PAI-1）、血管内皮生长因子（VEGF）和微m管密度（MVD）在非小细胞肺癌（NSCLC）组织中的表达以及与淋巴结转移的关系。方法：采用免疫组织化学方法联合检测52例NSCLC组织中uPA、PAI—1、VEGF和MVD的表达水平。结果：uPA、PAI—1、VEGF和MVD在NSCLC中的表达显著高于正常肺组织,影响淋巴结转移的相关因素是TNM分期（P〈0．001）、肿瘤侵犯程度（P=0．034）、uPA表达（P=0．048）、VEGF表达（P=0．047）。多因素分析表明VEGF高表达是淋巴结转移的独立影响因素（P=0．043）。结论：uPA、VEGF高表达与NSCLC的淋巴结转移密切相关,促进了肿瘤转移。     

Larger and more invasive colorectal carcinoma contains larger amounts of plasminogen activator inhibitor type 1 and its relative ratio over urokinase receptor correlates well with tumor size

BACKGROUND: Considering recent findings that both urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitors (PAIs) are involved in tumor growth through an urokinase-type plasminogen activator (uPA) activity-independent mechanism, the relation between the presence of these factors in tumor tissue and the clinicopathologic variables in colorectal carcinoma was reevaluated. METHODS: In 100 colorectal carcinoma patients, antigen levels of u-PA, uPAR, and PAI-1 and PAI-2 were assayed in both tumor tissues and their normal counterparts. Plasma levels of soluble uPAR also were determined. RESULTS: All uPAR, uPA, PAI-1, and PAI-2 antigen levels in tumor tissue were significantly higher than those in normal tissue. Levels of both uPAR and PAI-1 were significantly higher (3.09 +/- 1.37 and 6.63 +/- 7.49, respectively) in large tumors (>/=50 mm in greatest dimension) than those in smaller tumors (< 50 mm) (2.50 +/- 1.07 and 2.72 +/- 2.70, respectively) (P < 0.05). Significant positive correlation coefficients (r) were obtained between tumor size and the calculated ratios of PAI-1/uPAR (r = 0.490; P < 0.0001) and PAI-1/uPA (r = 0. 469; P < 0.0001). In addition to liver metastases (P = 0.004) and lymph node involvement (P = 0.04), high levels of uPAR (P = 0.05) also were found to be of independent prognostic value by multivariate analysis. CONCLUSIONS: Higher expression of uPAR was related to poor prognosis of patients with colorectal carcinoma and excess amounts of PAI-1 over uPAR or uPAR-bound uPA appeared to play an important role in tumor progression.     

uPA、uPAR、nm23-H1在大肠癌中的表达及其与肿瘤侵袭和转移的关系

 目的探讨尿激酶型纤溶酶原激活剂(uPA)、尿激酶型纤溶酶原激活剂受体(uPAR)和nm23H1基因蛋白在大肠癌中的表达及其与肿瘤侵袭和淋巴结转移的关系。方法应用免疫组化SABC法,对121例大肠癌手术根治标本进行uPA、uPAR和nm23H1基因蛋白测定。结果uPA、uPAR和nm23H1阳性表达率分别为62%、74%和48%。uPA和uPAR高表达与大肠癌侵袭和淋巴结转移关系密切(P<0.05)。nm23H1基因蛋白的低表达与大肠癌分化程度和淋巴结转移密切相关(P<0.05)。大肠癌中uPA和nm23H1蛋白表达呈负相关(P<0.05)。结论uPA、uPAR和nm23H1基因蛋白表达与大肠癌侵袭和转移有显著相关性;同时检测uPA和nm23H1表达状况,可作为预测大肠癌淋巴结转移及预后的有用指标。     

Correlation of tissue and blood plasminogen activation system in breast cancer

The plasminogen activation system plays a crucial role during cancer invasion and metastasis. In the solid tumor, urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor type-1 (PAI-1) and uPA receptor (uPAR) are considered as prognostic factors. In this study, we have investigated whether secretion of the uPA, PAI-1 and uPAR from the primary breast cancer tissue can be detected in the blood of the patients using the ELISA assay. We have found that the plasminogen activation system (uPA, PAI-1, uPAR) of tumor tissue is activated from the early stage of breast cancer. However, only a number of metastatic lymph nodes was a prognostic factor in multivariate analysis for relapse. The blood level of the plasminogen activation system correlated with that of tissue in an order of uPAR (r²=0.61; P=0.001), uPA (r²=0.35; P=0.001) and PAI-1 (r²=0.11; P=0.001). We conclude that the total uPAR level of cancer tissue can be substituted by that which is detected in the blood for further clinical applications.     

Expression of urokinase plasminogen activator, its receptor and type-1 inhibitor in malignant and benign prostate tissue

The plasminogen activation (PA) cascade participates in degradation of extracellular matrix during cancer invasion. We have studied the expression of urokinase-type plasminogen activator (uPA) mRNA, uPA receptor (uPAR) mRNA and immunoreactivity, and type-1 plasminogen activator inhibitor (PAI-1) mRNA and immunoreactivity in 16 prostate adenocarcinomas and 9 benign prostate hyperplasias. uPA mRNA and uPAR mRNA expression were found in 9 and 8 of the adenocarcinomas, respectively, and in 7 and 6 of the benign hyperplasias, respectively. In both malignant and benign lesions, expression of these 2 mRNAs was predominantly seen in cells identified as macrophages, which in most of the carcinomas (approximately 90%) were located in the interstitial tissue between the tumor cell islands, while in most of the benign hyperplasias they were located in the lumen of the glands and were in only a few cases (approximately 30%) found in the interstitial tissue. uPAR immunoreactivity correlated with the mRNA expression and was, in addition, found in neutrophils. PAI-1 mRNA was detected in 13 of the 16 carcinomas and in 8 of the 9 benign hyperplasias, located in scattered fibroblast-like cells in both groups, in some vascular structures and in a few macrophages located in the interstitial tissue of both malignant and benign lesions. A similar expression pattern was found for PAI-1 immunoreactivity. In 8 of the 16 carcinomas, all 3 components were present, and in several areas colocalization was observed in stromal cells in close proximity to cancer cell islands. No immunoreactivity and/or mRNA expression of uPA, uPAR or PAI-1 was observed in cancer cells or in other epithelial cells in any of the cases.     

非小细胞肺癌淋巴结转移相关因素的研究

目的肿瘤淋巴结转移与细胞外基质降解、浸润、迁移及肿瘤血管形成有关。检测尿激酶纤溶酶原激活物（uPA）、尿激酶纤溶酶原激活物抑制剂（PAI-1）、血管内皮生长因子（VEGF）和微血管密度（MVD）在非小细胞肺癌组织中的表达以及与淋巴结转移的关系。方法采用免疫组织化学方法联合检测52例非小细胞肺癌组织中uPA、PAI-1、VEGF和MVD的表达水平。结果uPA、PAI-1、VEGF和MVD在非小细胞肺癌中的表达显著高于正常肺组织,影响淋巴结转移的相关因素是TNM分期（P〈0．001）、肿瘤侵犯程度（P=0．034）、uPA表达（P=0．048）、VEGF表达（P=0．047）。多因素分析表明VEGF高表达是淋巴结转移的独立影响因素（P=0．043）。结论uPA、VEGF高表达与NSCLC．的淋巴结转移密切相关,促进了肿瘤转移。     

VEGF-C在胃癌中的表达与微血管密度和淋巴结转移的关系及临床意义

目的 探讨VEGF-C在胃癌中的表达与微血管密度和淋巴结转移及胃癌发生发展及预后的关系.方法 纳入行胃癌手术切除患者的病例样本共计96例,对这96例胃癌样本采用qPCR检测血管内皮生长因子-C(VEGF-C)的相对表达量及检测微血管密度(MVD)参数,并与淋巴结转移等预后情况进行相关性分析.结果 VEGF-C相对表达量与患者的一般资料如年龄、性别、以及肿瘤的特征如大小、发病的部位、侵袭深度,肿瘤的分期及分化程度、是否远处转移等并不存在相关性(P>0.05).而淋巴受累方面,淋巴受累组的VEGF-C相对表达量明显上调(P<0.05),而无淋巴受累组的相对表达量与正常组相比差异无统计学意义(P>0.05),VEGF-C相对表达量明显上调与淋巴结受累转移的风险有关.VEGF-C表达水平与MVD差异表达具有相关性.结论 VEGF-C相对表达量水平与胃癌的淋巴结转移及预后有一定的相关性,但还需进一步系统研究.     

Vascular endothelial growth factor and plasminogen activators in endometrial carcinoma and hyperplasia

Vascular endothelial growth factor (VEGF) and such plasminogen activation system components as uPA, PAI-1 and tPA were determined by enzyme immunoassay methods in endometrial tumors from 121 patients and 18 samples of endometrial hyperplasia of varying degree. Endometrial carcinoma concentrations of uPA vs. PAI-1 were significantly higher than those in hyperplasia. Significant direct correlations--uPA vs. VEGF, uPA vs. PAI-1 and PAI-1 vs. VEGF--were established in endometrial tumors, and inverse ones for tPA vs. uPA and tPA vs. VEGF. A marked correlation with prognostic factors was found for PAI-1 and VEGF: levels of these proteins were relatively higher in cases of tumor progression (FIGO stage and deeper myometrial invasion), poor cell differentiation, and loss of hormone sensitivity. Higher uPA expression was associated with deeper myometrial invasion while, in endometrial tumors with unfavorable prognosis, it was VEGF level alone that was significantly higher.     

Significance of plasminogen-activation system in the formation of macroscopic types and invasion in esophageal carcinoma

BACKGROUND: The roles of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in the formation of macroscopic types and invasion were investigated. MATERIALS AND METHODS: A total of 40 surgically-resected esophageal carcinoma tissues were immunohistochemically stained, and the expression of uPA, PAI-1 and the uPA/PAI-1 ratio, were evaluated. RESULTS: The expression of uPA was significantly stronger in the macroscopically infiltrative type (n = 20: p = 0.0027), whereas PAI-1 was significantly stronger in the localized type (n = 20: p = 0.0005). The uPA/PAI-1 ratio was significantly higher in the infiltrative type (p < 0.0001). A significant correlation was found between the U/P ratio and the depth of tumor invasion (r = 0.511, p = 0.0014). Analysis of tumors of uniform size (4.0-6.0 cm in length), showed that the depth of invasion was significantly greater in the infiltrative type (p = 0.0038). CONCLUSION: The results demonstrated that uPA and PAI-1 play important roles in invasion and formation of macroscopic types of esophageal carcinoma.     

The plasminogen activator and matrix metalloproteinase systems in colorectal cancer: relationship to tumour pathology

The aim of this study was to determine the expression of proteinases and inhibitors from the matrix metalloproteinase (MMP) (MMPs 1, 2, 3, 9, tissue inhibitors of metalloproteinases (TIMPs) 1, 2) and plasminogen activator ((PA) urokinase (uPA), tissue type (tPA), uPAR, plasminogen activator inhibitors (PAIs) 1, 2) systems in colorectal cancer pathology by gelatin zymography, enzyme-linked immunosorbent assays (ELISAs) and quenched fluorescent substrate hydrolysis. The levels of all studied MMPs, uPA, uPAR, TIMP-1 and PAIs were significantly greater in tumour tissues than normal tissues. However, tPA and TIMP-2 were greater in normal colon (P<0.05, Mann-Whitney) e.g. PAI-1: tumour, median 14.9 (range 0.2-80.2) ng/mg total protein; normal, 2.1 (0.1-65.0). Tumour levels of several factors, in particular MMP-1 and PAI-1, correlated with pathology, i.e. Dukes' stage, differentiation, lymphatic or vascular invasion and tumour depth. The interactions between proteinase systems in colorectal cancer are complex and the balance between active proteinases and their inhibitors is important for extracellular matrix (ECM) degradation/remodelling at each stage of the metastatic cascade.     

血管形成和纤维蛋白降解作用与乳腺癌侵袭转移的关系

目的研究血管形成和纤维蛋白降解作用与乳腺癌侵袭转移的关系。方法应用免疫组化方法,检测110例原发性乳腺癌患者中尿激酶型纤溶酶原激活物(uPA)和微血管密度(MVD)的表达,并结合临床、病理及随访资料进行分析。结果110例患者中,uPA高表达者59例,占53．6％;低表达者51例,占46．4％。MVD计数高者53例,占48．2％;计数低者57例,占51．8％。uPA表达与肿瘤大小、淋巴转移和TNM分期有显著相关性,MVD与肿瘤大小、TNM分期有显著相关性,二者表达与患者年龄、月经状况和激素受体状况无关。uPA和MVD高表达者的无复发生存期均低于低表达者的生存期,特别是uPA和MVD均为高表达者更易复发转移。多因素分析显示,uPA和MVD是影响无复发生存期的主要因素。结论血管形成和纤维蛋白降解作用与乳腺癌的侵袭转移行为密切相关,uPA和MVD可能是预测乳腺癌患者复发转移的独立预后因素。     

喉癌组织中尿激酶型纤溶酶原激活剂及其抑制剂的表达及意义

目的:研究尿激酶型纤溶酶原激活剂(urokinasetypeplasminogenactivator,uPA)和纤溶酶原激活剂抑制剂1(plasminogenactivatorinhibitor1,PAI1)在喉癌组织中的表达及其临床意义。方法:应用SABC法检测51例声门上型喉癌患者中的uPA与PAI1的表达,结合临床随访,分析其与临床病理指标的关系及预后的作用。结果:uPA和PAI1的染色阳性率分别为64.7%(33/51)和70.6%(36/51)。uPA和PAI1的表达均与临床分期和颈淋巴结状况相关,与肿瘤大小、T分期和病理学分级无关。单因素分析显示,uPA和PAI1的表达与颈淋巴结转移有相似预后作用;多因素分析显示,uPA和颈淋巴结转移是影响患者预后的独立因子。结论:uPA和PAI1的表达与喉癌的临床分期和颈淋巴结转移有关,uPA阳性表达者可能预后较差。     

子宫颈癌患者尿激酶型纤溶酶原激活物和抑制物的表达及其临床意义的研究

目的 :研究纤溶酶原激活物和抑制物在子宫颈癌的发生、发展及侵袭转移过程中的规律及对临床的指导意义。方法 :采用ELISA法检测 4 2例子宫颈癌患者和 10例良性子宫肿瘤患者的血浆和组织中uPA和PAI 1含量 ,按良恶性、手术前后、临床分期和组织类型等分别进行对照分析。结果 :子宫颈癌患者血浆中uPA和PAI 1含量随临床分期的升高逐渐增加。宫颈癌患者血浆uPA和PAI 1含量术后显著降低。淋巴结转移组血浆uPA含量高于无转移组。癌组织中的uPA和PAI 1含量高于癌周组织。正常宫颈、宫颈上皮内瘤变、宫颈鳞癌组织uPA含量呈上升趋势。腺癌的组织uPA含量高于鳞状细胞癌组 ,PAI 1含量无差异。结论 :检测宫颈癌患者uPA和PAI 1含量可能对其侵犯范围、盆腔淋巴结转移情况、预后等有一定的参考价值     

Expression of urokinase-type plasminogen-activator (upa) and its receptor (upar) in human ovarian-cancer cells and in-vitro invasion capacity

Expression of urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (t-PA), their inhibitor PAI-1 and the uPA-receptor (uPAR) was characterized in six human tumor cell lines (OV-MZ-6, -10, -13, -15, -19 and OVCAR-3) established from patients with cystadenocarcinoma of the ovary. The invasive potential of the ovarian cancer cell lines determined in an in vitro invasion assay did neither correlate with the antigen level of uPA, t-PA, PAI-1 or uPAR nor with the cell surface uPA activity, however, did correlate with the cell surface-bound plasmin activity. The in vitro invasiveness of three cancer cell lines selected displaying a different pattern of uPA and uPAR expression was significantly inhibited by a recombinant soluble truncated form of the uPAR functioning as a scavenger for uPA. Our results suggest that the interference of the uPA/uPAR interaction leads to a reduced in vitro invasiveness of human ovarian cancer cells independent of the level of uPA and uPAR expression.     

Immunolocalization of the components of the plasminogen activating system in breast carcinoma tissue

The plasminogen activating system plays an important role in the progression of carcinomas and the significance of this system in various carcinomas has been thoroughly investigated. To follow up these investigations, we examined the immunolocalization of the components of the plasminogen activating system, namely the urokinase-type plasminogen activator (uPA), its receptor (uPAR), and two inhibitors (PAI-1 and PAI-2), in 72 cases of breast carcinomas. uPA, uPAR and PAI-1 were uniformly expressed in 75.0%, 84.7% and 80.6% of the cases respectively, although their expression was less uniform in T3 or larger carcinomas (p<0.05). Furthermore, the immunoreactivities of these three proteins were often very similar in the lesions. PAI-2 expression was, to the contrary, statistically less extensive (p<0.01)than PAI-1, and only 52.8% of the cases were uniformly positive. The incidence of PAI-2 expression was statistically lower in T3 or larger carcinomas (p<0.01), and in stage III (p<0.01) and grade III carcinomas (p<0.05). Moreover, PAI-1 immunoreactivity was more commonly found in lymph node positive (p<0.05), T3 or larger and stage III carcinomas than PAI-2 immunoreactivity. These findings suggest that uPA, uPAR and PAI-1, whose expression should be regulated by carcinomas once they have grown to a certain degree, work in association with one another, probably promoting carcinoma progression, while PAI-2 might act as the inhibitor in this system. Furthermore, breast carcinomas containing more PAI-I than PAI-2 are more active in respect to both local proliferation and metastasis.     

Urokinase induces receptor mediated brain tumor cell migration and invasion

The plasminogen activation (PA) system plays an important role in tumor invasion by initiating pericellular proteolysis of the extracellular matrix (ECM) and inducing cell migration. Malignant brain tumors overexpress PA members and characteristically invade by migrating on ECM-producing white matter tracts and blood vessel walls. To determine whether urokinase-type plasminogen activator (uPA) and its receptor (uPAR) directly modulate the migration of brain tumor cells, we examined six human brain tumor cell lines, 2 astrocytomas (SW1088, SW1783), 2 medullobastomas (Daoy, D341Med), and 2 glioblastomas (U87MG, U118MG), for their surface uPAR expression, endogenous PA activity, and functional proteolytic activity by an ECM-degradation assay. Migration on Transwell membranes and invasion of Matrigel was then tested by pre-incubating the cells with increasing concentrations of either uPA, the proteolytically inactive amino-terminal fragment (ATF) of uPA, or the uPAR cleaving enzyme, phosphatidylinositol-specific phospholipase C (PI-PLC).All of the cell lines, except D341Med, express surface uPAR protein and uPA activity. High levels of uPAR and uPA activity correlated with cellular degradation of ECM, cell migration, and Matrigel invasion. Cell migration and invasion were enhanced by uPA or ATF in a dose dependent manner, while PI-PLC treatment abolished the uPA effect and inhibited migration and invasion. We conclude that ligation of uPAR by uPA directly induces brain tumor cell migration, independent of uPA-mediated proteolysis; and in concert with ECM degradation, markedly enhances invasion. Conversely, removing membrane bound uPAR from the surface of the cells studied inhibited their ability to migrate and invade even in the presence of proteolytically active uPA.