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1.
The mechanisms underlying migration of neutrophils across endothelium are not completely understood. The urokinase-type plasminogen activator receptor (uPAR) plays a key role in neutrophil adhesion and migration. In the present study, we addressed whether uPAR regulates neutrophil transendothelial migration. We first showed that siRNA-mediated knockdown of uPAR in human umbilical vein endothelial cells (HUVECs) did not affect neutrophil migration across HUVEC monolayers indicating that endothelial uPAR does not regulate neutrophil transmigration. In contrast, the transmigration was significantly inhibited by Fab' fragment of anti-uPAR monoclonal antibody and proteolytically inactive urokinase (uPA), whereas inhibition of proteolytical activity of endogenous uPA (with amiloride or plasminogen activator inhibitor-1) did not affect the transmigration. Both the anti-uPAR Fab' fragment and proteolytically inactive uPA did not exert significant effects upon the transmigration conducted in the presence of F(ab')(2) fragment of blocking antibody to integrin Mac-1 indicating that uPAR regulates Mac-1-dependent transmigration. Mac-1-dependent, but not Mac-1-independent, transmigration was significantly reduced in the presence of N-acetyl-d-glucosamine and d-mannose, the saccharides that disrupt uPAR/Mac-1 association, but was unaffected in the presence of control saccharides (d-sorbitol and sucrose). We conclude that physical association of uPAR with Mac-1 mediates the regulatory effect of uPAR over the transmigration. Finally, we provide evidence that the functional cooperation between uPAR and Mac-1 is essential at both adhesion and diapedesis steps of neutrophil migration across endothelium. Thus, uPAR expressed on neutrophil plasma membrane regulates transendothelial migration independently of uPA proteolytical activity and acting as a cofactor for integrin Mac-1. 相似文献
2.
Niranjan Yanamandra Santhi D. Konduri Sanjeeva Mohanam Dzung H. Dinh William C. Olivero Meena Gujrati Garth L. Nicolson Mandri Obeyeseke Jasti S. Rao 《Clinical & experimental metastasis》2000,18(7):611-615
Urokinase-type plasminogen activator receptors (uPARs) play an important role in tumor invasion by localizing degradative
enzymes at the invasive zone. Our previous studies with human glioblastoma cell line SNB19 expressing AS-uPAR stable tranfectant
lose their invasive properties when injected in vivo. The aim of the present study is to investigate whether the inhibition of tumor formation is due to apoptosis. Apoptosis
is a highly conserved cell suicide program essential for development and tissue homeostasis of all metazoan organisms. Key
to the apoptotic program is a family of cystein proteases termed caspases, which are important for execution of apoptosis
by cleavage of essential cellular proteins. We found loss of mitochondrial transmembrane potential, release of cytochrome
C from mitochondria and subsequent activation of Caspase-9 in SNB19 AS-uPAR cells compared to parental and vector controls.
Our results indicate that suppression of uPAR results in apoptosis and suggest that Caspase-9 dependent apoptosis plays an
important role in SNB19 AS-uPAR-induced apoptosis.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
3.
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. 相似文献
4.
Zanetti A Stoppacciaro A Marzullo A Ciabatta M Fazioli F Prat M Comoglio PM Baroni CD Ruco LP 《The Journal of pathology》1998,186(3):287-291
Met protein encoded by MET oncogene is the high affinity receptor for hepatocyte growth factor (HGF)/scatter factor (SF). HGF/SF has to be cleaved in its heterodimeric form by the urokinase-type plasminogen activator (uPA) to become active as a ligand for Met receptor. The expression of Met protein and of the high affinity receptor for uPA (uPA-R) was investigated in 39 samples of papillary carcinoma using immunohistochemistry. Reactivity for Met protein was present in 33 of 34 tumours, mostly with a diffuse pattern of staining. Reactivity for uPA-R was present in 78 per cent of papillary tumours and exhibited a pattern of staining similar to that of Met protein. Staining for uPA-R was present in 23 of 25 cases (92 per cent) of papillary carcinoma with prominent sclerosis, and in only 1 of 7 cases (14 per cent) without sclerosis. Peritumoural normal thyroid, follicular adenomas, and follicular carcinomas were negative for Met protein and for uPA-R. Hyperfunctioning tall thyroid cells showed weak membrane reactivity for uPA-R and for Met protein. The findings of immunohistochemistry were confirmed at the mRNA level using in situ hybridization, since the signal for uPA-R and Met RNAs was detected in most tumour cells of five cases of papillary carcinoma. 相似文献
5.
目的:癌症的侵袭与转移是一个非常复杂的过程,丝氨酸蛋白酶尿激酶受体已被证实在癌症进展发挥着重要的作用,尿激酶受体的高表达与癌症的不良预后密切相关。尿激酶受体已成为抗癌治疗研究的重要靶点之一。现就以抑制尿激酶受体为靶点治疗癌症的研究进展作一综述。 相似文献
6.
L. Lahtinen N. Huusko H. Myhnen A.-K. Lehtivarjo R. Pellinen M.P. Turunen S. Yl-Herttuala E. Pirinen A. Pitknen 《Neuroscience》2009,163(1):316-328
Urokinase-type plasminogen activator receptor (uPAR) is functionally a pleiotropic mediator involved in cell adhesion, proliferation, differentiation and migration as well as in matrix degradation, apoptosis, and angiogenesis in cancer tissue. Comparable cellular alterations occur in the brain during post-injury tissue repair. As the first step to assess the role of uPAR in brain tissue remodeling, we tested a hypothesis that uPAR expression is altered in the hippocampus during epilepsy-related circuitry reorganization. Epileptogenesis was triggered by inducing status epilepticus (SE) with electrical stimulation of the amygdala in rats. To monitor the development of SE and the occurrence of spontaneous seizures animals were continuously video-EEG monitored until sacrificed (1, 2, 4 or 14 days after SE). The hippocampal expression of uPAR was studied with real time qPCR and immunohistochemistry. Double-immunohistochemistry and confocal microscopy were used to investigate the expression of uPAR in astrocytes, microglia and neurons. We show that in the normal hippocampus the expression of uPAR was low and confined to small population of astrocytes and interneurons. In animals undergoing SE, uPAR expression increased dramatically, peaking at 1 and 4 days after SE. According to double-immunohistochemistry, uPAR was highly expressed in parvalbumin positive interneurons in the hippocampus and dentate gyrus, and in a subgroup of somatostatin and neuropeptide Y positive hilar interneurons. Increased uPAR expression during post-injury phase supports its contribution to tissue remodeling in the brain. Surviving hilar interneurons that are known to be denervated due to loss of afferent inputs in post-SE brain provide a target for future studies to investigate the contribution of uPAR in reinnervation of these cells, and to identify the signaling cascades that mediate the effects of uPAR. 相似文献
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Donadio AC Remedi MM Frede S Bonacci GR Chiabrando GA Pistoresi-Palencia MC 《Clinical & experimental metastasis》2002,19(5):437-444
The development of an effective antitumor immune response to control tumor growth is influenced by the tumor cell itself and/or
by the tumor microenvironment. Tumor invasion and tumor cell spreading require a finely tuned regulation of the formation
and loosening of adhesive contacts of tumor cells with the extracellular matrix (ECM). In our laboratory, a rat tumor cell
line derived from a spontaneous rat sarcoma revealed, by flow cytometry, a high frequency of intercellular adhesion molecule-1
(ICAM-1, 70.1 ± 8.7%) and urokinase-type plaminogen activator receptor (uPAR, 51.2 ± 5.2%) positive cells, while a weak expression
of MHC class II (IA, 2.2±0.2% and IE, 17.4±3.7%) and B7 (12.1±2.2%) antigens was detected. In our tumor experimental model,
after implantation of tumor cells, visible tumor masses were present at days 5–7 with a relatively fast tumor growth until
day 15 (progressive phase) followed by a suppression of the tumor growth (regressive phase). Here we present data that correlates
a significant decrease in the frequency of ICAM-1 and uPAR expressing tumor cells with the appearance of tumor cells in sites
distant from that of the primary tumor. In addition we describe the development of a cellular immune response which controls
the tumor progression and is associated with an increase in the expression of major histocompatibility complex (MHC) class
II IA antigen during tumor development. The histological examination at tumor progressive and regressive time points revealed
the relevant presence of polymorphonuclear neutrophils (PMNs) evidencing colliquative necrosis in tumor growth areas. Taken
together, these results support the idea that the balance between adhesive interactions, proteolytic activity and tumorigenicity
may lead to a tumor invasive phenotype.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
10.
S. I. Hong I. C. Park Y. S. Son S. H. Lee B. G. Kim J. I. Lee T. W. Lee Y. H. Kook Y. I. Min W. S. Hong 《Journal of Korean medical science》1996,11(1):33-37
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. 相似文献
11.
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 总被引:2,自引:0,他引:2
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 相似文献
12.
肝癌细胞株雌二醇与uPAR表达的关系 总被引:1,自引:0,他引:1
目的 观察人肝癌BEL-7402细胞株中雌二醇与uPAR表达的关系。方法 将肝癌BEL-7402细胞株培养于不同浓度雌二醇的培养液中,培养24h、48h及72h后收集各组细胞。通过免疫组化实验,检测各组细胞uPAR的表达。结果 雌二醇作用后的BEL-7402细胞uPAR表达的阳性率明显高于对照组(P〈0.05)。结论 雌二醇可促进肝癌BEL-7402细胞株uPAR的表达。 相似文献
13.
Urokinase-type plasminogen activator receptor (uPAR) augments brain damage in a murine model of ischemic stroke 总被引:1,自引:0,他引:1
Nagai N Okada K Kawao N Ishida C Ueshima S Collen D Matsuo O 《Neuroscience letters》2008,432(1):46-49
Urokinase-type plasminogen activator receptor (uPAR) is a key component of the plasminogen activation system at the cell surface. Recent studies showed that uPAR is expressed in the ischemic damaged brain, suggesting its involvement in brain damage. In this study, we evaluated the role of uPAR in ischemic brain damage induced by permanent middle cerebral artery (MCA) occlusion in mice with genetic deficiency of uPAR (uPAR(-/-)) or of uPA (uPA(-/-)). Brain damage at 3 days was smaller in uPAR(-/-) mice (4.5+/-1.0mm(3)) than in littermate wild-type mice (uPAR(+/+)) (9.1+/-1.8mm(3), p<0.05), whereas it was comparable in uPA(-/-) (8.0+/-4.1mm(3)) and uPA(+/+) (6.9+/-2.6mm(3)) mice. uPAR expression was upregulated in the ipsilateral cerebral cortex within 12h, and remained elevated for up to 3 days. At 1 or 2 days after MCA occlusion, uPAR expression was selectively localized in vessels at the border of the damaged area. These findings suggest that uPAR expressed by endothelial cells augments the ischemic brain damage via a uPA-independent mechanism. 相似文献
14.
R C Perkins V C Broaddus S Shetty S Hamilton S Idell 《American journal of respiratory cell and molecular biology》1999,21(5):637-646
Inhalation of asbestos is associated with pathologic changes in the pleural space, including pleural thickening, pleural plaques, and mesothelioma. These processes are characterized by altered local proteolysis, cellular proliferation, and cell migration, suggesting that the urokinase-type plasminogen activator receptor (uPAR) could be involved in the pathogenesis of asbestos-induced pleural disease. We hypothesized that mesothelial cell uPAR expression is induced by exposure to asbestos. To test this hypothesis, we used complementary techniques in rabbit and human mesothelial cells to determine whether uPAR expression is altered by exposure to asbestos. uPAR expression was induced by chrysotile and crocidolite asbestos, but not by wollastonite, as indicated by binding of radiolabeled urokinase-type plasminogen activator (uPA) to rabbit or human mesothelial cells. uPA was not induced by fiber exposure. Exposure to exogenous uPA increased uPA activity of cells exposed to wollastonite but not asbestos-treated MeT5A cells. uPAR expression increased further when asbestos was preincubated with vitronectin (VN) or serum. Increases in uPAR expression were confirmed by binding of uPA to uPAR in cell membrane preparations and immunofluorescent staining of uPAR at the cell surface, and were associated with increases in steady-state uPAR messenger RNA. Mesothelial cell uPAR expression was also induced by media from monocytes cultured with asbestos incubated with VN and serum. By antibody neutralization, the latter effect appeared to be in part mediated by transforming growth factor-beta. We found that asbestos increases uPAR at the surface of rabbit and human mesothelial cells, suggesting that altered expression of this receptor could be involved in asbestos-induced remodeling of the pleural mesothelium. 相似文献
15.
Dubuisson L Monvoisin A Nielsen BS Le Bail B Bioulac-Sage P Rosenbaum J 《The Journal of pathology》2000,190(2):190-195
The urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in tumour invasion. Previous studies have shown by RT-PCR that uPA and uPAR mRNAs are expressed in human hepatocellular carcinoma (HCC). Here, in situ hybridization, immunohistochemistry, and double immunofluorescence were used to identify the cells expressing uPA and uPAR in 26 HCCs. The results indicate that uPA and uPAR were expressed in every case, almost exclusively in stromal cells, mostly myofibroblasts and macrophages, except for rare tumoural hepatocytes expressing cytokeratin 7. These results show the important role of stromal cells of HCC in the pericellular proteolysis which facilitates cancer cell invasion. 相似文献
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18.
Monoclonal antibodies monospecific to single-chain urokinase-type plasminogen activator (scu-PA) 总被引:1,自引:0,他引:1
Until now, single-chain urokinase-type plasminogen activator (scu-PA) could not be distinguished from urokinase (UK) by immunological methods. Therefore, in our study monoclonal antibodies (mAbs) specific for scu-PA were raised in mice. These mAbs proved to discriminate between scu-PA, UK and plasmin-activated scu-PA. The clones producing these mAbs could be cultivated in a serum-free medium. Furthermore, very pure preparations were obtained by a one-step purification procedure on protein-A-sepharose. The mAbs described provide a future potential for immuno-affinity chromatography and for the specific determination of scu-PA. 相似文献
19.
Cytology of primary central nervous system neoplasms in cerebrospinal fluid specimens 总被引:3,自引:0,他引:3
Although two-thirds of tumors occurring in the central nervous system (CNS) are primary neoplasms, only 10% of positive cerebrospinal fluid (CSF) specimens are from primary CNS tumors. In this study, we reviewed the cytologic findings of 21 positive CSF specimens from primary CNS tumors. A computer search identified 21 cases of positive CSF specimens from patients with primary CNS tumors from the archives. Follow-up included review of medical charts and histologic correlation. The specimens were from 20 patients (9 females and 11 males). Their ages ranged from 6-83 yr, old with a mean of 30 yr. The cases included 9 medulloblastomas, 7 gliomas (3 glioblastoma multiformes, 2 anaplastic astrocytomas, and 2 ependymomas), 2 germinomas, 2 non-Hodgkin's large B-cell lymphomas, and 1 ganglioneurocytoma. Two cases were classified as suspicious and the remaining as positive for malignancy. Immunocytochemistry was employed in 3 cases to support the cytologic diagnosis. These cases included one large-cell lymphoma (leukocyte-common antigen-positive), one germinoma (placental alkaline phosphatase-positive), and the ganglioneurocytoma (neuron-specific enolase- and synaptophysin-positive). There were no false-positive cases. Our results suggest that positive CSF cytology in patients with a primary CNS tumor is a reliable indicator of malignancy and reflects leptomeningeal involvement. The use of immunocytochemistry is helpful in confirming the cytologic impression in some cases. 相似文献
20.
Gokaslan ZL Chintala SK York JE Boyapati V Jasti S Sawaya R Fuller G Wildrick DM Nicolson GL Rao JS 《Clinical & experimental metastasis》1998,16(8):713-719
The Institute for Molecular Medicine, Huntington Beach CA 92649 USA We have sought to determine the production and activity of serine proteases in primary and metastatic spinal tumors and the association of these enzymes with the invasive and metastatic properties of spinal column tumors. Using immunohistochemical techniques, the cellular localization and expression of uroki-nase- type plasminogen activator (uPA) was assessed, whereas its activity was determined by fibrin zymog-raphy, and the amounts of enzyme were measured by an enzyme-linked immunosorbent assay (ELISA) in primary spinal column tumors (chordoma, chondrosarcoma, and giant cell tumor) and metastatic tumors of the spine arising from various malignancies (breast, lung, thyroid, and renal cell carcinomas, and melanomas). Metastatic tumors displayed higher levels of uPA activity than did primary spinal tumors (P < 0.001). Immunohistochemical analysis revealed that uPA expression was highest in metastases from lung and breast carcinomas and melanomas, followed by metastatic tumors from thyr oid and renal cell carcinomas. Similar results were obtained for uPA activity and enzyme level as determined by fibrin zymography and ELISA, respectively. We conclude that metastatic spinal tumors possess higher levels of uPA expression and activity than the primary spinal tumors, which tend to be less aggressive and only locally invasive malignancies. The results suggest that the plasminogen system may participate in the metastasis of tumors to the spinal column.© Kluwer Academic Publishers 1998 相似文献