Expression and significance of urokinase-type plasminogen activator in human gliomas.
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To investigate the expression and clinical significance of urokinase type plasminogen activator (uPA) in human gliomas.mRNA and protein expressions of uPA were examined by Northern blot hybridization and immunohistochemical method in 43 cases of gliomas and 5 cases of normal brain tissues and their relationship to clinical indexes was comprehensively analyzed.All tissues expressed the 2.5 kb transcript of uPA mRNA. The uPA mRNA level in high-grade gliomas was considerably higher than that in low-grade gliomas and normal brain tissues (P < 0.01). Levels of uPA mRNA expression in tumor tissues with recurrence during 18 postoperative months and a survival period less than 3 years, were significantly higher than counterparts (P < 0.01). uPA mRNA expression was strongly correlated with the microvessel quantity (MVQ) in gliomas (r = 0.56, P < 0.01). uPA protein was mainly distributed in tumor cells and endothelial cells of glioblastomas and anaplastic astrocytomas.Expression of uPA is associated with the malignant progression, invasion and angiogenesis of gliomas, and it may play a critical role in the recurrence and prognosis of gliomas.Keywords:
Anaplastic astrocytoma
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The urokinase plasminogen activator system is involved in angiogenesis and tumor growth of malignant gliomas, which are highly neovascularized and so may be amenable to antiangiogenic therapy. In this paper, we describe the activity of A6, an octamer capped peptide derived from the non-receptor-binding region of urokinase plasminogen activator. A6 inhibited human microvascular endothelial cell migration but had no effect on the proliferation of human microvascular endothelial cells or U87MG glioma cells in vitro. In contrast, A6 or cisplatin (CDDP) alone suppressed subcutaneous tumor growth in vivo by 48% and 53%, respectively, and, more strikingly, the combination of A6 plus CDDP inhibited tumor growth by 92%. Such combination treatment also greatly reduced the volume of intracranial tumor xenografts and increased survival of tumor-bearing animals when compared with CDDP or A6 alone. Tumors from the combination treatment group had significantly reduced neovascularization, suggesting a mechanism involving A6-mediated inhibition of endothelial cell motility, thereby eliciting vascular sensitivity to CDDP-mediated toxicity. These data suggest that the combination of an angiogenesis inhibitor that targets endothelial cells with a cytotoxic agent may be a useful therapeutic approach.
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Urokinase-type plasminogen activator receptors (uPARs) play an important role in tumor invasion by localizing degradative enzymes at the invasive zone. In the present study, we examined the presence and distribution of uPARs in human gliomas in vivo. The amounts of uPARs were measured by radioreceptor assays and Northern blotting and were significantly higher in anaplastic astrocytomas and glioblastomas than they were in normal brain tissues and low-grade gliomas. In situ hybridization was performed to investigate the cellular source of uPAR mRNA in various types of astrocytomas and normal brain tissues. uPAR mRNA was localized in astrocytoma cells and endothelial cells within tumor tissue, especially near sites of vascular proliferation and at the leading edges of tumors. uPAR mRNA was also expressed in tumor cells near necrotic areas. Expression was barely detectable in low-grade astrocytomas and normal brain tissues. These results suggest that expression of uPAR in the invading astrocytoma cells may play a significant role in the invasive behaviors of glioblastomas.
Anaplastic astrocytoma
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Plasminogen activator inhibitor 1 (PAI-1) is believed to control proteolytic activity and cell migration during angiogenesis. We previously demonstrated in vivo that this inhibitor is necessary for optimal tumor invasion and vascularization. We also showed that PAI-1 angiogenic activity is associated with its control of plasminogen activation but not with the regulation of cell-matrix interaction. To dissect the role of the various components of the plasminogen activation system during angiogenesis, we have adapted the aortic ring assay to use vessels from gene-inactivated mice. The single deficiency of tPA, uPA, or uPAR, as well as combined deficiencies of uPA and tPA, did not dramatically affect microvessel formation. Deficiency of plasminogen delayed microvessel outgrowth. Lack of PAI-1 completely abolished angiogenesis, demonstrating its importance in the control of plasmin-mediated proteolysis. Microvessel outgrowth from PAI-1-/- aortic rings could be restored by adding exogenous PAI-1 (wild-type serum or purified recombinant PAI-1). Addition of recombinant PAI-1 led to a bell-shaped angiogenic response clearly showing that PAI-1 is proangiogenic at physiological concentrations and antiangiogenic at higher levels. Using specific PAI-1 mutants, we could demonstrate that PAI-1 promotes angiogenesis at physiological (nanomolar) concentrations through its antiproteolytic activity rather than by interacting with vitronectin.
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AIM To investigate the relationship between urokinase type plasminogen activator (uPA) activity and the malignant biological behavior of human gliomas. METHODS The amounts of uPA were measured by Northern blotting hybridization and immunohistochemical method in 43 cases of brain gliomas and 5 cases of normal brain tissues, and their relation to the clinical indexes was comprehensively analyzed. RESULTS All tissues expressed 2.5 kb transcripts of uPA mRNA. The uPA mRNA level were significantly higher in high grade gliomas than in low grade gliomas and normal brain tissues ( P 0.01), but no significant difference was observed between low grade gliomas and normal brain tissues ( P 0.05) . Levels of uPA mRNA expression in tumor tissues with recurrence in 18 months postoperatively and survival period less than 3 years were significantly higher than their counterparts ( P 0.01). The uPA mRNA was also expressed in tumor cells near necrotic areas. uPA mRNA expression was considerably correlated with the microvessel quantity (MVQ) in gliomas ( r =0.56, P 0.01), but had no significant correlation with the sex or age of the patients and tumor size . The distribution of uPA protein was mainly in tumor cells and endothelial cells of glioblastomas and anaplastic astrocytomas, whereas it was almost undetectable in low grade gliomas. CONCLUSION The expression of uPA gene is associated with the malignant progression of gliomas and plays an important role in the recurrence and invasive behaviors of high grade gliomas.
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Objective:To study the expression of urokinase type plasminogen activator (uPA) and its receptor (uPAR) mRNA in gastric cancer tissues and the relationship with gastric cancer cell invasion and metastasis. Methods:uPA and uPA expression levels have been detected by cDNA mRNA northern blot hybridization in 20 gastric cancers and their surrounding tissues. Results:Of 20 gastric cancer cases, there were 13 and 15 had higher uPA and uPAR mRNA expressions than their surrounding tissues respectively ( P 0 01). Both uPA and uPAR mRNA expressions for 12 out of 20 were higher than that of surroundings. The uPA and uPAR mRNA expression levels in 11 gastric cancer tissues with lymph node metastases were obviously higher than those without lymph node metastases. Conclusion:The expression level of uPA and uPAR mRNA increase in gastric cancer tissues and obviously relates with gastric cancer cell invasion and metatasis.
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The plasminogen activation system represents a potent mechanism of extracellular proteolysis and is an essential component of normal wound healing. It has also been implicated in the pathogenesis of chronic, nonhealing ulcers. Traditionally, urokinase-type plasminogen activator (uPA) has been associated with pericellular proteolytic activity involved in tissue remodelling processes, and tissue-type plasminogen activator (tPA) mainly with intravascular fibrinolysis.The present study was conducted to characterize the spatial distribution of the various plasminogen activation system components in chronic ulcers and acute, well-granulating wounds.The expression of uPA, tPA, urokinase receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), and vitronectin was investigated by immunohistochemical staining, in addition to uPA, tPA and PAI-1 expression by in-situ hybridization, in samples from eight chronic venous ulcers, five decubitus ulcers, five well-granulating acute wounds and five normal skin samples.In chronic venous leg ulcers tPA mRNA was detected in basal and suprabasal keratinocytes at the leading wound edge, while in well-granulating wounds and in decubitus ulcers tPA mRNA was expressed only in a few keratinocytes. However, tPA was widely expressed in fibroblast- and macrophage-like cells in the stroma of well-granulating wounds, while less tPA was detected in the granulation tissue of chronic ulcers. tPA mRNA and protein were localized in the superficial granular layers in normal skin. Although no qualitative differences in expression of uPA, PAI-1 or uPAR in the wound edge keratinocytes in chronic ulcers vs. normally granulating wounds were found, their expressions were more pronounced in the granulation tissue of well-granulating wounds.These results suggest that in poorly healing venous leg ulcers, the pattern of tPA expression is altered in keratinocytes at the leading edge of the wound, and the patterns of tPA, uPA and PAI-1 expression are altered in the granulation tissue.
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Abstract Background The urokinase plasminogen activating system (uPAS) is implicated in neoplastic progression and high tissue levels of uPAS components correlate with a poor prognosis in different human cancers. Despite that, relative few studies are available on the expression and function of the uPAS components in human seminomas. In the present study we characterized the expression of the urokinase plasminogen activator (uPA), its cognate receptor (uPAR) and the uPA inhibitors PAI-1 and PAI-2 in normal human testis and seminomas. Methods The expression of the above genes was evaluated by means of quantitative RT-PCR, western blot, zymographic analysis and immunohistochemistry. Results Quantitative RT-PCR analysis of 14 seminomas demonstrated that uPA and uPAR mRNAs were, with respect to control tissues, increased in tumor tissues by 3.80 ± 0.74 (p < 0.01) and 6.25 ± 1.18 (p < 0.01) fold, respectively. On the other hand, PAI-1 mRNA level was unchanged (1.02 ± 0.24 fold), while that of PAI-2 was significantly reduced to 0.34 ± 0.18 (p < 0.01) fold. Western blot experiments performed with protein extracts of three seminomas and normal tissues from the same patients showed that uPA protein levels were low or undetectable in normal tissues and induced in tumor tissues. On the same samples, zymographic analysis demonstrated increased uPA activity in tumor tissue extracts. Western blot experiments showed that also the uPAR protein was increased in tumor tissues by 1.83 ± 0.15 fold (p < 0.01). The increased expression of uPA and uPAR was further confirmed by immunohistochemical staining performed in 10 seminomas and autologous uninvolved peritumoral tissues. Finally, variation in the mRNA level of PAI-1 significantly correlated with tumor size. Conclusions We demonstrated the increased expression of uPA and uPAR in human seminomas with respect to normal testis tissues, which may be relevant in testicular cancer progression.
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Plasminogen activator inhibitor-1
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To investigate the expression and clinical significance of urokinase type plasminogen activator (uPA) in human gliomas.mRNA and protein expressions of uPA were examined by Northern blot hybridization and immunohistochemical method in 43 cases of gliomas and 5 cases of normal brain tissues and their relationship to clinical indexes was comprehensively analyzed.All tissues expressed the 2.5 kb transcript of uPA mRNA. The uPA mRNA level in high-grade gliomas was considerably higher than that in low-grade gliomas and normal brain tissues (P < 0.01). Levels of uPA mRNA expression in tumor tissues with recurrence during 18 postoperative months and a survival period less than 3 years, were significantly higher than counterparts (P < 0.01). uPA mRNA expression was strongly correlated with the microvessel quantity (MVQ) in gliomas (r = 0.56, P < 0.01). uPA protein was mainly distributed in tumor cells and endothelial cells of glioblastomas and anaplastic astrocytomas.Expression of uPA is associated with the malignant progression, invasion and angiogenesis of gliomas, and it may play a critical role in the recurrence and prognosis of gliomas.
Anaplastic astrocytoma
Northern blot
Microvessel
T-plasminogen activator
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Anaplastic astrocytoma
T-plasminogen activator
Northern blot
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Background and Objectives Urokinase type plasminogen activator (uPA) regulates a variety of processes involved in tissue morphogenesis, cell differentiation, migration and invasion. We analyzed the available informations to better interpret the pathogenetic relationship between uPA activity and the malignant biological behavior of human brain gliomas. Methods We retrospectively studied the presence and distribution of uPA in human brain gliomas by Northern blot hybridization and immunohistochemical methods in 43 cases of brain gliomas and 5 cases of normal brain tissues. Results All tissues expressed 2.5 kb transcripts of uPA mRNA. The uPA mRNA levels were significantly higher in high-grade gliomas than in low-grade gliomas and normal brain tissues (P < 0.01). Levels of uPA mRNA expression in tumor tissues with recurrence in 18 months postoperatively and survival period less than 3 years were significantly higher than counterparts (P < 0.01). The distribution of uPA protein in the immunoreactivity was mainly in tumor cells and microvascular endothelial cells of glioblastomas and anaplastic astrocytomas, localizing at cytoplasms, especially near sites of vascular proliferation and at the leading edges of tumors. Conclusions High expression of uPA gene is associated with the malignant progression of gliomas and demonstrates a high level of correlation with the recurrence and invasive behaviors of high grade gliomas. J. Surg. Oncol. 2000;74:90–94. © 2000 Wiley-Liss, Inc.
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