Expression and localization of urokinase-type plasminogen activator receptor in human gliomas.
Masaaki YamamotoRaymond SawayaSanjeeva MohanamVelidi H. RaoJanet M. BrunerGarth L. NicolsonJasti S. Rao
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Abstract:
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.Keywords:
Anaplastic astrocytoma
Human brain
T-plasminogen activator
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The urokinase-type plasminogen activator (uPA) and uPA receptor (UPAR) play important roles in the proteolytic cascade involved in the invasiveness of gliomas and other invasive tumors. High-level expression of uPAR has been correlated with high-grade glioma cell lines and tumors We report here that down-regulating uPAR levels by antisense strategy using an adenovirus construct (Ad-uPAR) inhibited glioma invasion in Matrigel and spheroid in vitro models. sc. (U87-MG) and intracranial (SNB19) injections of Ad-uPAR-infected glioma cells did not produce tumors in nude mice. However, injection of the Ad-uPAR construct into previously established so U87-MG tumors in nude mice caused regression of those tumors. Our results support the therapeutic potential of targeting the uPA-uPAR system for the treatment of gliomas and other cancers.
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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
Human brain
T-plasminogen activator
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Plasminogen activators regulate a variety of processes involved in tissue morphogenesis, as well as cell differentiation, migration, and invasion. We examined the relative amounts of mRNA and protein and localization of urokinase-type plasminogen activator (uPA) in human astrocytomas in vivo. Using fibrin zymography and densitometric quantitation, we found that uPA activity was significantly higher in malignant astrocytomas, especially in glioblastomas, than it was in normal brain tissues or low-grade gliomas. The amounts of uPA mRNA, as determined by Northern blot analysis, were higher in anaplastic astrocytomas and glioblastomas than in normal brain tissues and low-grade gliomas, consistent with the amount of uPA activity. To investigate the cellular source of uPA in various tissues, we performed immunocytochemical localization of uPA protein and in situ hybridization of uPA mRNA with astrocytomas and normal brain tissues. Immunocytochemical staining for uPA showed strong immunoreactivity in the tumor cells and vasculature of glioblastomas and anaplastic astrocytomas but undetectable or very low immunoreactivity for uPA in low-grade gliomas and normal brain tissues. uPA mRNA was located in astrocytoma and endothelial cells and was heterogeneously distributed within glioblastoma, with preferential localization near vascular proliferation and at the leading edge of the tumor. uPA expression was dramatically higher in highly malignant astrocytomas, especially glioblastomas, and was correlated with malignant progression of astrocytomas.
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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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Urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) play a major role in the infiltrative growth of glioblastoma. Downregulatoion of the uPA and uPAR has been reported to inhibit the growth glioblastoma. Here, we demonstrate that tristetraprolin (TTP) inhibits the growth of U87MG human glioma cells through downregulation of uPA and uPAR. Our results show that expression level of TTP is inversely correlated with those of uPA and uPAR in human glioma cells and tissues. TTP binds to the AU-rich elements within the 3' untranslated regions of uPA and uPAR and overexpression of TTP decreased the expression of uPA and uPAR through enhancing the degradation of their mRNAs. In addition, overexpression of TTP inhibited the growth and invasion of U87MG cells. Our findings implicate that TTP can be used as a promising therapeutic target to treat human glioma.
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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
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Anaplastic astrocytoma
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Northern blot
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We investigated the expression and cellular localization of plasminogen activator inhibitor type 1 (PAI-1) in human astrocytoma in vivo. Northern blot and densitometric quantitation of PAI-1 mRNA indicated that PAI-1 transcripts were significantly higher in human malignant astrocytomas and especially in glioblastomas than in low-grade gliomas and normal brain tissues in vivo. Using in situ hybridization with paraffin-embedded surgical specimens of human gliomas and normal brain tissues, PAI-1 mRNA was abundantly expressed in glioblastomas. PAI-1 mRNA was localized mainly in tumor cells and endothelial cells. The distribution of PAI-1 mRNA expression was particularly abundant around areas of vascular proliferation and in remnant tumor cells surrounding necrotic foci. PAI-1 mRNA was also expressed in both the tumor and endothelial cells of anaplastic astrocytomas, whereas it was not expressed or only weakly expressed in low-grade astrocytomas or normal brain tissues. These results suggest that high expression of PAI-1 is associated with the malignant progression of astrocytic tumors and that excessive PAI-1 expression might be associated with intratumoral necrosis in glioblastomas.
Anaplastic astrocytoma
Northern blot
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Plasminogen activator inhibitor-1
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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.
Human brain
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Northern blot
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