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  • 1
    Electronic Resource
    Electronic Resource
    Modulation of Serine Proteinases and Metalloproteinases During Morphogenic Glial-Endothelial Interactions (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 66 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The regulation of microvessel formation and the expression of CNS-specific endothelial properties are attributed to perivascular astroglia. Specific proteolytic pathways mediate processes such as tissue remodeling, differentiation, invasion, and metastasis. We used a coculture system in which C6 glial cells induce CNS microvascular endothelial cells to form capillary-like structures to examine the role of plasminogen activators and collagenases in CNS microvessel morphogenesis. Fibrin zymography revealed the presence of high-molecular weight urokinase-type plasminogen activator (uPA), low-molecular weight uPA, and uPA/inhibitor complexes within endothelial cultures and cocultures. Gelatin zymography revealed the presence of 92-, 72-, and 62-kDa type IV collagenases within endothelial cultures and cocultures. uPA activity was confirmed by incubating the extracts with amiloride, an inhibitor of uPA. Collagenase activity was confirmed by incubating the gels with EDTA, an inhibitor of metalloproteinases. Quantitative densitometry showed a six- to eightfold decrease in coculture uPA during capillary-like structure formation. Substantially less change in type IV 72-kDa procollagenase activity was seen in cocultures during capillary-like structure formation, but active type IV 62-kDa collagenase activity was significantly increased during capillary-like structure formation. These findings establish that uPA and activated type IV collagenase activity specifically regulates morphogenic endothelial responses to glial interactions and suggest mechanisms by which microvessels respond within the CNS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66041657.x
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  • 2
    Electronic Resource
    Electronic Resource
    Characterization of the Serpin, α1-Antichymotrypsin, in Normal Human Cerebrospinal Fluid (1992)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 58 (1992), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Cerebrospinal fluid (CSF) from 20 male patients with nonneurologic disease (age 64.5 ± 2.8 SEM) was analyzed for the presence of the serpin α1-antichymotrypsin (α1-ACT). A chymotrypsin-specific chromogenic substrate (succinyl-Ala-Ala-Pro-Phe-p-nitroanilide) was used to examine the CSF samples. All CSF samples showed inhibitory activity ranging from 45 to 80% inhibition. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the samples revealed the presence of a 68-kDa protein migrating identical to authentic human plasma α1-ACT. Complex formation was performed with iodinated bovine chymotrypsin for several representative CSF samples having the highest chymotrypsin inhibitory activity. Comparison was made with complex formation performed with commercially available authentic human plasma α1-ACT. These studies showed the formation of complexes at 37°C, regardless of whether the sample was subsequently boiled or not. In the case of CSF, two complex bands, mass smaller than with plasma α1-ACT, were formed at the lower temperature whereas a single higher Mr band was formed when the samples were boiled. To determine whether cleavage of the serpin occurred, these studies were repeated using human neutrophil cathepsin G as target protease. A complex of approximately 90 kDa was formed with human α1-ACT under these same conditions. α1-ACT has been detected in senile amyloid plaques in brains of Alzheimer's disease patients, the only plasma serine protease inhibitor localized to these structures. Another serpin, protease nexin I, is also found in these plaques, but this inhibitor does not circulate in plasma. Recently, the β-amyloid precursor protein itself has been identified as another serine protease inhibitor, protease nexin II, known to form complexes with bovine chymotrypsin as well as with the epidermal growth factor-binding protein. Protease nexin II does circulate in plasma; however, complexes of this inhibitor with chymotrypsin are twice as large as the complexes this protease forms with plasma α1-ACT or with the CSF samples. Using antisera to the β-amyloid precursor protein, other workers have detected both 125-kDa and 105-kDa proteins in human CSF, the 125 kDa reportedly detected by antisera against the Kunitz serine protease inhibitor-containing domain. The studies with α1-ACT in CSF should now allow us to evaluate this serpin and its function in CSF of patients with Alzheimer's and other neurodegenerative diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1992.tb09281.x
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  • 3
    Electronic Resource
    Electronic Resource
    Overexpression and localization of cathepsin B during the progression of human gliomas (1995)
    Springer
    Clinical & experimental metastasis 13 (1995), S. 49-56 
    Details
    ISSN: 1573-7276
    Keywords: cysteine proteases ; extracellular matrix ; glioblastoma multiforme ; invasion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Degradation of the extracellular matrix is a prerequisite for acquisition of the invasive phenotype. Several proteinases released by invading tumor cells appear to participate in the focal degradation of extracellular matrix proteins. Using an enzyme-linked immunosorbent assay, enzymatic assays, Western and Nothern blotting techniques, we determined whether increased levels of the cysteine protease cathepsin B correlated with the progression and invasion of human gliomas. The amount of cathepsin B activity and protein content were highest in glioblastomas, lower in anaplastic astrocytomas and lowest in normal brain tissue and low-grade gliomas. There were significantly higher amounts of Mr 25 000 and 26 000 bands in glioblastoma and anaplastic astrocytoma than in normal brain and low-grade glioma tissue extracts as determined by Western blotting with anti-cathepsin antibodies. In addition, cathepsin B transcripts were overexpressed in anaplastic astrocytoma (about two- to three-fold), in glioblastoma (about eight- to 10-fold), compared with normal brain tissue and low-grade glioma. Immunobistochemical staining for cathepsin B showed intense immunoreactivity in tumor and endothelial cells of glioblastomas and anaplastic astrocytomas but only weak immunoreactivity in low-grade glioma and normal brain tissues. Therefore, we conclude that cathepsin B expression is greatest in highly malignant astrocytomas, especially in glioblastomas, and is correlated with the malignant progression of astrocytomas.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00144018
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  • 4
    Electronic Resource
    Electronic Resource
    Role of extracellular matrix proteins in regulation of human glioma cell invasion in vitro (1996)
    Springer
    Clinical & experimental metastasis 14 (1996), S. 358-366 
    Details
    ISSN: 1573-7276
    Keywords: collagen ; extracellular matrix ; glioma ; invasion ; migration ; spheroid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Primary brain tumors lack the metastatic behavior that is in part believed to be promoted by the extracellular matrix (ECM) components of the basement membrane. This study was intended to examine the influence of the ECM components present in the basement membrane that may act as natural barriers to tumor cell invasion. We examined the effect of type I and type IV collagens, fibronectin, laminin, and hyaluronic acid on the migration and invasion of four established glioblastoma cell lines, SNB19, U251, UWRI, and UWR2. Lower concentrations of all the ECM components induced the migration and invasion of all the cell lines. However, in the case of SNB19, laminin inhibited both migration and invasion in a concentration-dependent manner. We have also examined the influence of individual ECM components on the migration of cells from a spheroid to a monolayer on ECM component-coated coverslips. Consistent with the invasion studies using the modified Boyden chamber assays, lower concentrations of ECM components induced the migration of cells from spheroids to monolayer. Again, laminin inhibited the migration of cells from SNB19 spheroids. These results indicate that ECM components induce the invasion of glioma cells, apart from components like laminin, which may act as natural inhibitors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00123395
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  • 5
    Electronic Resource
    Electronic Resource
    Expression of cysteine protease inhibitors in human gliomas and meningiomas (1996)
    Springer
    Clinical & experimental metastasis 14 (1996), S. 344-350 
    Details
    ISSN: 1573-7276
    Keywords: cathepsins ; cysteine protease inhibitors ; glioblastoma, meningiomas ; plasminogen activators
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Increased levels of human cysteine proteases have been implicated in the progression of tumors from the premalignant to the malignant state. The physiological activities of these proteases are regulated by their interactions with specific inhibitors. To our knowledge there have been no previous reports about the cysteine protease inhibitors (CPIs) in human brain tumors. In the study reported here, we determined CPI activity during glioma progression and compared that with normal human brain tissue. We also determined CPI activities in meningioma and glioblastoma cell lines in vitro. This activity was significantly higher in normal brain tissue and low-grade glioma than in anaplastic astrocytoma and glioblastoma. CPI activity was significantly higher in benign and atypical meningioma cell extracts in comparison with those from malignant meningiomas and with those from glioblastoma cell lines. After several passages, one benign meningioma cell line showed reduced levels of CPI and increased levels of cathepsin. Our results suggest that decreases in the activities of CPI may contribute to the malignant properties of brain tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00123393
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  • 6
    Electronic Resource
    Electronic Resource
    Downregulation of urokinase-type plasminogen activator receptor (uPAR) induces caspase-mediated cell death in human glioblastoma cells (2000)
    Springer
    Clinical & experimental metastasis 18 (2000), S. 611-615 
    Details
    ISSN: 1573-7276
    Keywords: antisense ; caspases ; glioblastoma ; oligonucleotides ; uPAR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011941114862
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  • 7
    Electronic Resource
    Electronic Resource
    Inhibition of in vivo tumorigenicity and invasiveness of a human glioblastoma cell line transfected with antisense uPAR vectors (1997)
    Springer
    Clinical & experimental metastasis 15 (1997), S. 440-446 
    Details
    ISSN: 1573-7276
    Keywords: antisense ; brain ; glioblastoma ; lacZ ; plasminogen activators ; tumor ; uPAR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Our previous studies showed that glioblastomas express increased urokinase-type plasminogen activator receptors (uPARs) in comparison to low-grade gliomas (Yamamoto et al., Cancer Res., 54, 5016-5020, 1994). To explore whether downregulation of uPAR inhibits tumor formation and invasiveness, a human glioblastoma cell line was transfected with a cDNA construct corresponding to 300 bp of the human uPAR's 5¢ end in an antisense orientation, resulting in a reduced number of uPA receptors. Co-culture studies with tumor spheroids and fetal rat brain aggregates showed that antisense SNB19-AS1 cells expressing reduced uPAR failed to invade fetal rat brain aggregates. Intracerebral injection of SNB19-AS1 stable transfectants failed to form tumors and were negative for uPAR expression in nude mice. Thus uPAR appears in this model to be essential for tumorigenicity and invasion of glioblastomas in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018410523635
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  • 8
    Electronic Resource
    Electronic Resource
    Expression and role of matrix metalloproteinases MMP-2 and MMP-9 in human spinal column tumors (1998)
    Springer
    Clinical & experimental metastasis 16 (1998), S. 721-728 
    Details
    ISSN: 1573-7276
    Keywords: immunohistochemistry ; MMPs ; proteases ; spinal metastases ; TIMPs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Matrix metalloproteinases (MMPs) have been implicated in the process of tumor invasion and metastasis formation. Thus, we determined the expression of MMPs in various primary and metastatic spinal tumors in order to assess the role of these enzymes in spinal invasion. MMP expression was examined by immuno-histochemical localization, and quantitative evaluation of MMP protein content was determined by enzyme-linked immunosorbant assay (ELISA) and Western blotting. MMP enzyme activity was determined by gelatin zymography. Lung carcinomas and melanomas metastatic to the spine were shown to have higher levels of MMP-9 activity than those of breast, thyroid, renal metastases and primary spinal tumors. Immunohistochemical analysis revealed similar difference in expression of MMP-9 in tissue samples. When the tissue samples were subjected to gelatin zymography for examination of MMP-2 and MMP-9 activity and to ELISA and Western blotting for quantitative estimation of protein content, the most striking results were obtained for lung carcinomas and melanomas relative to the other tumors. Lung carcinomas and melanomas metastatic to the spine had considerably higher levels of MMP-9 activity than those of primary spinal tumor or breast, thyroid, and renal carcinoma metastases. Within the metastatic tumor category, neoplasms that are known to be associated with the shortest overall survival rates and most aggressive behavior, such as lung carcinomas and melanomas, had the highest levels of MMP-2 and MMP-9 activity compared to those less aggressive metastatic tumors such as breast, renal cell, and thyroid carcinomas. Our results suggest that MMPs may contribute to the metastases to the spinal column, and overexpression of these enzymes may correlate with enhanced invasive properties of both primary and metastatic spinal tumors.© Kluwer Academic Publishers 1998
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006580728338
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  • 9
    Electronic Resource
    Electronic Resource
    Proteolysis and invasiveness of brain tumors: Role of urokinase-type plasminogen activator receptor (1994)
    Springer
    Journal of neuro-oncology 22 (1994), S. 153-160 
    Details
    ISSN: 1573-7373
    Keywords: plasminogen activators ; urokinase receptors ; plasminogen activator inhibitors ; invasiveness ; malignant brain tumors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The cellular receptor for urokinase-type plasminogen activator (uPAR) in glioblastoma cell lines has been identified and found to be similar to the uPAR expressed by other tumor cell lines. Increased levels of uPAR have been found in primary malignant brain tumor tissues, especially highly malignant glioblastoma, and, to a lesser degree, in malignant astrocytomas, suggesting that this receptor might be involved in efficient activation of pro-uPA and confinement of uPA activity on the cell surface of invading brain tumors. The cell surface uPARs in gliomas could constitute an optimum environment for the generation and activity of plasmin, which is known to play a crucial role in the dissolution of the extracellular matrix during tumor cell invasion.In situ hybridization studies have shown that uPAR mRNA is expressed abundantly in tumor cells and is consistently present at the invasive edges of malignant gliomas. These results imply that uPAR is involved in plasmincatalyzed proteolysis during glioma invasion and that interference with the uPA∶uPAR interactions could constitute a novel approach for developing therapeutic strategies to counteract invasion of brain tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01052890
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  • 10
    Electronic Resource
    Electronic Resource
    Modulation of fibrinolysis by ionizing radiation (1994)
    Springer
    Journal of neuro-oncology 22 (1994), S. 161-171 
    Details
    ISSN: 1573-7373
    Keywords: plasminogen activators ; serpins ; plasminogen activator inhibitor ; protease nexin ; fibrinolytic enzymes ; radiation necrosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Radiation-induced damage to the central nervous system is believed to be targeted to glial or endothelial cells or both, although the pathophysiology of this process is still poorly understood. A series of experiments were, therefore, conducted, including irradiation to primary rat astrocytes (in vitro) and rat spinal cords (in vivo). The levels of plasminogen activators (uPA and tPA) and their inhibitors (PNI and PAI-1) were determined by fibrin zymography, ELISA, amidolytic activity assay, complex formation, and Western blot analysis. Fibrin zymography revealed the presence of Mr 48,000 (uPA) and Mr 68,000 (tPA) lytic bands that were increased in irradiated samples. Three- to four-fold higher levels of tPA and 8- to 10-fold higher levels of uPA were detected in irradiated samples. Western blot analysis confirmed the presence of a 51-kDa band (PAI-1) in irradiated samples. PAI-1 is undetectable in nonirradiated spinal cord. Serum-free medium and cell and spinal cord extracts of nonirradiated samples showed a 43-kDa band (PNI), the intensity of which is decreased in irradiated samples. Four- to five-fold decreased levels of PNI were detected in irradiated serum-free media and cell extracts, but no levels of PNI were detected in irradiated spinal cord extracts. This study provides additional information regarding the proposed roles of plasminogen activators and their inhibitors in the development of CNS damage after irradiation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01052891
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