Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors. (1/1796)

Three different membrane-type matrix metalloproteinases (MT1-, MT2-, and MT3-MMPs) are known to activate in vitro the zymogen of MMP-2 (pro-MMP-2, progelatinase A), which is one of the key MMPs in invasion and metastasis of various cancers. In the present study, we have examined production and activation of pro-MMP-2, expression of MT1-, MT2-, and MT3-MMPs and their correlation with pro-MMP-2 activation, and localization of MMP-2, MT1-MMP, and MT2-MMP in human astrocytic tumors. The sandwich enzyme immunoassay demonstrates that the production levels of pro-MMP-2 in the anaplastic astrocytomas and glioblastomas are significantly higher than that in the low-grade astrocytomas (P<0.05 and P<0.01, respectively), metastatic brain tumors (P<0.05), or normal brains (P<0.01). Gelatin zymography indicates that the pro-MMP-2 activation ratio is significantly higher in the glioblastomas than in other astrocytic tumors (P<0.01), metastatic brain tumors (P<0.01), and normal brains (P<0.01). The quantitative reverse transcription polymerase chain reaction analyses demonstrate that MT1-MMP and MT2-MMP are expressed predominantly in glioblastoma tissues (17/17 and 12/17 cases, respectively), and their expression levels increase significantly as tumor grade increases. MT3-MMP is detectable in both astrocytic tumor and normal brain tissues, but the mean expression level is approximately 50-fold lower compared with that of MT1-MMP and MT2-MMP in the glioblastomas. The activation ratio of pro-MMP-2 correlates directly with the expression levels of MT1-MMP and MT2-MMP but not MT3-MMP. In situ hybridization indicates that neoplastic astrocytes express MT1-MMP and MT2-MMP in the glioblastoma tissues (5/5 cases and 5/5 cases, respectively). Immunohistochemically, MT1-MMP and MT2-MMP are localized to the neoplastic astrocytes in glioblastoma samples (17/17 cases and 12/17 cases, respectively), which are also positive for MMP-2. In situ zymography shows gelatinolytic activity in the glioblastoma tissues but not in the normal brain tissues. These results suggest that both MT1-MMP and MT2-MMP play a key role in the activation of pro-MMP-2 in the human malignant astrocytic tumors and that the gelatinolytic activity is involved in the astrocytic tumor invasion.  (+info)

Early induction of angiogenetic signals in gliomas of GFAP-v-src transgenic mice. (2/1796)

Angiogenesis is a prerequisite for solid tumor growth. Glioblastoma multiforme, the most common malignant brain tumor, is characterized by extensive vascular proliferation. We previously showed that transgenic mice expressing a GFAP-v-src fusion gene in astrocytes develop low-grade astrocytomas that progressively evolve into hypervascularized glioblastomas. Here, we examined whether tumor progression triggers angiogenetic signals. We found abundant transcription of vascular endothelial growth factor (VEGF) in neoplastic astrocytes at surprisingly early stages of tumorigenesis. VEGF and v-src expression patterns were not identical, suggesting that VEGF activation was not only dependent on v-src. Late-stage gliomas showed perinecrotic VEGF up-regulation similarly to human glioblastoma. Expression patterns of the endothelial angiogenic receptors flt-1, flk-1, tie-1, and tie-2 were similar to those described in human gliomas, but flt-1 was expressed also in neoplastic astrocytes, suggesting an autocrine role in tumor growth. In crossbreeding experiments, hemizygous ablation of the tumor suppressor genes Rb and p53 had no significant effect on the expression of VEGF, flt-1, flk-1, tie-1, and tie-2. Therefore, expression of angiogenic signals is an early event during progression of GFAP-v-src tumors and precedes hypervascularization. Given the close similarities in the progression pattern between GFAP-v-src and human gliomas, the present results suggest that these mice may provide a useful tool for antiangiogenic therapy research.  (+info)

Clinical importance of c-Met protein expression in high grade astrocytic tumors. (3/1796)

The clinical importance of the expression of c-Met protein, the receptor of hepatocyte growth factor/scatter factor, was evaluated in neuroepithelial tissue tumors. c-Met immunohistochemistry was performed using the streptavidin-biotin-peroxidase complex method with anti-c-Met polyclonal antibody. Specimens were classified as c-Met negative (< 30%) or c-Met positive (> or = 30%) according to the proportion of immunopositive cells under microscopic examination. All c-Met-positive cases occurred in high grade astrocytic tumors, not in other neuroepithelial tissue tumors. Most c-Met-positive astrocytic tumors were classified histologically as high grade tumors. Epidermal growth factor-receptor (EGFR) and MIB-1 immunohistochemistry were also performed for high grade astrocytic tumors. Survival analysis was performed for patients with these tumors with variables including c-Met positivity, EGFR positivity, and MIB-1 labeling index. Positivity of c-Met was independent from EGFR positivity and MIB-1 labeling index, and the c-Met-positive group showed a significant shorter survival (p < 0.05). c-Met immunopositivity may be a parameter of biological aggressiveness in high grade astrocytic tumors. Examination of c-Met expression in astrocytic tumors provides significant clinical information, especially as a prognostic factor.  (+info)

Secondary glioblastoma remarkably reduced by steroid administration after anaplastic transformation from gliomatosis cerebri--case report. (4/1796)

A 45-year-old female presented with gliomatosis cerebri manifesting as hemiballismus-like involuntary movement in the arm, motor weakness in the leg, and hypesthesia in her left side. Computed tomography showed only diffuse swelling of the right cerebral hemisphere, but T2-weighted magnetic resonance imaging revealed a diffuse lesion spreading from the right thalamus to the temporal, parietal, and occipital lobes on the same side. No abnormal enhancement was recognized. Cerebral angiography showed no specific finding. A right occipital lobectomy was performed to confirm the diagnosis of gliomatosis cerebri. Anaplastic transformation was recognized 5 months later. The disease did not resolve with radiation or interferon administration, but steroid therapy achieved remarkably effective tumor regression. The patient died due to pneumonia. Autopsy showed the features of diffuse glioblastoma. Steroid therapy may be an effective treatment for gliomatosis cerebri before the terminal stage.  (+info)

Requirements for measles virus induction of RANTES chemokine in human astrocytoma-derived U373 cells. (5/1796)

Interferons and chemokines play a critical role in regulating the host response to viral infection. Measles virus, a member of the Paramyxoviridae family, induces RANTES expression by astrocytes. We have examined the mechanism of this induction in U373 cells derived from a human astrocytoma. RANTES was induced in a dose- and time-dependent manner by measles virus infection. Inhibition of receptor binding by the anti-CD46 antibody TRA-2.10 and of virus-membrane fusion by the tripeptide X-Phe-Phe-Gly reduced RANTES expression. Formalin-inactivated virus, which can bind but not fuse, and extensively UV-irradiated virus, which can bind and fuse, were both ineffective. Therefore, virus binding to the cellular receptor CD46 and subsequent membrane fusion were necessary, but not sufficient, to induce RANTES. UV irradiation of virus for less than 10 min proportionally inhibited viral transcription and RANTES expression. RANTES induction was decreased in infected cells treated with ribavirin, which inhibits measles virus transcription. However, RANTES mRNA was superinduced by measles virus in the presence of cycloheximide. These data suggest that partial transcription of the viral genome is sufficient and necessary for RANTES induction, whereas viral protein synthesis and replication are not required. This hypothesis was supported by the fact that RANTES was induced through transient expression of the measles virus nucleocapsid gene but not by measles genes encoding P or L proteins or by leader RNA in A549 cells. Thus, transcription of specific portions of measles virus RNA, such as the nucleocapsid gene, appears able to generate the specific signaling required to induce RANTES gene expression.  (+info)

Persistent infection of human oligodendrocytic and neuroglial cell lines by human coronavirus 229E. (6/1796)

Human coronaviruses (HuCV) cause common colds. Previous reports suggest that these infectious agents may be neurotropic in humans, as they are for some mammals. With the long-term aim of providing experimental evidence for the neurotropism of HuCV and the establishment of persistent infections in the nervous system, we have evaluated the susceptibility of various human neural cell lines to acute and persistent infection by HuCV-229E. Viral antigen, infectious virus progeny and viral RNA were monitored during both acute and persistent infections. The astrocytoma cell lines U-87 MG, U-373 MG, and GL-15, as well as neuroblastoma SK-N-SH, neuroglioma H4, and oligodendrocytic MO3.13 cell lines, were all susceptible to an acute infection by HuCV-229E. The CHME-5 immortalized fetal microglial cell line was not susceptible to infection by this virus. The MO3.13 and H4 cell lines also sustained a persistent viral infection, as monitored by detection of viral antigen and infectious virus progeny. Sequencing of the S1 gene from viral RNA after approximately 130 days of infection showed two point mutations, suggesting amino acid changes during persistent infection of MO3.13 cells but none for H4 cells. Thus, persistent in vitro infection did not generate important changes in the S1 portion of the viral spike protein, which was shown for murine coronaviruses to bear hypervariable domains and to interact with cellular receptor. These results are consistent with the potential persistence of HuCV-229E in cells of the human nervous system, such as oligodendrocytes and possibly neurons, and the virus's apparent genomic stability.  (+info)

Simultaneous alterations of retinoblastoma and p53 protein expression in astrocytic tumors. (7/1796)

The genetic alterations frequently involved in glial malignancies are in the tumor suppressor genes, Rb and p53. An altered Rb expression or p53 overexpression is thought to indicate defective tumor suppression and subsequently more aggressive tumors. Therefore, to assess the alterations in the conjoint expression of Rb and p53 proteins in formalin fixed paraffin embedded sections, 64 astrocytic tumors were studied (16 astrocytomas,7 gemistocytic astrocytomas, 19 anaplastic astrocytomas and 22 glioblastomas) using the avidin biotin immunoperoxidase technique. Fifty two cases (81.25%) were found to be positive for p53 protein. Seventeen of these showed aberrant heterogenous staining for pRb, of which 7 were glioblastomas. Only one case of astrocytoma showed aberrant expression of both p53 and Rb. Thus, of the 64 tumors, simultaneous aberrant expression of both p53 and Rb was seen in 21.9% of cases. This was more commonly observed among glioblastoma cases (7/22). No statistical difference was found between the survival rate of heterogenous pRb and p53 positivity in different grades of tumors. In glioblastomas, the survival rate appeared to be less in patients expressing heterogenous pRb, but this was not statistically significant. These results lead us to suspect that p53 and pRb pathways are inactivated, either through mutation or as part of the neoplastic process in astrocytic tumors.  (+info)

Procarbazine and high-dose tamoxifen as a second-line regimen in recurrent high-grade gliomas: a phase II study. (8/1796)

PURPOSE: A phase II study was conducted in patients with high-grade gliomas that recurred after surgery plus radiotherapy and a first-line nitrosourea-based regimen. Our aim was to investigate the efficacy of procarbazine (PCB) combined with high-dose tamoxifen in relation to tumor control, toxicity, and time to progression (TTP). PATIENTS AND METHODS: Fifty-three patients were treated with procarbazine in repeated 30-day courses at 100 mg/m2/d plus tamoxifen 100 mg/d, with a 30-day interval between courses. Thirty-four patients had been pretreated with a first-line nitrosourea-based chemotherapy regimen (group A), and 19 patients had also been pretreated with a second-line chemotherapy regimen consisting of carboplatin and teniposide (group B). Twenty-one of the patients had also been procarbazine pretreated, whereas the remaining 32 patients were not procarbazine pretreated. RESULTS: The response was assessed in 51 patients, 28 of whom had glioblastoma multiforme (GBM) and 23 of whom had anaplastic astrocytoma (AA). There were two complete responses (CR) (4%) and 13 partial responses (PR) (25.5%). The overall response rate (CR + PR) was 29.5% (SE, 6.4; 95% confidence interval [CI], 23 to 35.8). Seventeen patients (32%) had stable disease (SE, 6.2; 95% CI, 21 to 33.6). The median TTP was 13 weeks for patients with GBM and 33 weeks for patients with AA (P = .006). The median survival time (MST) was 27 weeks for patients with GBM and 57 weeks for those with AA (P = .006). CONCLUSION: Combined PCB and tamoxifen as a second-line regimen gave a reasonably high response rate in patients with heavily pretreated high-grade gliomas. However, although it resulted in an improvement in the patients' quality of life and/or performance status, it was not followed by an increased TTP or MST.  (+info)

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