Expression of Adhesion Factors and Degrading Proteins in Primary and Secondary Glioblastomas and Their Precursor Tumors

Tews, Dominique S.; Nissen, Anja

doi:10.1159/000024520

Cited by 64 publications

(67 citation statements)

References 56 publications

(69 reference statements)

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“…4,13,14 However, when using archival frozen tissues (n ϭ 5 specimens) and formalin-fixed, paraffin-embedded blocks (n ϭ 21 specimens) from control brains, we were able to detect TN-C expression constantly in the ECM of the white matter, a finding that is consistent with recently published data by Tews and Nissen. 31 Based on these results, we conclude that, in the adult human brain, there still is a critical amount of total TN-C in the ECM of the white matter. This finding is highly important in the clinical setting, because it restricts systemic therapeutic approaches and forces us to develop highly specific MoAbs for radioimmunotherapy as applied in a locoregional therapeutic approach.…”

Section: The Normal Human Brainmentioning

confidence: 69%

Expression of tenascin‐C in various human brain tumors and its relevance for survival in patients with astrocytoma

Leins

Riva

Lindstedt

et al. 2003

Cancer

133

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BACKGROUNDTenascin‐C (TN‐C), a large extracellular matrix (ECM) glycoprotein with a molecular weight of 180–250 kilodaltons, is present in several normal adult tissues. TN‐C is up‐regulated during embryogenesis, in wound healing, and in tumor tissues. Glioblastoma multiforme (GBM) is the most frequent and malignant astrocytic tumor comprised of poorly differentiated, neoplastic astrocytes. Recently, TN‐C‐based radioimmunotherapy was administered to patients with GBM.METHODSIn the current study, the authors used immunohistochemistry to conduct a systematic investigation of TN‐C distribution patterns in normal human brain tissue and in a large variety of brain tumors (n = 485 tumors). Immunoreactivity for TN‐C was assessed with regard to its localization within tumor cells, blood vessels, and ECM using three different monoclonal antibodies (clones BC2, BC4, and TN2).RESULTSIn control human brains, a significant difference was noted in the expression of TN‐C when comparing gray with white matter using either Western blot analysis or immunohistochemistry. TN‐C was found in the white matter of the frontal, temporal, parietal, and occipital lobes and in the hippocampus, where the immunoreaction was especially strong in the hippocampal formation. In 181 astrocytomas of different grades (World Health Organization [WHO] Grade 2–4), TN‐C immunopositivity was seen to varying degrees in the cellular and stromal components of the tumor and in tumor‐associated vessels. Glioblastomas (n = 113 tumors) showed strong immunopositivity in the vessels and moderate immunopositivity of the ECM. A statistically significant reduction of TN‐C immunopositivity in tumor‐associated vessels or ECM was observed in anaplastic astrocytomas (WHO Grade 3) compared with GBM (WHO Grade 4). A Kaplan–Meier analysis showed that patients who had GBM lesions that lacked TN‐C immunopositivity in the ECM had a significantly longer survival (median, 28 months; standard error, 7.8 months) (n = 12 patients) compared with patients who had GBM lesions with TN‐C immunopositivity (median, 12 months; standard error, 1.6 months) (n = 87 patients). In meningiomas (n = 24 tumors), the neoplastic cells, the ECM of the tumor, and the vessels were TN‐C negative. In schwannomas (n = 31 tumors), the tumor cells were TN‐C negative; whereas, in > 50% of tumors, the vessels and the ECM of regressively altered tumor areas were positive. In metastatic carcinomas (n = 53 tumors), the tumor cells were negative; seldom were vessels stained positive for TN‐C. Focal areas of the ECM, often accompanied with fibrotic changes, were immunopositive for TN‐C.CONCLUSIONSThe most constant TN‐C immunopositivity was noted in the ECM of the fibrotic stroma in highly malignant brain tumors and along the tumor border, especially in high‐grade astrocytomas. The current results suggest that TN‐C expression may be correlated with the grade of malignancy in astrocytic tumors and that the presence or absence of TN‐C expression in the stroma of astrocytic tumors may play a not yet clearly understood role in shortening or prolonging, respectively, the survival of patients. Cancer 2003. © 2003 American Cancer Society.

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Section: The Normal Human Brainmentioning

confidence: 69%

Expression of tenascin‐C in various human brain tumors and its relevance for survival in patients with astrocytoma

Leins

Riva

Lindstedt

et al. 2003

Cancer

133

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“…In a recent study, activation of MVP (LRP) expression in glioblastomas has also been shown by immunohistochemistry. 21 Generally, the brain in humans 6 and rats 22 contains very low numbers of vaults. Only during late embryonic and early postnatal development of rats is intense vault immunostaining present in the microglia, which represents macrophage-like cells.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the human major vault protein in astrocytic brain tumor cells

et al. 2001

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Evidence has shown that the major human vault protein (MVP), which is identical to lung resistance-related protein (LRP), may be causally involved in a special type of multidrug resistance (MDR). The purpose of this study was to investigate the expression and cellular localization of MVP in cells derived from brain tumors and other tumors of neuroectodermal origin. Using both established cell lines (n ‫؍‬ 22) and primary explants (n ‫؍‬ 30), we show that a distinct overexpression of the MVP gene at the mRNA (RT-PCR) and protein (Western blot) levels is a characteristic feature of cells derived from astrocytic brain tumors. Primary cultures obtained from meningioma specimens also expressed high MVP levels, in contrast to neuroblastoma and medulloblastoma cells, which rarely contained detectable amounts of MVP. Normal human astrocytes cultured in vitro expressed MVP, although at low amounts compared with most malignant cell types. Basal MVP expression correlated with resistance against diverse antineoplastic drugs including anthracyclins, cisplatin and etoposide. By Western blot, MVP was also detected in all tumor samples taken from 7 glioma and 3 meningioma patients. Taken together, these data suggest overexpression of MVP as one explanation for the low efficacy of chemotherapeutic treatment of astrocytic brain tumors.

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“…To explore the biological mechanisms by which the high expression level of cathepsin D could affect the survival times of the patients with glioblastoma, the infiltrative areas of glioblastomas were examined with magnetic resonance imagings. Because cathepsin D takes part in degradation of the extracellular matrix and is strongly expressed by invading glioblastoma cells at the infiltrative margin (16), cathepsin D may be associated with the invasive nature of glioblastomas. Among the six patients with very high expression level of cathepsin D (R1.0), three manifested leptomeningeal disseminations on the Gdenhanced magnetic resonance imaging.…”

Section: Serum Cathepsin D In Glioma Patientsmentioning

confidence: 99%

Cathepsin D Is a Potential Serum Marker for Poor Prognosis in Glioma Patients

Fukuda

Iwadate²,

Machida³

et al. 2005

Cancer Research

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Cathepsin D is an aspartyl protease involved in protein catabolism and tissue remodeling which can be secreted from cancer cells. To identify a potential serum marker for gliomas, we investigated the gene expression levels of cathepsin D in 87 tissue samples and measured the protein concentrations in sera of glioma patients. The tissue samples consisted of 43 glioblastomas, 13 anaplastic astrocytomas, 22 astrocytomas, and 9 normal brain tissues. The results of real-time quantitative reverse transcription-PCR analysis showed that cathepsin D transcript levels became significantly higher as the glioma grade advanced (P = 0.0466, glioblastoma and anaplastic astrocytoma; P = 0.0008, glioblastoma and astrocytoma; P = 0.0271, glioblastoma and normal brain tissue; unpaired t test). Immunohistochemical analysis with anticathepsin D antibody revealed dense and spotty staining in the tumor cells with high transcript levels. The low expression of cathepsin D significantly correlated with long survival of the glioma patients. Furthermore, the glioblastoma patients with high gene expression of cathepsin D lived significantly shorter than those with low expression (P = 0.0104, Cox-Mantel logrank test) and frequently had leptomeningeal dissemination (P = 0.0016, C 2 test). The multivariate analysis confirmed that the cathepsin D expression level was an independent predictor for short survival (P = 0.0102, Cox proportional hazard regression model). Measurement of the serum cathepsin D concentrations by ELISA showed a significant increase in the patients with high-grade gliomas as compared with the lowgrade tumors (P = 0.0081, C 2 test). These results collectively suggest that cathepsin D could be a potential serum marker for the prediction of aggressive nature of human gliomas. (Cancer Res 2005; 65(12): 5190-4)

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Expression of Adhesion Factors and Degrading Proteins in Primary and Secondary Glioblastomas and Their Precursor Tumors

Cited by 64 publications

References 56 publications

Expression of tenascin‐C in various human brain tumors and its relevance for survival in patients with astrocytoma

Expression of tenascin‐C in various human brain tumors and its relevance for survival in patients with astrocytoma

Overexpression of the human major vault protein in astrocytic brain tumor cells

Cathepsin D Is a Potential Serum Marker for Poor Prognosis in Glioma Patients

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