| Records |
| Author |
Celiku, O.; Tandle, A.; Chung, J.-Y.; Hewitt, S.M.; Camphausen, K.; Shankavaram, U. |
| Title |
Computational analysis of the mesenchymal signature landscape in gliomas |
Type |
Journal Article |
| Year |
2017 |
Publication |
BMC Medical Genomics |
Abbreviated Journal |
BMC Med Genomics |
| Volume |
10 |
Issue |
1 |
Pages |
13 |
| Keywords |
Cd44; Computational modeling; Epithelial to mesenchymal transition; Glioma |
| Abstract |
BACKGROUND: Epithelial to mesenchymal transition, and mimicking processes, contribute to cancer invasion and metastasis, and are known to be responsible for resistance to various therapeutic agents in many cancers. While a number of studies have proposed molecular signatures that characterize the spectrum of such transition, more work is needed to understand how the mesenchymal signature (MS) is regulated in non-epithelial cancers like gliomas, to identify markers with the most prognostic significance, and potential for therapeutic targeting. RESULTS: Computational analysis of 275 glioma samples from “The Cancer Genome Atlas” was used to identify the regulatory changes between low grade gliomas with little expression of MS, and high grade glioblastomas with high expression of MS. TF (transcription factor)-gene regulatory networks were constructed for each of the cohorts, and 5 major pathways and 118 transcription factors were identified as involved in the differential regulation of the networks. The most significant pathway – Extracellular matrix organization – was further analyzed for prognostic relevance. A 20-gene signature was identified as having prognostic significance (HR (hazard ratio) 3.2, 95% CI (confidence interval) = 1.53-8.33), after controlling for known prognostic factors (age, and glioma grade). The signature's significance was validated in an independent data set. The putative stem cell marker CD44 was biologically validated in glioma cell lines and brain tissue samples. CONCLUSIONS: Our results suggest that the differences between low grade gliomas and high grade glioblastoma are associated with differential expression of the signature genes, raising the possibility that targeting these genes might prolong survival in glioma patients. |
| Address |
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 10 Center Drive, Bldg. 10, Rm. B3B70, Bethesda, MD, 20892, USA. uma@mail.nih.gov |
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English |
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| ISSN |
1755-8794 |
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| Notes |
PMID:28279210 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96602 |
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| Author |
Jensen, S.S.; Petterson, S.A.; Halle, B.; Aaberg-Jessen, C.; Kristensen, B.W. |
| Title |
Effects of the lysosomal destabilizing drug siramesine on glioblastoma in vitro and in vivo |
Type |
Journal Article |
| Year |
2017 |
Publication |
BMC Cancer |
Abbreviated Journal |
BMC Cancer |
| Volume |
17 |
Issue |
1 |
Pages |
178 |
| Keywords |
Brain slice cultures; Cancer stem cell; Glioblastoma; Lysosomes; Siramesine; Spheroids |
| Abstract |
BACKGROUND: Glioblastoma is the most frequent and most malignant brain tumor with the patients having a median survival of only 14.6 months. Although glioblastoma patients are treated with surgery, radiation and chemotherapy recurrence is inevitable. A stem-like population of radio- and chemoresistant brain tumor-initiating cells combined with the invasive properties of the tumors is believed to be critical for treatment resistance. In the present study, the aim was to investigate the effect of a novel therapeutic strategy using the lysosomotropic detergent siramesine on glioblastomas. METHODS: Standard glioma cell lines and patient-derived spheroids cultures with tumor-initiating stem-like cells were used to investigate effects of siramesine on proliferation and cell death. Responsible mechanisms were investigated by inhibitors of caspases and cathepsins. Effects of siramesine on migrating tumor cells were investigated by a flat surface migration assay and by implanting spheroids into organotypic rat brain slice cultures followed by confocal time-lapse imaging. Finally the effect of siramesine was investigated in an orthotopic mouse glioblastoma model. Results obtained in vitro and in vivo were confirmed by immunohistochemical staining of histological sections of spheroids, spheroids in brain slice cultures and tumors in mice brains. RESULTS: The results showed that siramesine killed standard glioma cell lines in vitro, and loss of acridine orange staining suggested a compromised lysosomal membrane. Co-treatment of the cell lines with inhibitors of caspases and cathepsins suggested differential involvement in cell death. Siramesine caused tumor cell death and reduced secondary spheroid formation of patient-derived spheroid cultures. In the flat surface migration model siramesine caused tumor cell death and inhibited tumor cell migration. This could not be reproduced in the organotypic three dimensional spheroid-brain slice culture model or in the mice xenograft model. CONCLUSIONS: In conclusion the in vitro results obtained with tumor cells and spheroids suggest a potential of lysosomal destabilizing drugs in killing glioblastoma cells, but siramesine was without effect in the organotypic spheroid-brain slice culture model and the in vivo xenograft model. |
| Address |
Institute of Clinical Research, University of Southern Denmark, Winslowparken 19.3, 5000, Odense C, Denmark. bjarne.winther.kristensen@rsyd.dk |
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1471-2407 |
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PMID:28270132 |
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no |
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ref @ user @ |
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96603 |
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Brown, D.V.; Filiz, G.; Daniel, P.M.; Hollande, F.; Dworkin, S.; Amiridis, S.; Kountouri, N.; Ng, W.; Morokoff, A.P.; Mantamadiotis, T. |
| Title |
Expression of CD133 and CD44 in glioblastoma stem cells correlates with cell proliferation, phenotype stability and intra-tumor heterogeneity |
Type |
Journal Article |
| Year |
2017 |
Publication |
PloS one |
Abbreviated Journal |
PLoS One |
| Volume |
12 |
Issue |
2 |
Pages |
e0172791 |
| Keywords |
AC133 Antigen/*metabolism; Animals; Antigens, CD44/*metabolism; Basic Helix-Loop-Helix Transcription Factors/metabolism; Biomarkers, Tumor/metabolism; Brain Neoplasms/*metabolism/pathology; Cell Proliferation; Female; Glioblastoma/*metabolism/pathology; Humans; Hypoxia; Mice; Mice, Inbred BALB C; Neoplasm Recurrence, Local; Neoplastic Stem Cells/*metabolism/pathology; Nerve Tissue Proteins/metabolism; Phenotype |
| Abstract |
Glioblastoma (GBM) is a heterogeneous tumor of the brain with a poor prognosis due to recurrence and drug resistance following therapy. Genome-wide profiling has revealed the existence of distinct GBM molecular subtypes that respond differently to aggressive therapies. Despite this, molecular subtype does not predict recurrence or drug resistance and overall survival is similar across subtypes. One of the key features contributing to tumor recurrence and resistance to therapy is proposed to be an underlying subpopulation of resistant glioma stem cells (GSC). CD133 expression has been used as a marker of GSCs, however recent evidence suggests the relationship between CD133 expression, GSCs and molecular subtype is more complex than initially proposed. The expression of CD133, Olig2 and CD44 was investigated using patient derived glioma stem-like cells (PDGCs) in vitro and in vivo. Different PDGCs exhibited a characteristic equilibrium of distinct CD133+ and CD44+ subpopulations and the influence of environmental factors on the intra-tumor equilibrium of CD133+ and CD44+ cells in PDGCs was also investigated, with hypoxia inducing a CD44+ to CD133+ shift and chemo-radiotherapy inducing a CD133+ to CD44+ shift. These data suggest that surveillance and modulation of intra-tumor heterogeneity using molecular markers at initial surgery and surgery for recurrent GBM may be important for more effective management of GBM. |
| Address |
Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia |
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English |
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1932-6203 |
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PMID:28241049 |
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no |
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ref @ user @ |
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96604 |
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| Author |
Ludwig, K.; Kornblum, H.I. |
| Title |
Molecular markers in glioma |
Type |
Journal Article |
| Year |
2017 |
Publication |
Journal of Neuro-Oncology |
Abbreviated Journal |
J Neurooncol |
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Issue |
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Pages |
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| Keywords |
Glioblastoma; Glioma stem cell; Molecular markers; Mutations; Pathways |
| Abstract |
Gliomas are the most malignant and aggressive form of brain tumors, and account for the majority of brain cancer related deaths. Malignant gliomas, including glioblastoma are treated with radiation and temozolomide, with only a minor benefit in survival time. A number of advances have been made in understanding glioma biology, including the discovery of cancer stem cells, termed glioma stem cells (GSC). Some of these advances include the delineation of molecular heterogeneity both between tumors from different patients as well as within tumors from the same patient. Such research highlights the importance of identifying and validating molecular markers in glioma. This review, intended as a practical resource for both clinical and basic investigators, summarizes some of the more well-known molecular markers (MGMT, 1p/19q, IDH, EGFR, p53, PI3K, Rb, and RAF), discusses how they are identified, and what, if any, clinical relevance they may have, in addition to discussing some of the specific biology for these markers. Additionally, we discuss identification methods for studying putative GSC's (CD133, CD15, A2B5, nestin, ALDH1, proteasome activity, ABC transporters, and label-retention). While much research has been done on these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature. Furthermore, it is unlikely that the investigator will be able to utilize one single marker to prospectively identify and isolate GSC from all, or possibly, any gliomas. |
| Address |
Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. Hkornblum@mednet.ucla.edu |
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0167-594X |
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| Notes |
PMID:28233083 |
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no |
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ref @ user @ |
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96605 |
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Alshehri, M.M.; Robbins, S.M.; Senger, D.L. |
| Title |
The Role of Neurotrophin Signaling in Gliomagenesis: A Focus on the p75 Neurotrophin Receptor (p75NTR/CD271) |
Type |
Journal Article |
| Year |
2017 |
Publication |
Vitamins and Hormones |
Abbreviated Journal |
Vitam Horm |
| Volume |
104 |
Issue |
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Pages |
367-404 |
| Keywords |
Brain tumor; Cd271; Cancer stem cells; Glioblastoma; Glioma invasion; Nerve growth factor; Neurotrophin; p75(NTR) |
| Abstract |
The p75 neurotrophin receptor (p75NTR, a.k.a. CD271), a transmembrane glycoprotein and a member of the tumor necrosis family (TNF) of receptors, was originally identified as a nerve growth factor receptor in the mid-1980s. While p75NTR is recognized to have important roles during neural development, its presence in both neural and nonneural tissues clearly supports the potential to mediate a broad range of functions depending on cellular context. Using an unbiased in vivo selection paradigm for genes underlying the invasive behavior of glioma, a critical characteristic that contributes to poor clinical outcome for glioma patients, we identified p75NTR as a central regulator of glioma invasion. Herein we review the expanding role that p75NTR plays in glioma progression with an emphasis on how p75NTR may contribute to the treatment refractory nature of glioma. Based on the observation that p75NTR is expressed and functional in two critical glioma disease reservoirs, namely, the highly infiltrative cells that evade surgical resection, and the radiation- and chemotherapy-resistant brain tumor-initiating cells (also referred to as brain tumor stem cells), we propose that p75NTR and its myriad of downstream signaling effectors represent rationale therapeutic targets for this devastating disease. Lastly, we provide the provocative hypothesis that, in addition to the well-documented cell autonomous signaling functions, the neurotrophins, and their respective receptors, contribute in a cell nonautonomous manner to drive the complex cellular and molecular composition of the brain tumor microenvironment, an environment that fuels tumorigenesis. |
| Address |
Arnie Charbonneau Cancer Centre, University of Calgary, Calgary, AB, Canada. Electronic address: senger@ucalgary.ca |
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English |
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0083-6729 |
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| Notes |
PMID:28215302 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96606 |
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