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Author Rosager, A.M.; Sorensen, M.D.; Dahlrot, R.H.; Boldt, H.B.; Hansen, S.; Lathia, J.D.; Kristensen, B.W. url  doi
openurl 
  Title Expression and prognostic value of JAM-A in gliomas Type Journal Article
  Year (down) 2017 Publication Journal of Neuro-Oncology Abbreviated Journal J Neurooncol  
  Volume Issue Pages  
  Keywords Astrocytic brain tumors; Glioma; Junctional adhesion molecule-A; Prognosis; Tumor stem cell  
  Abstract Gliomas are among the most lethal cancers, being highly resistant to both chemo- and radiotherapy. The expression of junctional adhesion molecule-A (JAM-A) was recently identified on the surface of stem cell-like brain tumor-initiating cells and suggested to function as a unique glioblastoma niche adhesion factor influencing the tumorigenic potential of brain tumor-initiating cells. We have recently identified high JAM-A expression to be associated with poor outcome in glioblastomas, and our aim was to further investigate the expression of JAM-A in gliomas focusing especially on the prognostic value in WHO grade II and III gliomas. JAM-A protein expression was evaluated by immunohistochemistry and advanced quantitative image analysis with continuous estimates of staining intensity. The JAM-A antibody stained tumor cell membranes and cytoplasm to various extent in different glioma subtypes, and the intensity was higher in glioblastomas than low-grade gliomas. We could not detect an association with overall survival in patients with grade II and III tumors. Double-immunofluorescence stainings in glioblastomas revealed co-expression of JAM-A with CD133, SOX2, nestin, and GFAP in tumor cells as well as some co-expression with the microglial/macrophage marker IBA-1. In conclusion, JAM-A expression was higher in glioblastomas compared to low-grade gliomas and co-localized with recognized stem cell markers suggesting an association of JAM-A with glioma aggressiveness. No significant association between JAM-A expression and overall survival was found in grade II and III gliomas. Further research is needed to determine the function and clinical impact of JAM-A in gliomas.  
  Address Department of Clinical Research, University of Southern Denmark, Winslowparken 19, 3rd floor, 5000, Odense, Denmark  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0167-594X ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28677106 Approved no  
  Call Number ref @ user @ Serial 96579  
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Author Voss, D.M.; Spina, R.; Carter, D.L.; Lim, K.S.; Jeffery, C.J.; Bar, E.E. url  doi
openurl 
  Title Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression Type Journal Article
  Year (down) 2017 Publication Scientific Reports Abbreviated Journal Sci Rep  
  Volume 7 Issue 1 Pages 4292  
  Keywords  
  Abstract We have previously shown that glioblastoma stem cells (GSCs) are enriched in the hypoxic tumor microenvironment, and that monocarboxylate transporter-4 (MCT4) is critical for mediating GSC signaling in hypoxia. Basigin is involved in many physiological functions during early stages of development and in cancer and is required for functional plasma membrane expression of MCT4. We sought to determine if disruption of the MCT-Basigin interaction may be achieved with a small molecule. Using a cell-based drug-screening assay, we identified Acriflavine (ACF), a small molecule that inhibits the binding between Basigin and MCT4. Surface plasmon resonance and cellular thermal-shift-assays confirmed ACF binding to basigin in vitro and in live glioblastoma cells, respectively. ACF significantly inhibited growth and self-renewal potential of several glioblastoma neurosphere lines in vitro, and this activity was further augmented by hypoxia. Finally, treatment of mice bearing GSC-derived xenografts resulted in significant inhibition of tumor progression in early and late-stage disease. ACF treatment inhibited intratumoral expression of VEGF and tumor vascularization. Our work serves as a proof-of-concept as it shows, for the first time, that disruption of MCT binding to their chaperon, Basigin, may be an effective approach to target GSC and to inhibit angiogenesis and tumor progression.  
  Address Department of Neurological Surgery, Case Western Reserve University School of Medicine and The Case Comprehensive Cancer Center, Cleveland, OH, USA. eli.bar@case.edu  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 2045-2322 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28655889 Approved no  
  Call Number ref @ user @ Serial 96580  
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Author Gravina, G.L.; Mancini, A.; Colapietro, A.; Vitale, F.; Vetuschi, A.; Pompili, S.; Rossi, G.; Marampon, F.; Richardson, P.J.; Patient, L.; Patient, L.; Burbidge, S.; Festuccia, C. url  doi
openurl 
  Title The novel CXCR4 antagonist, PRX177561, reduces tumor cell proliferation and accelerates cancer stem cell differentiation in glioblastoma preclinical models Type Journal Article
  Year (down) 2017 Publication Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine Abbreviated Journal Tumour Biol  
  Volume 39 Issue 6 Pages 1010428317695528  
  Keywords Adult; Animals; Cell Differentiation/drug effects; Cell Line, Tumor; Cell Movement/drug effects; Cell Proliferation/drug effects; Chemokine CXCL12/*genetics; Disease-Free Survival; Glioblastoma/*drug therapy/genetics; Humans; Mice; Neoplasm Recurrence, Local/*drug therapy/genetics/pathology; Neoplastic Stem Cells/drug effects/pathology; Neovascularization, Pathologic/*drug therapy/genetics/pathology; Receptors, CXCR4/antagonists & inhibitors/*genetics; Signal Transduction/drug effects; Tumor Microenvironment/drug effects; Cxcr4; Glioblastoma; angiogenesis; monocyte infiltration  
  Abstract Glioblastoma is the most frequent and the most lethal primary brain tumor among adults. Standard of care is the association of radiotherapy with concomitant or adjuvant temozolomide. However, to date, recurrence is inevitable. The CXCL12/CXCR4 pathway is upregulated in the glioblastoma tumor microenvironment regulating tumor cell proliferation, local invasion, angiogenesis, and the efficacy of radio-chemotherapy. In this study, we evaluated the effects of the novel CXCR4 antagonist, PRX177561, in preclinical models of glioblastoma. CXCR4 expression and PRX177561 effects were assessed on a panel of 12 human glioblastoma cells lines and 5 patient-derived glioblastoma stem cell cultures. Next, the effect of PRX177561 was tested in vivo, using subcutaneous injection of U87MG, U251, and T98G cells as well as orthotopic intrabrain inoculation of luciferase-transfected U87MG cells. Here we found that PRX177561 impairs the proliferation of human glioblastoma cell lines, increases apoptosis, and reduces CXCR4 expression and cell migration in response to stromal cell-derived factor 1alpha in vitro. PRX177561 reduced the expression of stem cell markers and increased that of E-cadherin and glial fibrillary acidic protein in U87MG cells consistent with a reduction in cancer stem cells. In vivo, PRX177561 reduced the weight and increased the time to progression of glioblastoma subcutaneous tumors while increasing disease-free survival and overall survival of mice bearing orthotopic tumors. Our findings suggest that targeting stromal cell-derived factor 1 alpha/CXCR4 axis by PRX177561 might represent a novel therapeutic approach against glioblastoma and support further investigation of this compound in more complex preclinical settings in order to determine its therapeutic potential.  
  Address 1 Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1010-4283 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28639900 Approved no  
  Call Number ref @ user @ Serial 96581  
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Author Liu, Y.; Shen, Y.; Sun, T.; Yang, W. url  doi
openurl 
  Title Mechanisms regulating radiosensitivity of glioma stem cells Type Journal Article
  Year (down) 2017 Publication Neoplasma Abbreviated Journal Neoplasma  
  Volume 64 Issue 5 Pages 655-665  
  Keywords glioma stem cells; radiosensitivity signaling pathways.  
  Abstract Malignant glioblastoma (GBM) has become a very common and difficult brain tumor given its low cure rate and high recurrence rate. GBMs are resistant to treatments because glioma stem cells (GSCs)/glioma-initiating cells (GICs), a specific subpopulation of GBM, possess properties of tumor stem cells, such as unlimited proficiency, self-renewal, differentiation and resistance to chemotherapy and radiotherapy, and exhibit a very strong DNA repair capability. Radiotherapy has become a preponderant treatment, and researchers have found many significant tumor microenvironmental factors and valuable signaling pathways regulating the GSC radioresistance, including NOTCH, Wnt/beta-catenin, Hedgehog, STAT3, and PI3K/AKT/mTOR. Therefore, we seek to boost GSC radiosensitivity through activating or inactivating pathways alone or together to eliminate the likely source of glioma and prolong survival of patients.  
  Address  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0028-2685 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28592117 Approved no  
  Call Number ref @ user @ Serial 96582  
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Author Goncalves, D.P.N.; Rodriguez, R.D.; Kurth, T.; Bray, L.J.; Binner, M.; Jungnickel, C.; Gur, F.N.; Poser, S.W.; Schmidt, T.L.; Zahn, D.R.T.; Androutsellis-Theotokis, A.; Schlierf, M.; Werner, C. url  doi
openurl 
  Title Enhanced targeting of invasive glioblastoma cells by peptide-functionalized gold nanorods in hydrogel-based 3D cultures Type Journal Article
  Year (down) 2017 Publication Acta Biomaterialia Abbreviated Journal Acta Biomater  
  Volume 58 Issue Pages 12-25  
  Keywords 3D culture; Cancer stem cells; Glioblastoma Multiforme; Gold nanorods; Photothermolysis  
  Abstract Cancer stem cells (CSCs) are responsible for drug resistance, tumor recurrence, and metastasis in several cancer types, making their eradication a primary objective in cancer therapy. Glioblastoma Multiforme (GBM) tumors are usually composed of a highly infiltrating CSC subpopulation, which has Nestin as a putative marker. Since the majority of these infiltrating cells are able to elude conventional therapies, we have developed gold nanorods (AuNRs) functionalized with an engineered peptide capable of specific recognition and selective eradication of Nestin positive infiltrating GBM-CSCs. These AuNRs generate heat when irradiated by a near-infrared laser, and cause localized cell damage. Nanoparticle internalization assays performed with GBM-CSCs or Nestin negative cells cultured as two-dimensional (2D) monolayers or embedded in three-dimensional (3D) biodegradable-hydrogels of tunable mechanical properties, revealed that the AuNRs were mainly internalized by GBM-CSCs, and not by Nestin negative cells. The AuNRs were taken up via energy-dependent and caveolae-mediated endocytic mechanisms, and were localized inside endosomes. Photothermal treatments resulted in the selective elimination of GBM-CSCs through cell apoptosis, while Nestin negative cells remained viable. Results also indicated that GBM-CSCs embedded in hydrogels were more resistant to AuNR photothermal treatments than when cultured as 2D monolayers. In summary, the combination of our engineered AuNRs with our tunable hydrogel system has shown the potential to provide an in vitro platform for the evaluation and screening of AuNR-based cancer therapeutics, leading to a substantial advancement in the application of AuNRs for targeted GBM-CSC therapy. STATEMENT OF SIGNIFICANCE: There is an urgent need for reliable and efficient therapies for the treatment of Glioblastoma Multiforme (GBM), which is currently an untreatable brain tumor form with a very poor patient survival rate. GBM tumors are mostly comprised of cancer stem cells (CSCs), which are responsible for tumor reoccurrence and therapy resistance. We have developed gold nanorods functionalized with an engineered peptide capable of selective recognition and eradication of GBM-CSCs via heat generation by nanorods upon NIR irradiation. An in vitro evaluation of nanorod therapeutic activities was performed in 3D synthetic-biodegradable hydrogel models with distinct biomechanical cues, and compared to 2D cultures. Results indicated that cells cultured in 3D were more resistant to photothermolysis than in 2D systems.  
  Address Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials Dresden, Hohe Strasse 6, 01069 Dresden, Germany  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1742-7061 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28576716 Approved no  
  Call Number ref @ user @ Serial 96583  
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