Stmc-32. the mesenchymal subtype of glioma stem-like cells exhibits reduced endoplasmic reticulum stress
GBM is a lethal brain tumor that contains two major cancer stem cell subtypes (Proneural, PN and Mesenchymal, MES) bestowed with tumor initiating properties. Of these two subtypes, the MES glioma stem-like cells (GSCs) are associated with increased radioresistance, and thus it is important to identify essential molecules that regulate their survival and proliferation. Here, we performed 2D gel proteomic comparison of PN versus MES tumors and discovered higher expression of the endoplasmic chaperone protein GRP78 in the MES subtype of GBMs. In addition, TCGA analyses showed significantly higher expression of GRP78 and SOD2 ...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Guo, X., Audia, A., Mukheef, F., Patel, H., Li, G., Bhat, K. Tags: STEM CELLS Source Type: research
Stmc-31. stimulation of microglia and macrophages and growth attenuation of brain tumor-initiating cells with tumor necrosis factor-alpha
Microglia and macrophages (M/Ms) are functionally plastic entities that are compelled by glioblastoma (GBM) to adopt anti-inflammatory phenotypes and become major players in GBM progression. Understanding how to reverse this compulsion and maintain a pro-inflammatory tumor microenvironment is critical to developing effective therapeutics for GBM. Our studies have uncovered that GBM-associated M/Ms (GAM/Ms) can be pharmacologically compelled to shed the influence of GBM and secrete inhibitory factors that decrease the proliferation of GBM stem cell (GSC) lines and xenografts (Nature Neurosci 17:46-55, 2014). GSCs are a cell...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Poon, C. C., Sarkar, S., Blough, M., Cairncross, J. G., Yong, V. W., Kelly, J. Tags: STEM CELLS Source Type: research
Stmc-30. trafficking and effect on survival of bevacizumab in glioblastoma
Most patients with recurrent glioblastoma (GBM) are treated with bevacizumab, a humanized monoclonal antibody (mAb) that binds VEGF-A and inhibits its binding to VEGFR. Approximately 30% of GBM patients are non-responsive to bevacizumab and the underlying mechanism for the lack of response is unknown. It has been assumed that bevacizumab solely targets circulating VEGF-A. We hypothesized that bevacizumab and human IgGs in general gain access to the perivascular niche that contains cancer stem cells (CSCs) in GBM. We found that bevacizumab gains access to the perivascular tumor area through leaky blood vessels and was inter...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Muller-Greven, G., Carlin, C., Toms, S., Ahluwalia, M. S., Bredel, M., Lathia, J., Rich, J., Hamerlik, P., Gladson, C. Tags: STEM CELLS Source Type: research
Stmc-29. genetic engineering of glioma cells with histone-2b-gfp tag to track and characterize quiescent glioma stem cells
Glioblastoma (GBM) is the most common malignant brain tumor with a dismal prognosis and limited therapy options. Advances in culture methods have led to the establishment of patient-derived glioma stem cell (GSC) lines that preserve genomic and physiologic characteristics of GBM. Quiescent populations of GSCs have been proposed as the main source of GBM recurrence after therapy. We are applying CRISPR to introduce a doxycycline inducible histone-2B-GFP (H2B-GFP) labeling system at the AAVS1 locus, a "safe harbor" for transgene insertions. The H2B-GFP label allows to track and isolate quiescent glioma cells that retain high...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Tejero, R., Huang, Y., Tome-Garcia, J., Zou, H., Friedel, R. Tags: STEM CELLS Source Type: research
Stmc-28. intact egfr defines human germinal matrix and glioblastoma populations with shared and epigenetically imprinted stem cell properties
Epidermal growth factor receptor (EGFR) signaling is important for neural development and is frequently dysregulated in glioblastoma (GBM), but its developmental relationship to human gliomagenesis remains poorly understood. Using an EGF-ligand-binding strategy, we isolated EGFR+/– populations from fresh human germinal matrix (GM) and GBM tissues, enriching for cells with intact ligand-binding domain (EGFR+INTACT), and directly compared their downstream functional and molecular phenotypes. In both GM and GBM, only EGFR+ INTACT populations displayed stem cell properties in vitro, and in GBM, tumor initiation in vivo. ...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Tome-Garcia, J., Tejero-Villalba, R., Zaslavsky, E., Nudelman, G., Yong, R., Walsch, M., Friedel, R., Doetsch, F., Tsankova, N. Tags: STEM CELLS Source Type: research
Stmc-27. novel lysine demethylase kdm1a inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway
Glioma Stem Cells (GSCs) play a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we demonstrated that lysine-specific histone demethylase 1A (KDM1A/LSD1) is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Sareddy, G. R., Viswanadhapalli, S., Surapaneni, P., Suzuki, T., Brenner, A., Vadlamudi, R. Tags: STEM CELLS Source Type: research
STMC-26. MULTIVALENT CATIONIC LIPOSOMES FOR siRNA TRANSFECTION OF PATIENT DERIVED GLIOMA INITIATING CELLS
Glioma initiating cells (GICs) have been implicated as the root cause of treatment failure and tumor recurrence in glioblastoma multiforme (GBM). Therapeutic targeting of GICs is therefore essential to ensure effective treatment without relapse. A novel approach to modulate protein expression in cancer cells is the delivery of siRNAs using liposomes. However, past attempts to transfect cells using neutral liposomes have proven challenging and inefficient owing to the highly refractory nature of these cells. We therefore sought to develop a multivalent cationic liposome (MVCL) formulation for efficient and reproducible...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Ravi, V., Madhankumar, A. B. Tags: STEM CELLS Source Type: research
Stmc-24. novel inhibitor of cdk5 signaling axis suppresses self-renewal properties of gbm stem cells and induces apoptosis
Cancer stem cells exert enormous influence on neoplastic behavior, in part by governing asymmetric cell division and the balance between self-renewal and multipotent differentiation. Growth is favored by deregulated stem cell division, which enhances the self-renewing population and diminishes the differentiation program. To uncover mechanisms relevant to deregulated cell division in human glioma stem cells, we first developed a novel adult Drosophila brain tumor model in which brat-RNAi is driven by the neuroblast specific promoter inscuteable. Suppressing Brat in this population led to accumulation of actively proliferat...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Mukherjee, S., Chau, M., Tucker-Burden, C., Zhang, C., Kong, J., Read, R., Brat, D. Tags: STEM CELLS Source Type: research
Stmc-23. ethical perspectives on unproven stem cell transplants in neuro-oncological disease
The application of stem cell transplants in clinical practice has become increasingly common, and many neurological diseases, including malignant brain tumors, are being targeted for intervention with stem cell transplants. The transplant procedures currently being carried out are frequently unregulated and may endanger patients. In most cases, patients undergoing such operations are not included in a clinical trial, and often do not provide genuinely informed consent. We performed a systematic search of the PubMed database to identify articles that referenced the use of the ethics of stem cell transplants in the treatment...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Cote, D., Smith, T., Bredenoord, A., Broekman, M. Tags: STEM CELLS Source Type: research
Stmc-22. a biosynthetic metabolic pathway in glioblastoma controls growth via reactive species balance
In glioblastoma (GBM; grade IV astrocytoma), subpopulations of highly tumorigenic cells called brain tumor initiating cells (BTICs) have been characterized by their unique capacity to promote tumor growth and therapeutic resistance. BTIC maintenance is increased via nitric oxide produced by nitric oxide synthases (NOS) in BTICs and the tumor vasculature. NOS require the co-factor tetrahydrobiopterin (BH4) for NO generation and will make superoxide if BH4 is deficient. As the first and rate-limiting enzyme of the de novo pathway synthesizing BH4 is GTP cyclohydrolase 1 (GCH1), GCH1 activity can control reactive nitrogen and...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Tran, A., Walker, K., Hocevar, L., Harrison, D., Chen, W., Darley-Usmar, V., Gillespie, Y., Cooper, S., Hjelmeland, A. Tags: STEM CELLS Source Type: research
STMC-21. ASTROCYTOMA MUTATIONS IDH1, p53 AND ATRX COOPERATE TO BLOCK DIFFERENTIATION OF NEURAL STEM CELLS VIA Sox2
The presence of a common IDH1 mutation in two divergent tumor lineages, astrocytoma and oligodendroglioma, suggests that it is a driver mutation that occurs early in the cascade of mutations in a progenitor-like cell. To test the hypothesis that mutant IDH1 is a driver of gliomagenesis, we used human embryonic stem cell derived neural stem cells (NSCs) to overexpress mutant IDH1 protein systematically in combination with p53 and ATRX knockdown, thereby modeling the mutations found in astrocytomas. Expression of mutant IDH1 resulted in robust production of 2-hydroxyglutarate. Mutant IDH1 alone paradoxically decreased prolif...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Modrek, A., Golub, D., Khan, T., Zhang, G., Kader, M., Bowman, C., Prado, J., Bayin, N. S., Frenster, J., Lhakhang, T., Heguy, A., Dankert, J., Tsirigos, A., Snuderl, M., Neubert, T., Placantonakis, D. Tags: STEM CELLS Source Type: research
Stmc-20. migrating glioma cells express stem cell markers and give rise to new tumors upon xenografting
In conclusion, migrating tumor cells preserve expression of stem cell markers and functional CSC characteristics. Since CSCs are reported to be highly resistant to therapy, these results emphasize that the CSC phenotype should be taken into consideration in future treatment of GBMs. (Source: Neuro-Oncology)
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Munthe, S., Sorensen, M., Thomassen, M., Burton, M., Kruse, T., Lathia, J., Poulsen, F., Kristensen, B. Tags: STEM CELLS Source Type: research
Stmc-18. anatomic compartmentalization of cancer stem cell signatures in glioblastoma
Cancer stem cells (CSCs) can be defined by functional attributes that include tumor initiation, persistent proliferation, and sustained self-renewal, but their gene signatures and specific anatomic contexts remain obscure. To characterize candidate signatures and explore specific locations in glioblastoma enriched for putative CSCs, we analyzed 270 transcriptomes of anatomic features and CSC profiles of the Ivy Glioblastoma Atlas (http://glioblastoma.alleninstitute.org/). The features included the leading edge, infiltrating tumor (transition zone between leading edge and cellular tumor), cellular tumor, pseudopalisading ce...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Puchalski, R., Shah, N., Miller, J., Cobbs, C., Hawrylycz, M. Tags: STEM CELLS Source Type: research
Stmc-17. n-cadherin upregulation mediates slow proliferation and therapeutic resistance in glioma stem cells
In conclusion, our data indicate that increased N-cadherin expression induces a state of slow growth in GSCs through a reduction of Wnt/ β-catenin signaling, which underlies their therapeutic resistance. Therefore, N-cadherin represents a new important target to antagonize tumor recurrence in glioblastoma. (Source: Neuro-Oncology)
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Osuka, S., Sampetrean, O., Onishi, N., Saya, H., Meir, E. V. Tags: STEM CELLS Source Type: research
Stmc-16. ezh2-mediated arl13b regulate ciliogenesis in gbm
Glioblastoma stem cells (GSCs) are known to be responsible for GBM therapeutic resistance. Previously we have reported exceptional plasticity within GBM during chemotherapy, which is associated with increases in GSC subpopulations. The Initial investigation indicated that Polycomb group protein EZH2 is critical for therapeutic stress-induced cellular plasticity. Chemical inhibition, as well as shRNA-mediated knockdown of EZH2, suppresses cellular plasticity-mediated increases in GSCs. To elucidate molecular mechanisms of EZH2-mediated therapeutic resistance, gene expression analysis was performed in the presence of the EZH...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Atashi, F., Hasan, T., Lee, G., Guo, D., Park, C., Lesniak, M., James, C. D., Ahmed, A. Tags: STEM CELLS Source Type: research
