scholarly journals Dihydropyrimidinase‑related protein 5 controls glioblastoma stem cell characteristics as a biomarker of proneural‑subtype glioblastoma stem cells

2020 ◽  
Vol 20 (2) ◽  
pp. 1153-1162
Author(s):  
Min Gi Park ◽  
Sunyoung Seo ◽  
Seok Won Ham ◽  
Sang‑Hun Choi ◽  
Hyunggee Kim
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Related Protein ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell

scholarly journals DYRK1A Negatively Regulates CDK5-SOX2 Pathway and Self-Renewal of Glioblastoma Stem Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 4011
Author(s):  
Brianna Chen ◽  
Dylan McCuaig-Walton ◽  
Sean Tan ◽  
Andrew P. Montgomery ◽  
Bryan W. Day ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Critical Role ◽  
Stem Cell Differentiation ◽  
Neural Progenitor Cell ◽  
Cellular Heterogeneity ◽  
Differentiation Potential ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell

Glioblastoma display vast cellular heterogeneity, with glioblastoma stem cells (GSCs) at the apex. The critical role of GSCs in tumour growth and resistance to therapy highlights the need to delineate mechanisms that control stemness and differentiation potential of GSC. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) regulates neural progenitor cell differentiation, but its role in cancer stem cell differentiation is largely unknown. Herein, we demonstrate that DYRK1A kinase is crucial for the differentiation commitment of glioblastoma stem cells. DYRK1A inhibition insulates the self-renewing population of GSCs from potent differentiation-inducing signals. Mechanistically, we show that DYRK1A promotes differentiation and limits stemness acquisition via deactivation of CDK5, an unconventional kinase recently described as an oncogene. DYRK1A-dependent inactivation of CDK5 results in decreased expression of the stemness gene SOX2 and promotes the commitment of GSC to differentiate. Our investigations of the novel DYRK1A-CDK5-SOX2 pathway provide further insights into the mechanisms underlying glioblastoma stem cell maintenance.

scholarly journals Glioblastoma Stem Cells as a New Therapeutic Target for Glioblastoma

2015 ◽  
Vol 9 ◽  
pp. CMO.S30271 ◽  
Author(s):  
Rasime Kalkan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Signaling Pathways ◽  
Therapeutic Target ◽  
Fatal Outcome ◽  
Cellular Heterogeneity ◽  
Cell Phenotype ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell

Primary and secondary glioblastomas (GBMs) are two distinct diseases. The genetic and epigenetic background of these tumors is highly variable. The treatment procedure for these tumors is often unsuccessful because of the cellular heterogeneity and intrinsic ability of the tumor cells to invade healthy tissues. The fatal outcome of these tumors promotes researchers to find out new markers associated with the prognosis and treatment planning. In this communication, the role of glioblastoma stem cells in tumor progression and the malignant behavior of GBMs are summarized with attention to the signaling pathways and molecular regulators that are involved in maintaining the glioblastoma stem cell phenotype. A better understanding of these stem cell-like cells is necessary for designing new effective treatments and developing novel molecular strategies to target glioblastoma stem cells. We discuss hypoxia as a new therapeutic target for GBM. We focus on the inhibition of signaling pathways, which are associated with the hypoxia-mediated maintenance of glioblastoma stem cells, and the knockdown of hypoxia-inducible factors, which could be identified as attractive molecular target approaches for GBM therapeutics.

scholarly journals Localization patterns of cathepsins K and X and their predictive value in glioblastoma

2018 ◽  
Vol 52 (4) ◽  
pp. 433-442 ◽  
Author(s):  
Barbara Breznik ◽  
Clara Limback ◽  
Andrej Porcnik ◽  
Andrej Blejec ◽  
Miha Koprivnikar Krajnc ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Stem Cell ◽  
Mrna Expression ◽  
Predictive Value ◽  
Cathepsin K ◽  
Mrna Levels ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell ◽  
Cathepsin X

AbstractBackgroundGlioblastoma is a highly aggressive central nervous system neoplasm characterized by extensive infiltration of malignant cells into brain parenchyma, thus preventing complete tumor eradication. Cysteine cathepsins B, S, L and K are involved in cancer progression and are overexpressed in glioblastoma. We report here for the first time that cathepsin X mRNA and protein are also abundantly present in malignant glioma.Materials and methodsGene expression of cathepsins K and X was analyzed using publically-available tran-scriptomic datasets and correlated with glioma grade and glioblastoma subtype. Kaplan-Maier survival analysis was performed to evaluate the predictive value of cathepsin K and X mRNA expression. Cathepsin protein expression was localized and semi-quantified in tumor tissues by immunohistochemistry.ResultsHighest gene expression of cathepsins K and X was found in glioblastoma, in particular in the mesenchymal subtype. Overall, high mRNA expression of cathepsin X, but not that of cathepsin K, correlated with poor patients’ survival. Cathepsin K and X proteins were abundantly and heterogeneously expressed in glioblastoma tissue. Immuno-labeling of cathepsins K and X was observed in areas of CD133-positive glioblastoma stem cells, localized around arterioles in their niches that also expressed SDF-1α and CD68. mRNA levels of both cathepsins K and X correlated with mRNA levels of markers of glioblastoma stem cells and their niches.ConclusionsThe presence of both cathepsins in glioblastoma stem cell niche regions indicates their possible role in regulation of glioblastoma stem cell homing in their niches. The clinical relevance of this data needs to be elaborated in further prospective studies.

scholarly journals Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3

2016 ◽  
Author(s):  
Maureen M. Sherry-Lynes ◽  
Sejuti Sengupta ◽  
Shreya Kulkarni ◽  
Brent H. Cochran
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Types ◽  
Self Renewal ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Stem Cell ◽  
Histone H3k27 ◽  
Direct Target ◽  
Polycomb Complex ◽  
Stat3 Inhibition

SUMMARYThe growth factor and cytokine regulated transcription factor STAT3 is required for the self-renewal of several stem cell types including tumor stem cells from glioblastoma. Here we show that STAT3 inhibition leads to the upregulation of the histone H3K27me2/3 demethylase Jmjd3 (KDM6B), which can reverse polycomb complex-mediated repression of tissue specific genes. STAT3 binds to the Jmjd3 promoter, suggesting that Jmjd3 is a direct target of STAT3. Overexpression of Jmjd3 slows glioblastoma stem cell growth and neurosphere formation, whereas knockdown of Jmjd3 rescues the STAT3 inhibitor-induced neurosphere formation defect. Consistent with this observation, STAT3 inhibition leads to histone H3K27 demethylation of neural differentiation genes, such as Myt1, FGF21, and GDF15. These results demonstrate that the regulation of Jmjd3 by STAT3 maintains repression of differentiation specific genes and is therefore important for the maintenance of self-renewal of normal neural and glioblastoma stem cells.

scholarly journals TMIC-22. IDENTIFICATION OF CANCER-ASSOCIATED FIBROBLASTS IN GLIOBLASTOMA and Defining Their Protumoral Effects

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi252-vi252
Author(s):  
Jonathan Rick ◽  
Alan Nguyen ◽  
Ankush Chandra ◽  
Harsh Wadhwa ◽  
Sumedh Shah ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Cancer Associated Fibroblasts ◽  
Rna Seq ◽  
Glioblastoma Stem Cells ◽  
Perivascular Niche ◽  
Glioblastoma Stem Cell ◽  
Blocking Antibodies

Abstract While cancer-associated fibroblasts (CAFs) and their pro-tumoral effects have been demonstrated in systemic cancers, CAFs had been presumed absent in glioblastoma given the lack of normal fibroblasts in the healthy brain. Here, we show that 5–26% (mean=12%) of cells in human glioblastomas express CAF markers α-SMA or PDGFR-β, morphologically resemble fibroblasts, and transcriptomically resemble by RNA-seq CAFs from other cancers. Glioblastoma CAFs were chemotactically attracted to glioblastoma-initiating stem cells (P=0.02). While glioblastoma CAFs did not affect differentiated glioblastoma cell proliferation (P=0.4), CAFs increased glioblastoma stem cell proliferation (P=0.002) and expression of glioblastoma stem cell-associated genes (P< 0.001). To identify mediators of CAF/glioblastoma stem cell interactions, we created a resource of inferred crosstalk by mapping the expression of receptors to that of their cognate ligands/agonists, using our RNA-seq results from glioblastoma CAFs and stem cells, revealing PDGF-β/PDGFR and osteopontin/CD44 to mediate stem cell recruitment of CAFs and CAF enrichment of stem cells, as confirmed by blocking antibodies (P=0.02–0.03). CAFs also render the glioblastoma microenvironment more pro-tumoral by promoting M2 polarization of tumor-associated macrophages (P=0.01), an effect we found to arise from unique CAF production of the EDA splice variant of fibronectin binding toll-like receptor 4 (TLR4), a known EDA receptor expressed by macrophages (P=0.02). In patient glioblastomas, CAFs were enriched 3-fold in the subventricular zone (SVZ) (P=0.04) which houses the neural stem cells that generate glioblastoma stem cells. SVZs from epilepsy cases or autopsies of glioblastoma-containing brains without ventricular involvement lacked CAFs. Depleting CAFs in xenografts derived from neurosphere-containing glioblastoma stem cells slowed their growth in vivo (P< 0.001). These findings are among the first to identify and profile glioblastoma CAFs. CAF recruitment by glioblastoma stem cells and creation of a pro-tumoral microenvironment in the perivascular niche housing glioblastoma stem cells, particularly in the SVZ, makes them an intriguing therapeutic target.

scholarly journals Active targeting co-delivery of therapeutic Sur siRNA and an antineoplastic drug via epidermal growth factor receptor-mediated magnetic nanoparticles for synergistic programmed cell death in glioblastoma stem cells

2020 ◽  
Vol 4 (2) ◽  
pp. 574-588
Author(s):  
Xueqin Wang ◽  
Ruifang Li ◽  
Yongxia Zhu ◽  
Zichao Wang ◽  
Huiru Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Epidermal Growth Factor Receptor ◽  
Stem Cell ◽  
Magnetic Nanoparticles ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Active Targeting ◽  
Glioblastoma Stem Cell ◽  
Epidermal Growth

An EGFR-targeted theranostic composite, and targeted co-delivery of therapeutic siRNAs and DOX for glioblastoma stem cell treatments.

Glioblastoma stem cells and stem cell-targeting immunotherapies

2015 ◽  
Vol 123 (3) ◽  
pp. 449-457 ◽  
Author(s):  
Rogelio Esparza ◽  
Tej D. Azad ◽  
Abdullah H. Feroze ◽  
Siddhartha S. Mitra ◽  
Samuel H. Cheshier
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Targeting ◽  
Glioblastoma Stem Cells

scholarly journals The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype

Cell Cycle ◽  
2009 ◽  
Vol 8 (20) ◽  
pp. 3274-3284 ◽  
Author(s):  
John M. Heddleston ◽  
Zhizhong Li ◽  
Roger E. McLendon ◽  
Anita B. Hjelmeland ◽  
Jeremy N. Rich
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cell Phenotype ◽  
Glioblastoma Stem Cells ◽  
Cancer Stem Cell Phenotype ◽  
Stem Cell Phenotype

scholarly journals A Core Regulatory Circuit in Glioblastoma Stem Cells Links MAPK Activation to a Transcriptional Program of Neural Stem Cell Identity

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Gregory Riddick ◽  
Svetlana Kotliarova ◽  
Virginia Rodriguez ◽  
H. S. Kim ◽  
Amanda Linkous ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cell ◽  
Transcriptional Program ◽  
Mapk Activation ◽  
Glioblastoma Stem Cells ◽  
Cell Identity ◽  
Regulatory Circuit
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