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 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 Hedgehog Pathway Inhibition Hampers Sphere and Holoclone Formation in Rhabdomyosarcoma

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Ana Almazán-Moga ◽  
Patricia Zarzosa ◽  
Isaac Vidal ◽  
Carla Molist ◽  
Irina Giralt ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Common Type ◽  
Hedgehog Pathway ◽  
Cellular Heterogeneity ◽  
Self Renewal ◽  
Pathway Inhibition

Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children and can be divided into two main subtypes: embryonal (eRMS) and alveolar (aRMS). Among the cellular heterogeneity of tumors, the existence of a small fraction of cells called cancer stem cells (CSC), thought to be responsible for the onset and propagation of cancer, has been demonstrated in some neoplasia. Although the existence of CSC has been reported for eRMS, their existence in aRMS, the most malignant subtype, has not been demonstrated to date. Given the lack of suitable markers to identify this subpopulation in aRMS, we used cancer stem cell-enriched supracellular structures (spheres and holoclones) to study this subpopulation. This strategy allowed us to demonstrate the capacity of both aRMS and eRMS cells to form these structures and retain self-renewal capacity. Furthermore, cells contained in spheres and holoclones showed significant Hedgehog pathway induction, the inhibition of which (pharmacologic or genetic) impairs the formation of both holoclones and spheres. Our findings point to a crucial role of this pathway in the maintenance of these structures and suggest that Hedgehog pathway targeting in CSC may have great potential in preventing local relapses and metastases.

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 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 miRNA function and modulation in stem cells and cancer stem cells

2014 ◽  
Vol 1 (1) ◽  
Author(s):  
Andrew J. DeCastro ◽  
James DiRenzo
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cell Phenotype ◽  
Pluripotent State ◽  
Differentiated Cells ◽  
Non Coding Rnas ◽  
Multicellular Organisms ◽  
Stem Cell Phenotype

AbstractStem cells belong to a unique class of cells that is collectively responsible for the development and subsequent maintenance of all tissues comprising multicellular organisms. These cells possess unique characteristics that allow them to remain in a pluripotent state, while also continuing to generate differentiated cells. microRNAs, a specialized class of non-coding RNAs, are integral components of the network of pathways that modulates this combination of abilities. This review highlights recent discoveries about the roles miRNAs play in governing stem cell phenotype, and discusses the potential therapeutic utility that miRNAs may have in the treatment of multiple diseases. Additionally, it addresses a novel mode of regulation of stem cell phenotype through lincRNA-mediated modulation of select miRNAs, and the role of secreted, stem cell-derived miRNAs in exerting a paracrine influence on surrounding non-stem cells.

scholarly journals The role of translationally controlled tumor protein in proliferation ofDrosophilaintestinal stem cells

2019 ◽  
Vol 116 (52) ◽  
pp. 26591-26598 ◽  
Author(s):  
Young V. Kwon ◽  
Bingqing Zhao ◽  
Chiwei Xu ◽  
Jiae Lee ◽  
Chiao-Lin Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Signaling Pathways ◽  
Hippo Pathway ◽  
Tissue Homeostasis ◽  
Translationally Controlled Tumor Protein ◽  
Cellular Processes ◽  
The Hippo Pathway

Translationally controlled tumor protein (TCTP) is a highly conserved protein functioning in multiple cellular processes, ranging from growth to immune responses. To explore the role of TCTP in tissue maintenance and regeneration, we employed the adultDrosophilamidgut, where multiple signaling pathways interact to precisely regulate stem cell division for tissue homeostasis. Tctp levels were significantly increased in stem cells and enteroblasts upon tissue damage or activation of the Hippo pathway that promotes regeneration of intestinal epithelium. Stem cells with reduced Tctp levels failed to proliferate during normal tissue homeostasis and regeneration. Mechanistically, Tctp forms a complex with multiple proteins involved in translation and genetically interacts with ribosomal subunits. In addition, Tctp increases both Akt1 protein abundance and phosphorylation in vivo. Altogether, Tctp regulates stem cell proliferation by interacting with key growth regulatory signaling pathways and the translation process in vivo.

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 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 Biomimetic oyster shell–replicated topography alters the behaviour of human skeletal stem cells

2018 ◽  
Vol 9 ◽  
pp. 204173141879400 ◽  
Author(s):  
Shona J Waddell ◽  
María C de Andrés ◽  
Penelope M Tsimbouri ◽  
Enateri V Alakpa ◽  
Maggie Cusack ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Oyster Shell ◽  
Cell Phenotype ◽  
Cell Area ◽  
Cell Behaviour ◽  
Cell Therapies ◽  
Pinctada Maxima ◽  
Skeletal Stem Cell

The regenerative potential of skeletal stem cells provides an attractive prospect to generate bone tissue needed for musculoskeletal reparation. A central issue remains efficacious, controlled cell differentiation strategies to aid progression of cell therapies to the clinic. The nacre surface from Pinctada maxima shells is known to enhance bone formation. However, to date, there is a paucity of information on the role of the topography of P. maxima surfaces, nacre and prism. To investigate this, nacre and prism topographical features were replicated onto polycaprolactone and skeletal stem cell behaviour on the surfaces studied. Skeletal stem cells on nacre surfaces exhibited an increase in cell area, increase in expression of osteogenic markers ALP ( p < 0.05) and OCN ( p < 0.01) and increased metabolite intensity ( p < 0.05), indicating a role of nacre surface to induce osteogenic differentiation, while on prism surfaces, skeletal stem cells did not show alterations in cell area or osteogenic marker expression and a decrease in metabolite intensity ( p < 0.05), demonstrating a distinct role for the prism surface, with the potential to maintain the skeletal stem cell phenotype.

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