scholarly journals Glioma Stem Cells and Their Microenvironments: Providers of Challenging Therapeutic Targets

2016 ◽  
Vol 2016 ◽  
pp. 1-20 ◽  
Author(s):  
Elena Codrici ◽  
Ana-Maria Enciu ◽  
Ionela-Daniela Popescu ◽  
Simona Mihai ◽  
Cristiana Tanase
Keyword(s):  
Stem Cells ◽  
Cell Biology ◽  
Malignant Gliomas ◽  
Therapy Resistance ◽  
Metabolic Reprogramming ◽  
Glioma Stem Cells ◽  
Macrophage Colony ◽  
Potential Use ◽  
Macrophage Colony Stimulation Factor

Malignant gliomas are aggressive brain tumors with limited therapeutic options, possibly because of highly tumorigenic subpopulations of glioma stem cells. These cells require specific microenvironments to maintain their “stemness,” described as perivascular and hypoxic niches. Each of those niches induces particular signatures in glioma stem cells (e.g., activation of Notch signaling, secretion of VEGF, bFGF, SDF1 for the vascular niche, activation of HIF2α, and metabolic reprogramming for hypoxic niche). Recently, accumulated knowledge on tumor-associated macrophages, possibly delineating a third niche, has underlined the role of immune cells in glioma progression,viaspecific chemoattractant factors and cytokines, such as macrophage-colony stimulation factor (M-CSF). The local or myeloid origin of this new component of glioma stem cells niche is yet to be determined. Such niches are being increasingly recognized as key regulators involved in multiple stages of disease progression, therapy resistance, immune-escaping, and distant metastasis, thereby substantially impacting the future development of frontline interventions in clinical oncology. This review focuses on the microenvironment impact on the glioma stem cell biology, emphasizing GSCs cross talk with hypoxic, perivascular, and immune niches and their potential use as targeted therapy.

scholarly journals Rewiring of purine metabolism in response to acidosis stress in glioma stem cells

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Xiaoyu Xu ◽  
Liping Wang ◽  
Qingce Zang ◽  
Shanshan Li ◽  
Limei Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Metabolic Flux ◽  
De Novo ◽  
Therapy Resistance ◽  
Low Ph ◽  
Metabolic Reprogramming ◽  
Significant Feature ◽  
Glioma Stem Cells ◽  
Flux Analysis ◽  
Acidic Conditions

AbstractGlioma stem cells (GSCs) contribute to therapy resistance and poor outcomes for glioma patients. A significant feature of GSCs is their ability to grow in an acidic microenvironment. However, the mechanism underlying the rewiring of their metabolism in low pH remains elusive. Here, using metabolomics and metabolic flux approaches, we cultured GSCs at pH 6.8 and pH 7.4 and found that cells cultured in low pH exhibited increased de novo purine nucleotide biosynthesis activity. The overexpression of glucose-6-phosphate dehydrogenase, encoded by G6PD or H6PD, supports the metabolic dependency of GSCs on nucleotides when cultured under acidic conditions, by enhancing the pentose phosphate pathway (PPP). The high level of reduced glutathione (GSH) under acidic conditions also causes demand for the PPP to provide NADPH. Taken together, upregulation of G6PD/H6PD in the PPP plays an important role in acidic-driven purine metabolic reprogramming and confers a predilection toward glioma progression. Our findings indicate that targeting G6PD/H6PD, which are closely related to glioma patient survival, may serve as a promising therapeutic target for improved glioblastoma therapeutics. An integrated metabolomics and metabolic flux analysis, as well as considering microenvironment and cancer stem cells, provide a precise insight into understanding cancer metabolic reprogramming.

Role of psoriatic keratinocytes in the metabolic reprogramming of dermal mesenchymal stem cells

2021 ◽  
Author(s):  
Yue Cao ◽  
Nan‐Nan Liang ◽  
Wen‐Juan Chang ◽  
Jun‐Qin Li ◽  
Juan‐Juan Jiao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Metabolic Reprogramming

scholarly journals HAUSP Stabilizes SOX2 through Deubiquitination to Maintain Self-renewal and Tumorigenic Potential of Glioma Stem Cells

2021 ◽  
Author(s):  
Zhi Huang ◽  
Kui Zhai ◽  
Qiulian Wu ◽  
Xiaoguang Fang ◽  
Qian Huang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Glioma Stem Cells ◽  
Posttranslational Regulation ◽  
Malignant Growth ◽  
Self Renewal ◽  
Animal Survival ◽  
Promising Target ◽  
Tumorigenic Potential ◽  
Therapeutic Opportunity

Glioblastoma (GBM) is the most lethal brain tumor containing glioma stem cells (GSCs) that promote malignant growth and therapeutic resistance. The self-renewal and tumorigenic potential of GSCs are maintained by core stem cell transcription factors including SOX2. Defining the posttranslational regulation of SOX2 may offer new insights into GSC biology and potential therapeutic opportunity. Here, we discover that HAUSP stabilizes SOX2 through deubiquitination to maintain GSC self-renewal and tumorigenic potential. HAUSP is preferentially expressed in GSCs in perivascular niches in GBMs. Disrupting HAUSP by shRNA or its inhibitor P22077 promoted SOX2 degradation, induced GSC differentiation, impaired GSC tumorigenic potential, and suppressed GBM tumor growth. Importantly, pharmacological inhibition of HAUSP synergized with radiation to inhibit GBM growth and extended animal survival, indicating that targeting HAUSP may overcome GSC-mediated radioresistance. Our findings reveal an unappreciated crucial role of HAUSP in the GSC maintenance and provide a promising target for developing effective anti-GSC therapeutics to improve GBM treatment.

scholarly journals CSIG-27. PRC2-INDEPENDENT FUNCTION OF EZH2/HP1BP3 COMPLEX IN GLIOMA STEM CELLS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi49-vi50
Author(s):  
Junxia Zhang ◽  
Tianfu Yu ◽  
Ning Liu
Keyword(s):  
Stem Cells ◽  
Transcriptional Repression ◽  
Glioma Stem Cells ◽  
Independent Function ◽  
Set Domain ◽  
Heterochromatin Protein 1 ◽  
Heterochromatin Protein ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase

Abstract Glioblastoma (GBM) displays cellular and genetical heterogeneity harboring a subpopulation of glioma stem cells (GSCs). Enhancer of zeste homolog 2 (EZH2), a histone lysine methyltransferase, is the core subunit of the polycomb repressor 2 (PRC2) complex, mediates gene transcriptional repression in both normal and tumor stem cells. An oncogenic role of EZH2 as a PRC2-dependent transcriptional silencer is well established; however, non-canonical functions of EZH2 are incompletely understood. Here we found a novel oncogenic mechanism for EZH2 in a PRC2-indenpend way in GSCs. Using HPLC-MS/MS and IP assay, EZH2 bound to HP1BP3 (heterochromatin protein 1 binding protein 3), a heterochromatin-related protein, with its pre-SET domain. Overexpression of H1P3B3 enhanced the proliferation, self-renewal and temozolomide (TMZ) resistance of GBM cells. Intriguingly, H1PBP3 was up-regulated in high grade gliomas with proneural (PN) subtypes and had a high predictive value on prognosis in patients with PN gliomas. Furthermore, EZH2 and HP1BP3 co-activated the expression of WNT7B by blocking the methylation of H3K9, thereby increasing TMZ resistance and tumorigenicity of glioblastoma cells. Interestingly, inhibition of WNT7B autocrine via LGK974, a specific porcupine inhibitor, effectively reversed the TMZ resistance of both GSCs and GBM glioma cells expressing HP1BP3. Hence, targeting the PRC2-independent function of EZH2 is an effective approach to enhance the efficacy of treating GBM.

scholarly journals MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells

2018 ◽  
Vol 115 (22) ◽  
pp. 5768-5773 ◽  
Author(s):  
Sarmistha Talukdar ◽  
Anjan K. Pradhan ◽  
Praveen Bhoopathi ◽  
Xue-Ning Shen ◽  
Laura A. August ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Therapy Resistance ◽  
Protective Mechanism ◽  
Glioma Stem Cells ◽  
Loss Of Function ◽  
Egfr Signaling ◽  
Anoikis Resistance ◽  
Functional Link ◽  
Small Subpopulation

Glioma stem cells (GSCs) comprise a small subpopulation of glioblastoma multiforme cells that contribute to therapy resistance, poor prognosis, and tumor recurrence. Protective autophagy promotes resistance of GSCs to anoikis, a form of programmed cell death occurring when anchorage-dependent cells detach from the extracellular matrix. In nonadherent conditions, GSCs display protective autophagy and anoikis-resistance, which correlates with expression of melanoma differentiation associated gene-9/Syntenin (MDA-9) (syndecan binding protein; SDCBP). When MDA-9 is suppressed, GSCs undergo autophagic death supporting the hypothesis that MDA-9 regulates protective autophagy in GSCs under anoikis conditions. MDA-9 maintains protective autophagy through phosphorylation of BCL2 and by suppressing high levels of autophagy through EGFR signaling. MDA-9 promotes these changes by modifying FAK and PKC signaling. Gain-of-function and loss-of-function genetic approaches demonstrate that MDA-9 regulates pEGFR and pBCL2 expression through FAK and pPKC. EGFR signaling inhibits autophagy markers (ATG5, Lamp1, LC3B), helping to maintain protective autophagy, and along with pBCL2 maintain survival of GSCs. In the absence of MDA-9, this protective mechanism is deregulated; EGFR no longer maintains protective autophagy, leading to highly elevated and sustained levels of autophagy and consequently decreased cell survival. In addition, pBCL2 is down-regulated in the absence of MDA-9, leading to cell death in GSCs under conditions of anoikis. Our studies confirm a functional link between MDA-9 expression and protective autophagy in GSCs and show that inhibition of MDA-9 reverses protective autophagy and induces anoikis and cell death in GSCs.

scholarly journals TMIC-01. THE DYSTROGLYCAN RECEPTOR MAINTAINS GLIOMA STEM CELLS IN THE VASCULAR NICHE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi247-vi247
Author(s):  
Bryan Day ◽  
Justin Lathia ◽  
Zara Bruce ◽  
Kathleen Ensbey ◽  
Yi Chieh Lim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Critical Factor ◽  
Glioma Stem Cells ◽  
Structural Element ◽  
Α Subunit ◽  
Vascular Niche ◽  
Cns Neoplasms ◽  
Tumour Initiation

Abstract Glioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding alpha (α) subunit of the dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the vascular niche. Glycosylated αDG is also expressed highly on the most aggressive mesenchymal-like GBM tumour tissue. Furthermore, we found that DG acts to maintain a de-differentiated stem cell-like phenotype via tight control of MAPK activation. Antibody-based blockade of αDG induces robust ERK-mediated differentiation leading to reduced GSC potential. DG was shown to be required for tumour initiation, with constitutive loss significantly delaying or preventing tumourigenic potential in-vivo. These findings reveal a central role of the DG receptor not only as a structural element but also as a critical factor in the maintenance of GSCs in the GBM vascular niche.

scholarly journals TMIC-36. CROSSTALK OF GLIOMA STEM CELLS WITH VASCULAR ENDOTHELIAL CELLS PERSISTS THEIR PRONEURAL PHENOTYPE AND THERAPY RESISTANCE VIA ENDOCAN-CD11A INTERACTION

2017 ◽  
Vol 19 (suppl_6) ◽  
pp. vi251-vi251
Author(s):  
Soniya Bastola ◽  
Marat Pavlyukov ◽  
Yasmin Ghochani ◽  
Hai Yu ◽  
Suojun Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Therapy Resistance ◽  
Glioma Stem Cells ◽  
Vascular Endothelial

scholarly journals Extracellular Vesicles: Evolving Factors in Stem Cell Biology

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Muhammad Nawaz ◽  
Farah Fatima ◽  
Krishna C. Vallabhaneni ◽  
Patrice Penfornis ◽  
Hadi Valadi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Tumor Microenvironment ◽  
Extracellular Vesicles ◽  
Cell Biology ◽  
Trophic Factors ◽  
Stem Cell Biology ◽  
Cell Fates ◽  
Bidirectional Communication

Stem cells are proposed to continuously secrete trophic factors that potentially serve as mediators of autocrine and paracrine activities, associated with reprogramming of the tumor microenvironment, tissue regeneration, and repair. Hitherto, significant efforts have been made to understand the level of underlying paracrine activities influenced by stem cell secreted trophic factors, as little is known about these interactions. Recent findings, however, elucidate this role by reporting the effects of stem cell derived extracellular vesicles (EVs) that mimic the phenotypes of the cells from which they originate. Exchange of genetic information utilizing persistent bidirectional communication mediated by stem cell-EVs could regulate stemness, self-renewal, and differentiation in stem cells and their subpopulations. This review therefore discusses stem cell-EVs as evolving communication factors in stem cell biology, focusing on how they regulate cell fates by inducing persistent and prolonged genetic reprogramming of resident cells in a paracrine fashion. In addition, we address the role of stem cell-secreted vesicles in shaping the tumor microenvironment and immunomodulation and in their ability to stimulate endogenous repair processes during tissue damage. Collectively, these functions ensure an enormous potential for future therapies.

The Role of Nucleophosmin In Hematopoietic Stem Cells and the Pathogenesis of Myelodysplastic Syndrome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 95-95 ◽  
Author(s):  
Keisuke Ito ◽  
Paolo Sportoletti ◽  
John G Clohessy ◽  
Grisendi Silvia ◽  
Pier Paolo Pandolfi
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Cell Biology ◽  
De Novo ◽  
Stem Cell Biology ◽  
Hematopoietic Stem

Abstract Abstract 95 Myelodysplastic syndrome (MDS) is an incurable stem cell disorder characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Nucleophosmin (NPM) is directly implicated in primitive hematopoiesis, the pathogenesis of hematopoietic malignancies and more recently of MDS. However, little is known regarding the molecular role and function of NPM in MDS pathogenesis and in stem cell biology. Here we present data demonstrating that NPM plays a critical role in the maintenance of hematopoietic stem cells (HSCs) and the transformation of MDS into leukemia. NPM is located on chromosome 5q and is frequently lost in therapy-related and de novo MDS. We have previously shown that Npm1 acts as a haploinsufficient tumor suppressor in the hematopoietic compartment and Npm1+/− mice develop a hematologic syndrome with features of human MDS, including increased susceptibility to leukemogenesis. As HSCs have been demonstrated to be the target of the primary neoplastic event in MDS, a functional analysis of the HSC compartment is essential to understand the molecular mechanisms in MDS pathogenesis. However, the role of NPM in adult hematopoiesis remains largely unknown as Npm1-deficiency leads to embryonic lethality. To investigate NPM function in adult hematopoiesis, we have generated conditional knockout mice of Npm1, using the Cre-loxP system. Analysis of Npm1 conditional mutants crossed with Mx1-Cre transgenic mice reveals that Npm1 plays a crucial role in adult hematopoiesis and ablation of Npm1 in adult HSCs leads to aberrant cycling and followed by apoptosis. Analysis of cell cycle status revealed that HSCs are impaired in their ability to maintain quiescence after Npm1-deletion and are rapidly depleted in vivo as well as in vitro. Competitive reconstitution assay revealed that Npm1 acts cell-autonomously to maintain HSCs. Conditional inactivation of Npm1 leads to an MDS phenotype including a profoundly impaired ability to differentiate into cells of the erythroid lineage, megakaryocyte dyspoiesis and centrosome amplification. Furthermore, Npm1 loss evokes a p53-dependent response and Npm1-deleted HSCs undergo apoptosis in vivo and in vitro. Strikingly, transfer of the Npm1 mutation into a p53-null background rescued the apoptosis of Npm1-ablated HSCs and resulted in accelerated transformation to an aggressive and lethal form of acute myeloid leukemia. Our findings highlight the crucial role of NPM in stem cell biology and identify a new mechanism by which MDS can progress to leukemia. This has important therapeutic implications for de novo MDS as well as therapy-related MDS, which is known to rapidly evolve to leukemia with frequent loss or mutation of TRP53. Disclosures: No relevant conflicts of interest to declare.

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