scholarly journals The Roles of miRNA in Glioblastoma Tumor Cell Communication: Diplomatic and Aggressive Negotiations

2020 ◽  
Vol 21 (6) ◽  
pp. 1950 ◽  
Author(s):  
Andrei Buruiană ◽  
Ștefan Ioan Florian ◽  
Alexandru Ioan Florian ◽  
Teodora-Larisa Timiș ◽  
Carmen Mihaela Mihu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Cell Communication ◽  
Glioma Cells ◽  
Glioma Stem Cells ◽  
Patient Stratification ◽  
Egfr Signaling ◽  
Egfr Signaling Pathway ◽  
Target Therapies ◽  
Novel Target

Glioblastoma (GBM) consists of a heterogeneous collection of competing cellular clones which communicate with each other and with the tumor microenvironment (TME). MicroRNAs (miRNAs) present various exchange mechanisms: free miRNA, extracellular vesicles (EVs), or gap junctions (GJs). GBM cells transfer miR-4519 and miR-5096 to astrocytes through GJs. Oligodendrocytes located in the invasion front present high levels of miR-219-5p, miR-219-2-3p, and miR-338-3p, all related to their differentiation. There is a reciprocal exchange between GBM cells and endothelial cells (ECs) as miR-5096 promotes angiogenesis after being transferred into ECs, whereas miR-145-5p acts as a tumor suppressor. In glioma stem cells (GSCs), miR-1587 and miR-3620-5p increase the proliferation and miR-1587 inhibits the hormone receptor co-repressor-1 (NCOR1) after EVs transfers. GBM-derived EVs carry miR-21 and miR-451 that are up-taken by microglia and monocytes/macrophages, promoting their proliferation. Macrophages release EVs enriched in miR-21 that are transferred to glioma cells. This bidirectional miR-21 exchange increases STAT3 activity in GBM cells and macrophages, promoting invasion, proliferation, angiogenesis, and resistance to treatment. miR-1238 is upregulated in resistant GBM clones and their EVs, conferring resistance to adjacent cells via the CAV1/EGFR signaling pathway. Decrypting these mechanisms could lead to a better patient stratification and the development of novel target therapies.

The Ultrastructural Difference between CD133-positive U251 Glioma Stem Cells and Normal U251 Glioma Cells

2012 ◽  
Vol 36 (6) ◽  
pp. 404-408 ◽  
Author(s):  
Bo Yang ◽  
You Wang ◽  
Chunxu Yang ◽  
Wen Ouyang ◽  
Fuxiang Zhou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Glioma Cells ◽  
Glioma Stem Cells ◽  
Ultrastructural Difference

scholarly journals ANGI-03OBSERVATION OF GLIOMA STEM CELLS TRANSFORM INTO ENDOTHELIAL CELLS VIA LIVE CELL IMAGING

2015 ◽  
Vol 17 (suppl 5) ◽  
pp. v41.3-v41
Author(s):  
Xin Mei ◽  
Yinsheng Chen ◽  
Zhongping Chen
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Live Cell ◽  
Glioma Stem Cells

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-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

Proteasome inhibitors sensitize glioma cells and glioma stem cells to TRAIL-induced apoptosis by PKCε-dependent downregulation of AKT and XIAP expressions

2011 ◽  
Vol 23 (8) ◽  
pp. 1348-1357 ◽  
Author(s):  
Sarit Kahana ◽  
Susan Finniss ◽  
Simona Cazacu ◽  
Cunli Xiang ◽  
Hae-Kyung Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Proteasome Inhibitors ◽  
Glioma Cells ◽  
Glioma Stem Cells ◽  
Induced Apoptosis

scholarly journals CBMS-7 IGF1/N-cadherin/Clusterin signaling axis mediates adaptive radioresistance of glioma stem cells

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi3-vi3
Author(s):  
Satoru Osuka ◽  
Dan Zhu ◽  
Zhaobin Zhang ◽  
Chaoxi Li ◽  
Christian T Stackhouse ◽  
...  
Keyword(s):  
Stem Cells ◽  
Glioma Stem Cells ◽  
Adhesive Properties ◽  
Resistance Pathway ◽  
Signaling Axis ◽  
Igf1r Inhibitor ◽  
Novel Target ◽  
Tcga Dataset ◽  
Igf1 Receptor

Abstract Glioblastoma (GBM) is composed of a variety of tumor cell populations including those with stem cell properties, known as glioma stem cells (GSCs). GSCs are innately less sensitive to radiation than the tumor bulk and are believed to drive GBM formation and recurrence following repeated irradiation. However, it is unclear how GSCs adapt to avoid the toxicity of repeated irradiation used in clinical practice. We established radioresistant human and mouse GSCs by exposing them to repeated rounds of irradiation in order to uncover critical mediators of adaptive radioresistance. Surviving subpopulations acquired strong radioresistance in vivo, which was accompanied by increased cell-cell adhesion, slower proliferation, an elevation of stemness properties and N-cadherin expression. Increasing N-cadherin expression rendered parental GSCs radioresistant, reduced their proliferation, and increased their stemness and intercellular adhesive properties. Conversely, radioresistant GSCs reduced their acquired phenotypes upon CRISPR/Cas9-mediated knockout of N-cadherin. Mechanistically, elevated N-cadherin expression resulted in the accumulation of β-catenin at the cell surface, which decreased Wnt/ β-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. Restoration of wild type N-cadherin, but not mutant N-cad lacking β-catenin binding region, led to increased radioresistance in N-cadherin knockout GSCs, indicating the importance of the binding between N-cadherin and β-catenin. We also demonstrated that N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype can be reversed with picropodophyllin (PPP), a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation. Moreover, the elevation of N-cad and Clusterin are related to prognosis of GBM in the TCGA dataset. In conclusion, our data indicate that IGF1R inhibitor can block the N-cadherin-mediated resistance pathway. Our research provides a deeper understanding of adaptive radioresistance after repeated irradiation, and validates the IGF1/N-cadherin/β-catenin/Clusterin signaling axis as a novel target for radio-sensitization, which has direct therapeutic applicability.

scholarly journals Adenovirus infection promotes the formation of glioma stem cells by glioblastoma cells through the TLR9/NEAT1/STAT3 pathway

2020 ◽  
Author(s):  
Jian Zang ◽  
Min-hua Zheng ◽  
Xiu-li Cao ◽  
Yi-zhe Zhang ◽  
Yu-fei Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Glioma Cells ◽  
Tumor Model ◽  
Glioma Stem Cells ◽  
Stem Cell Markers ◽  
Qrt Pcr ◽  
Lineage Differentiation ◽  
Stat3 Signaling

Abstract BackgroundGlioma stem cells (GSCs) are glioma cells with stemness and are responsible for a variety of malignant behaviors of glioma. Evidence has shown that signals from tumor microenvironment (TME) enhance stemness of glioma cells, but the identity of the signaling molecules and underlying mechanisms have been incompletely elucidated.MethodsHuman samples and glioma cell lines were cultured in vitro to determine the effects of viral infection by sphere formation, qRT-PCR, Western blot, FACS and immunofluorescence; for in vivo analysis, mice subcutaneous tumor model was carried; while bioinformatics analysis and qRT-PCR were applied for further mechanistic studies.ResultsIn this study, we show that infection of patient-derived glioma cells with adenovirus (ADV) increases the formation of tumor spheres. ADV infection upregulated stem cell markers, and the resultant tumor spheres held the capacities of self-renewal and multi-lineage differentiation, and had stronger potential to form xenograft tumors in immune-compromised mice. ADV promoted GSC formation likely via TLR9, because TLR9 was upregulated after ADV infection, and knockdown of TLR9 reduced ADV-induced GSCs. Consistently, MYD88, as well as total STAT3 and phosphorylated (p-)STAT3, were also upregulated in ADV-induced GSCs. Knockdown of MYD88 or pharmaceutical inhibition of STAT3 attenuated stemness of ADV-induced GSCs. Moreover, we found that ADV infection upregulated lncRNA NEAT1, which is downstream to TLRs and play important roles in cancer stem cells via multiple mechanisms including strengthening STAT3 signaling. Indeed, knockdown of NEAT1 impaired stemness of ADV-induced GSCs. Lastly, we show that HMGB1, a damage associated molecular pattern (DAMP) that also triggers TLR signaling, upregulated stemness markers in glioma cells.ConclusionsIn summary, our data indicate that ADV, which has been developed as vectors for gene therapy and oncolytic virus, promotes the formation of GSCs via TLR9/NEAT1/STAT3 signaling.

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