scholarly journals CCR5-Mediated Signaling is Involved in Invasion of Glioblastoma Cells in Its Microenvironment

2020 ◽  
Vol 21 (12) ◽  
pp. 4199
Author(s):  
Metka Novak ◽  
Miha Koprivnikar Krajnc ◽  
Barbara Hrastar ◽  
Barbara Breznik ◽  
Bernarda Majc ◽  
...  
Keyword(s):  
Stem Cells ◽  
Low Grade ◽  
Glioblastoma Cells ◽  
Ccr5 Gene ◽  
Glioblastoma Stem Cells ◽  
Primary Glioblastoma ◽  
Tissue Sections ◽  
Stromal Microenvironment ◽  
Close Proximity

The chemokine CCL5/RANTES is a versatile inflammatory mediator, which interacts with the receptor CCR5, promoting cancer cell interactions within the tumor microenvironment. Glioblastoma is a highly invasive tumor, in which CCL5 expression correlates with shorter patient survival. Using immunohistochemistry, we identified CCL5 and CCR5 in a series of glioblastoma samples and cells, including glioblastoma stem cells. CCL5 and CCR5 gene expression were significantly higher in a cohort of 38 glioblastoma samples, compared to low-grade glioma and non-cancerous tissues. The in vitro invasion of patients-derived primary glioblastoma cells and glioblastoma stem cells was dependent on CCL5-induced CCR5 signaling and is strongly inhibited by the small molecule CCR5 antagonist maraviroc. Invasion of these cells, which was enhanced when co-cultured with mesenchymal stem cells (MSCs), was inhibited by maraviroc, suggesting that MSCs release CCR5 ligands. In support of this model, we detected CCL5 and CCR5 in MSC monocultures and glioblastoma-associated MSC in tissue sections. We also found CCR5 expressing macrophages were in close proximity to glioblastoma cells. In conclusion, autocrine and paracrine cross-talk in glioblastoma and, in particular, glioblastoma stem cells with its stromal microenvironment, involves CCR5 and CCL5, contributing to glioblastoma invasion, suggesting the CCL5/CCR5 axis as a potential therapeutic target that can be targeted with repositioned drug maraviroc.

scholarly journals The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals

2017 ◽  
Vol Volume 12 ◽  
pp. 1369-1384 ◽  
Author(s):  
Yahua Wang ◽  
Xue Ying ◽  
Haolun Xu ◽  
Helu Yan ◽  
Xia Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Glioblastoma Cells ◽  
Glioblastoma Stem Cells

scholarly journals OMRT-11. The effect of microenvironment on glioblastoma stem cells therapeutic resistance

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii9-ii9
Author(s):  
Tamara Lah Turnsek ◽  
Barbara Breznik ◽  
Bernarda Majc ◽  
Metka Novak ◽  
Andrej Porčnik ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Combined Treatment ◽  
Cell Plasticity ◽  
Glioblastoma Stem Cells ◽  
Mesenchymal Transition ◽  
Non Invasive ◽  
Differential Gene

Abstract Epithelial-to-mesenchymal transition (EMT) is an essential molecular and cellular process in physiologic processes and invasion of various types of carcinoma and glioblastoma (GBM) cells. EMT is activated and regulated by specific endogenous triggers in complex network of intercellular interactions and signaling pathways. The hallmark of cancer-linked EMT are intermediate states that show notable cell plasticity, characteristic of cancer stem cells (CSCs), including glioblastoma stem cells – GSCs. GSCs resistance to irradiation (IR) and temozolomide (TMZ) chemotherapy is responsible for early relapses, even at distant brain sites. As GSCs are mostly homing to their “niches” as slowly-dividing GSC-subtype, mimicking a proneural-like non- invasive phenotype PN-genotype, we assume that this, by undergoing an EMT-like transition, GSCs are-reprogrammed to an invasive mesenchymal (MES) GBs/GSCs phenotype in a processes, called PMT (1). However, it is not known, if and by which environmental cues within the niche, this transition of GSCs is induced in vivo. In this work, we are presenting the transriptome data obtained when we exposed GSC spheroids to irradiation alone, TMZ alone and to the combined treatment in vitro and compared their differential genetic fingerprints related to EMT/PMT transition to the GSCs PMT transition, when embedded in their natural microenvironment in the GBM organoid model. The differential gene expression upon GSCs therapeutic perturbation (when alone and vs in the tumoroid microenvironment) will reveal the effects of the major candidate genes, associated with micronevironmendt stromal cells and matrix are contributing their observed EMT/PMT transition of GSCs in vivo. •1. Majc, B., Sever, T., Zarić, M, Breznik, B., Turk, B, Lah Turnšek, T. Epithelial- to-mesenchymal transition as the driver of changing carcinoma and glioblastoma microenvironment. DOI: 10.1016/j.bbamcr.2020.118782

scholarly journals Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2028 ◽  
Author(s):  
Julia Biedermann ◽  
Matthias Preussler ◽  
Marina Conde ◽  
Mirko Peitzsch ◽  
Susan Richter ◽  
...  
Keyword(s):  
Redox State ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Idh1 Mutation ◽  
The Cancer Genome Atlas ◽  
Low Grade ◽  
Dependent Manner ◽  
Glioblastoma Cells ◽  
Isocitrate Dehydrogenase 1 ◽  
Nicotinamide Phosphoribosyltransferase

IDH1R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+), whereas IDH1R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-HG have been the subject of intense research, the 2-HG independent effects of IDH1R132H are still ambiguous. The present study demonstrates that IDH1R132H expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro. Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD+ levels upon IDH1R132H transduction. However, in astrocytes IDH1R132H led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1R132H cells utilize NAD+ to restore NADP pools, which only astrocytes could compensate via induction of NAMPT. We found that the expression of NAMPT is lower in patient-derived IDH1-mutant glioma cells and xenografts compared to IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data analysis confirmed lower NAMPT expression in IDH1-mutant versus IDH1-wildtype gliomas. We show that the IDH1 mutation directly affects the energy homeostasis and redox state in a cell-type dependent manner. Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas.

Delivery and cytotoxicity of doxorubicin and temozolomide to primary glioblastoma cells using gold nanospheres and gold nanorods

2016 ◽  
Vol 8 (1) ◽  
Author(s):  
Jyoti Verma ◽  
Henk A. Van Veen ◽  
Sumit Lal ◽  
Cornelis J.F. Van Noorden
Keyword(s):  
Gold Nanoparticles ◽  
Cell Cultures ◽  
Gold Nanorods ◽  
Silica Coating ◽  
Glioblastoma Cell ◽  
Glioblastoma Cells ◽  
Gold Nanospheres ◽  
Primary Glioblastoma ◽  
Direct Delivery

AbstractNanoparticles with coating entrapping a chemotherapeutic drug for delivery have not been tested for their cytotoxic effects in in-vitro glioblastoma cell cultures to increase treatment efficacy. Therefore, we synthesized silica-coated gold nanorods and gold nanospheres that were loaded with doxorubicin or temozolomide. The morphology of the nanoparticles was characterized using transmission electron microscopy (TEM), the molecular structure was characterized using infrared spectroscopy and in vitro efficacy was determined using glioblastoma cell cultures. TEM analysis showed that gold nanorods had a length of 49–65 nm and a diameter of 8.5–14 nm whereas gold nanospheres had a diameter of 9.5–37 nm. Infrared spectroscopy of doxorubicin and temozolomide and the silica coating revealed molecular fingerprints such as bending, stretching and vibrations of chemical bonds that confirmed the presence of silica coating and drug loading of the gold nanoparticles. In the biological assessment of the effects of drug-loaded gold nanoparticles on primary glioblastoma cell cultures, cytotoxicity, viability and the ratio of cyototoxicity and viability were used as parameters to analyze the effects on the cells of drug delivery via gold nanoparticles on the cells. Our data suggest that doxorubicin in the concentration range of 0.12–3.16 μM when delivered using both gold nanorods and nanospheres induced a 3.8–5.5-fold increased cytotoxicity in comparison to direct delivery. Temozolomide in the concentration range of 4.6–115 μM when delivered by either type of gold nanoparticles induced a 2–4-fold increased cytotoxicity in comparison to direct delivery. Nanospheres were more effective in delivery and cytotoxicity of doxorubicin and temozolomide to glioblastoma cells than gold nanorods. Our data suggest that gold nanoparticles and in particular gold nanospheres are more effective in delivery of doxorubicin and temozolomide to primary glioblastoma cells in culture than direct delivery.

scholarly journals Corneal stromal mesenchymal stem cells: reconstructing a bioactive cornea and repairing the corneal limbus and stromal microenvironment

2021 ◽  
Vol 14 (3) ◽  
pp. 448-455
Author(s):  
Xian-Ning Liu ◽  
◽  
Yun Chen ◽  
Yao Wang ◽  
◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Anterior Part ◽  
Corneal Stroma ◽  
Limbal Stem Cells ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Stromal Microenvironment ◽  
Application Prospects

Corneal stroma-derived mesenchymal stem cells (CS-MSCs) are mainly distributed in the anterior part of the corneal stroma near the corneal limbal stem cells (LSCs). CS-MSCs are stem cells with self-renewal and multidirectional differentiation potential. A large amount of data confirmed that CS-MSCs can be induced to differentiate into functional keratocytes in vitro, which is the motive force for maintaining corneal transparency and producing a normal corneal stroma. CS-MSCs are also an important component of the limbal microenvironment. Furthermore, they are of great significance in the reconstruction of ocular surface tissue and tissue engineering for active biocornea construction. In this paper, the localization and biological characteristics of CS-MSCs, the use of CS-MSCs to reconstruct a tissue-engineered active biocornea, and the repair of the limbal and matrix microenvironment by CS-MSCs are reviewed, and their application prospects are discussed.

scholarly journals Brusatol Inhibits Proliferation and Invasion of Glioblastoma by Down-Regulating the Expression of ECM1

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhang’an Dai ◽  
Lin Cai ◽  
Yingyu Chen ◽  
Silu Wang ◽  
Qian Zhang ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Herbal Extract ◽  
Extracellular Matrix Protein ◽  
Glioblastoma Cells ◽  
Primary Glioblastoma ◽  
Proliferation And Invasion

Brusatol (Bru), a Chinese herbal extract, has a variety of anti-tumor effects. However, little is known regarding its role and underlying mechanism in glioblastoma cells. Here, we found that Bru could inhibit the proliferation of glioblastoma cells in vivo and in vitro. Besides, it also had an inhibitory effect on human primary glioblastoma cells. RNA-seq analysis indicated that Bru possibly achieved these effects through inhibiting the expression of extracellular matrix protein 1 (ECM1). Down-regulating the expression of ECM1 via transfecting siRNA could weaken the proliferation and invasion of glioblastoma cells and promote the inhibitory effect of Bru treatment. Lentivirus-mediated overexpression of ECM1 could effectively reverse this weakening effect. Our findings indicated that Bru could inhibit the proliferation and invasion of glioblastoma cells by suppressing the expression of ECM1, and Bru might be a novel effective anticancer drug for glioblastoma cells.

scholarly journals Anti-vimentin, anti-TUFM, anti-NAP1L1 and anti-DPYSL2 nanobodies display cytotoxic effect and reduce glioblastoma cell migration

2020 ◽  
Vol 12 ◽  
pp. 175883592091530 ◽  
Author(s):  
Alja Zottel ◽  
Ivana Jovčevska ◽  
Neja Šamec ◽  
Jernej Mlakar ◽  
Jernej Šribar ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Migration ◽  
Cell Lines ◽  
Water Soluble ◽  
Glioblastoma Cell ◽  
Glioblastoma Cells ◽  
Mitochondrial Translation ◽  
Cytotoxic Effects ◽  
Glioblastoma Stem Cells ◽  
Glioblastoma Cell Lines

Background: Glioblastoma is a particularly common and very aggressive primary brain tumour. One of the main causes of therapy failure is the presence of glioblastoma stem cells that are resistant to chemotherapy and radiotherapy, and that have the potential to form new tumours. This study focuses on validation of eight novel antigens, TRIM28, nucleolin, vimentin, nucleosome assembly protein 1-like 1 (NAP1L1), mitochondrial translation elongation factor (EF-TU) (TUFM), dihydropyrimidinase-related protein 2 (DPYSL2), collapsin response mediator protein 1 (CRMP1) and Aly/REF export factor (ALYREF), as putative glioblastoma targets, using nanobodies. Methods: Expression of these eight antigens was analysed at the cellular level by qPCR, ELISA and immunocytochemistry, and in tissues by immunohistochemistry. The cytotoxic effects of the nanobodies were determined using AlamarBlue and water-soluble tetrazolium tests. Annexin V/propidium iodide tests were used to determine apoptotsis/necrosis of the cells in the presence of the nanobodies. Cell migration assays were performed to determine the effects of the nanobodies on cell migration. Results: NAP1L1 and CRMP1 were significantly overexpressed in glioblastoma stem cells in comparison with astrocytes and glioblastoma cell lines at the mRNA and protein levels. Vimentin, DPYSL2 and ALYREF were overexpressed in glioblastoma cell lines only at the protein level. The functional part of the study examined the cytotoxic effects of the nanobodies on glioblastoma cell lines. Four of the nanobodies were selected in terms of their specificity towards glioblastoma cells and protein overexpression: anti-vimentin (Nb79), anti-NAP1L1 (Nb179), anti-TUFM (Nb225) and anti-DPYSL2 (Nb314). In further experiments to optimise the nanobody treatment schemes, to increase their effects, and to determine their impact on migration of glioblastoma cells, the anti-TUFM nanobody showed large cytotoxic effects on glioblastoma stem cells, while the anti-vimentin, anti-NAP1L1 and anti-DPYSL2 nanobodies were indicated as agents to target mature glioblastoma cells. The anti-vimentin nanobody also had significant effects on migration of mature glioblastoma cells. Conclusion: Nb79 (anti-vimentin), Nb179 (anti-NAP1L1), Nb225 (anti-TUFM) and Nb314 (anti-DPYSL2) nanobodies are indicated for further examination for cell targeting. The anti-TUFM nanobody, Nb225, is particularly potent for inhibition of cell growth after long-term exposure of glioblastoma stem cells, with minor effects seen for astrocytes. The anti-vimentin nanobody represents an agent for inhibition of cell migration.

scholarly journals Zika Virus with Increased CpG Dinucleotide Frequencies Shows Oncolytic Activity in Glioblastoma Stem Cells

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 579 ◽  
Author(s):  
Ivan Trus ◽  
Nathalie Berube ◽  
Peng Jiang ◽  
Janusz Rak ◽  
Volker Gerdts ◽  
...  
Keyword(s):  
Stem Cells ◽  
Zika Virus ◽  
Brain Cells ◽  
In Ovo ◽  
Glioblastoma Stem Cells ◽  
Oncolytic Therapy ◽  
Cpg Dinucleotide ◽  
Virus Interactions ◽  
Oncolytic Activity

We studied whether cytosine phosphate–guanine (CpG) recoding in a viral genome may provide oncolytic candidates with reduced infection kinetics in nonmalignant brain cells, but with high virulence in glioblastoma stem cells (GSCs). As a model, we used well-characterized CpG-recoded Zika virus vaccine candidates that previously showed genetic stability and safety in animal models. In vitro, one of the CpG-recoded Zika virus variants had reduced infection kinetics in nonmalignant brain cells but high infectivity and oncolytic activity in GSCs as represented by reduced cell proliferation. The recoded virus also efficiently replicated in GSC-derived tumors in ovo with a significant reduction of tumor growth. We also showed that some GSCs may be resistant to Zika virus oncolytic activity, emphasizing the need for personalized oncolytic therapy or a strategy to overcome resistance in GSCs. Collectively, we demonstrated the potential of the CpG recoding approach for oncolytic virus development that encourages further research towards a better understanding of host–tumor–CpG-recoded virus interactions.

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