P48 * AFM STIFFNESS MEASUREMENTS OF GLIOMA CELLS AND CYTOSKELETAL PROTEIN ANALYSIS FOLLOWING CD44 KNOCKDOWN: IMPLICATIONS FOR GLIOMA CELL INVASION

To investigate the effect of geldanamycin (GDM) on the invasion ability of glioma cell induced by hepatocyte growth factor (HGF). Malignant glioma cell line U251-MG and U87-MG were cultured’and the capability of cell invasion was detected using a Transwell culture system. HGF significantly promoted the invasion ability of both U251-MG and U87-MG cells as compared with the normal control (NC) (P < 0.05). Forty eight hours after GDM treatment, the invasive growth of glioma cells was significantly decreased as compared with either NC or HGF group (P < 0.05). When cells were exposed to GDM plus HGF for 48 h, the cell invasion capability was greatly reduced as compared with either NC or HGF group (P < 0.05). The number of invaded cells in GDM plus HGF group was similar to that of GDM group.GDM can inhibit the invasion ability of glioma cells induced by HGF.

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TAMI-52. NEURONAL MECHANISMS OF BRAIN TUMOR INVASION

Neuro-Oncology ◽

10.1093/neuonc/noab196.835 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi209-vi209

Author(s):

Varun Venkataramani ◽

Yvonne Yang ◽

Marc Schubert ◽

Carlo Beretta ◽

Michael Botz ◽

...

Keyword(s):

Brain Tumor ◽

Neuronal Activity ◽

Cell Invasion ◽

Glioma Cell ◽

Tumour Progression ◽

Glioma Cells ◽

Movement Patterns ◽

Calcium Transients ◽

High Temporal Resolution ◽

Branching Points

Abstract Incurable gliomas are characterized by their infiltration into the whole brain. Recently, we described tumor microtubes as a novel structure contributing to glioma cell invasion and uncovered synaptic contacts on glioma cells that drive brain tumour progression. However, the exact effects of neuronal activity on glioma cell motility are yet unclear. Here, we show how a recently described neuronal-like cellular transcription state of glioblastoma cells is correlated to glioma cell invasion in vivo. To unravel the details of neuronal features of glioma invasion in space and time, we established a novel approach of intravital imaging for brain tumor cells with a membrane-bound GFP combined with deep learning algorithms that are used to track glioma cell processes with a high temporal resolution over several hours. This approach uncovers how invading tumor microtubes use Levy-like movement patterns indicative of efficient search patterns often employed by animal predators searching for scarce resources such as food. Neuronal activity is able to accelerate the tumor microtube dynamics, accelerate the Levy-like movement patterns and increase the overall invasion speed of glioma cells. These processes are mediated by local calcium transients in glioma cell somata and tumor microtubes. In accordance, genetic manipulation and pharmacological perturbation of AMPA receptors reduces tumor microtube length, number and branching points by interfering with intracellular calcium transients. All in all, the work here uncovers novel neuronal activity-mediated mechanisms of glioma cell invasion, a hallmark of this yet fatal disease.

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Geldanamycin inhibits migration of glioma cells in vitro: A potential role for hypoxia-inducible factor (HIF-1?) in glioma cell invasion

Journal of Cellular Physiology ◽

10.1002/jcp.10306 ◽

2003 ◽

Vol 196 (2) ◽

pp. 394-402 ◽

Cited By ~ 78

Author(s):

David Zagzag ◽

Motohiro Nomura ◽

David R. Friedlander ◽

CY Blanco ◽

Jean-Pierre Gagner ◽

...

Keyword(s):

Cell Invasion ◽

Glioma Cell ◽

Potential Role ◽

Hypoxia Inducible Factor ◽

Glioma Cells

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Human Malignant Glioma Cells Migrate to Fibronectin and Laminin: Role of Extracellular Matrix Components in Glioma Cell Invasion

Biological Aspects of Brain Tumors ◽

10.1007/978-4-431-68150-2_57 ◽

1991 ◽

pp. 408-415 ◽

Cited By ~ 2

Author(s):

Takanori Ohnishi ◽

Norio Arita ◽

Shoju Hiraga ◽

Masahide Higuchi ◽

Toru Hayakawa

Keyword(s):

Extracellular Matrix ◽

Malignant Glioma ◽

Cell Invasion ◽

Glioma Cell ◽

Glioma Cells ◽

Extracellular Matrix Components ◽

Human Malignant Glioma ◽

Matrix Components ◽

Malignant Glioma Cells

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Transfection of glioma cells with the neural-cell adhesion molecule NCAM: Effect on glioma-cell invasion and growthin vivo

International Journal of Cancer ◽

10.1002/ijc.2910580119 ◽

1994 ◽

Vol 58 (1) ◽

pp. 116-122 ◽

Cited By ~ 55

Author(s):

Klaus Edvardsen ◽

Paal-Henning Pedersen ◽

Rolf Bjerkvig ◽

Gregers G. Hermann ◽

Jesper Zeuthen ◽

...

Keyword(s):

Cell Adhesion ◽

Adhesion Molecule ◽

Cell Invasion ◽

Glioma Cell ◽

Cell Adhesion Molecule ◽

Neural Cell Adhesion Molecule ◽

Glioma Cells ◽

Neural Cell ◽

Neural Cell Adhesion

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Inhibition of glioblastoma cell invasion by hsa-miR-145-5p and hsa-miR-31-5p co-overexpression in human mesenchymal stem cells

Journal of Neurosurgery ◽

10.3171/2017.8.jns1788 ◽

2018 ◽

Vol 130 (1) ◽

pp. 44-55 ◽

Cited By ~ 5

Author(s):

Ryota Kurogi ◽

Akira Nakamizo ◽

Satoshi O. Suzuki ◽

Masahiro Mizoguchi ◽

Koji Yoshimoto ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Invasion ◽

Glioma Cell ◽

Malignant Gliomas ◽

Brain Slices ◽

Glioma Cells ◽

Dependent Manner ◽

Study Results ◽

U87 Cells

OBJECTIVEHuman bone marrow–derived mesenchymal stem cells (hMSCs) show tropism for brain tumors and may be a useful vehicle for drug or gene delivery to malignant gliomas. Recently, some microRNAs (miRNAs) have been shown to suppress the invasiveness of malignant gliomas.METHODSTo test their potential to become vehicles for the delivery of miRNA to malignant gliomas, hMSCs were engineered so that hMSC secretion of miRNAs that inhibit glioma cell invasion was enabled without altering the hMSC tropism for glioma cells.RESULTSIn coculture, hMSCs cotransfected with hsa-miR-145-5p and -31-5p miRNAs showed markedly reduced invasion by U87 glioma cells in a contact-dependent manner both in vitro and ex vivo, with invasion of hMSCs cotransfected with these 2 miRNAs by the U87 cells reduced to 60.7% compared with control cells. According to a Matrigel invasion assay, the tropism of the hMSCs for U87 cells was not affected. In glioma cell lines U251 and LN229, hMSCs exhibited tropism in vivo, and invasion of hMSCs cotransfected with hsa-miR-145-5p and -31-5p was also significantly less than that of control cells. When U87 cells were coimplanted into the striatum of organotypic rat brain slices with hMSCs cotransfected with hsa-miR-145 and -31-5p, the relative invasive area decreased by 37.1%; interestingly, these U87 cells showed a change to a rounded morphology that was apparent at the invasion front. Whole-genome microarray analysis of the expression levels of 58,341 genes revealed that the co-overexpression of hsa-miR-145-5p and -31-5p downregulated FSCN1 expression in U87 cells.CONCLUSIONSThis study demonstrates that miRNA overexpression in hMSCs can alter the function of glioma cells via contact-dependent transfer. Co-overexpression of multiple miRNAs may be a useful and novel therapeutic strategy. The study results suggest that hMSCs can be applied as a delivery vehicle for miRNAs.

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P13.01 Neuronal activity drives distinct invasion modes of glioma cells

Neuro-Oncology ◽

10.1093/neuonc/noab180.112 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii32-ii33

Author(s):

Y Yang ◽

V Venkataramani ◽

M Schubert ◽

C Beretta ◽

M Botz ◽

...

Keyword(s):

Brain Tumors ◽

Cell Motility ◽

Neuronal Activity ◽

Cell Invasion ◽

Glioma Cell ◽

Molecular Mechanisms ◽

Glioma Cells ◽

Machine Learning Algorithms ◽

Cell Dynamics ◽

Whole Brain

Abstract BACKGROUND Gliomas are incurable brain tumors characterized by their infiltrative growth which makes them a whole-brain disease. Previously we described membrane protrusions called tumor microtubes (TMs), and glutamatergic synapses between neurons and glioma cells, as mechanisms contributing to glioma cell invasion and tumor progression. However, the interrelation of the two, and the exact mechanisms of glioma cell dynamics over time was unknown. Therefore, we investigate neuronal synaptic input on TM-associated glioma cell motility. MATERIAL AND METHODS Here we established a novel workflow for analyzing single glioma cell dynamics over several hours with in-vivo two-photon microscopy. First, a membranous fluorescent marking of patient-derived glioma cells was established to reliably track membrane changes. Secondly, augmented microscopy based on deep- and machine-learning algorithms was used to track glioma cells. Neuronal activity was manipulated with different doses of isoflurane anesthesia, and used to study its effects on glioma cell dynamics. RESULTS This novel method revealed that motility of glioma cells can be described by the displacement of whole glioma cell somata (somatokinesis) and TM dynamics. TM motility in turn could be sub-categorized into protrusion, retraction and branching. Next, we describe three different invasion modes, all with similarities to different cell types involved in CNS development. Lastly, the effects of neuronal activity on glioma cell invasion were investigated. With the application of high anesthesia and subsequently reduced neuronal activity, TM turnover, branching events and as a result glioma cell invasion were inhibited, but in a heterogeneous manner. CONCLUSION The novel workflow allowed to comprehensively characterize glioma cell invasion over several hours. Its application demonstrates novel, hitherto unknown cellular mechanisms of glioma cell invasion, and provides a link between TM biology and neuron-glioma communication. Finally, neuronal input drives distinct subtypes of glioma cell motility patterns.All in all, this work presents an important first step in understanding mechanisms that lead to the whole- brain colonization of glioma cells making these brain tumors incurable. A further characterization of the exact molecular mechanisms that drive neuronal activity-dependent glioma cell motility is warranted.

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Pisosterol Induces G2/M Cell Cycle Arrest and Apoptosis via the ATM/ATR Signaling Pathway in Human Glioma Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200203160117 ◽

2020 ◽

Vol 20 (6) ◽

pp. 734-750

Author(s):

Wallax A.S. Ferreira ◽

Rommel R. Burbano ◽

Claudia do Ó. Pessoa ◽

Maria L. Harada ◽

Bárbara do Nascimento Borges ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Signaling Pathway ◽

Glioma Cell ◽

Molecular Mechanisms ◽

Glioma Cells ◽

Dependent Manner ◽

M Cell ◽

Trypan Blue Exclusion ◽

Cycle Arrest

Background: Pisosterol, a triterpene derived from Pisolithus tinctorius, exhibits potential antitumor activity in various malignancies. However, the molecular mechanisms that mediate the pisosterol-specific effects on glioma cells remain unknown. Objective: This study aimed to evaluate the antitumoral effects of pisosterol on glioma cell lines. Methods: The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue exclusion assays were used to evaluate the effect of pisosterol on cell proliferation and viability in glioma cells. The effect of pisosterol on the distribution of the cells in the cell cycle was performed by flow cytometry. The expression and methylation pattern of the promoter region of MYC, ATM, BCL2, BMI1, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, MDM2, p14ARF and TP53 was analyzed by RT-qPCR, western blotting and bisulfite sequencing PCR (BSP-PCR). Results: Here, it has been reported that pisosterol markedly induced G2/M arrest and apoptosis and decreased the cell viability and proliferation potential of glioma cells in a dose-dependent manner by increasing the expression of ATM, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, p14ARF and TP53 and decreasing the expression of MYC, BCL2, BMI1 and MDM2. Pisosterol also triggered both caspase-independent and caspase-dependent apoptotic pathways by regulating the expression of Bcl-2 and activating caspase-3 and p53. Conclusions: It has been, for the first time, confirmed that the ATM/ATR signaling pathway is a critical mechanism for G2/M arrest in pisosterol-induced glioma cell cycle arrest and suggests that this compound might be a promising anticancer candidate for further investigation.

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CSIG-13. TRPM7 INDUCES TUMORIGENESIS AND STEMNESS THROUGH NOTCH ACTIVATION IN GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.125 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii30-ii30

Author(s):

Jingwei Wan ◽

Alyssa Guo ◽

Mingli Liu

Keyword(s):

Notch Signaling ◽

Glioma Cell ◽

Glioma Cells ◽

Inhibitory Effect ◽

Notch Signaling Pathway ◽

Normal Brain ◽

Diffuse Astrocytoma ◽

Notch1 Signaling ◽

Signaling Activation ◽

Proliferation And Invasion

Abstract Our group found that the inhibitory effect of TRPM7 on proliferation and invasion of human glioma cell is mediated by multiple mechanisms. TRPM7 regulates miR-28-5p expression, which suppresses cell proliferation and invasion in glioma cells by targeting Ras-related protein Rap1b. In particular, our group found that TRPM7 channels regulate glioma stem cell (GSC) growth/proliferation through STAT3 and Notch signaling. However, which Notch component(s) is crucial for its activity regulated by TRPM7, and its relationship with other GSC markers, such as CD133 and ALDH1, remain unclear. In the current project, we elucidate the mechanisms of TRMP7’s regulation of Notch signaling pathway that contribute to the development and progression of glioma and maintenance of self-renewal and tumorigenicity of GSC using multiple glioma cell lines (GC) with different molecular subtypes and GSCs derived from the GC lines. 1) We first analyzed TRPM7 expression using the Oncomine database (https://www.oncomine.org) and found that the TRPM7 mRNA expression is significantly increased in anaplastic astrocytoma, diffuse astrocytoma, and GBM patients compared to that in normal brain tissue controls. 2) TRPM7 is expressed in GBM, and its channel activity is correlated with Notch1 activation. Inhibition of TRPM7 downregulates Notch1 signaling, while upregulation of TRPM7 upregulates Notch1 signaling. 3) GSC markers, CD133 and ALDH1, are correlated with TRPM7 in GBM. 4) Targeting TRPM7 suppresses the growth and proliferation of glioma cells through G1/S arrests and apoptosis of glioma cells. 5) Targeting Notch1 suppresses the TRPM7-induced growth and proliferation of glioma cells, as well as the expression of GSC markers CD133 and ALDH1. In summary, TRPM7 is responsible for sustained Notch signaling activation, enhanced expression of GSC markers, and regulation of glioma stemness, which contribute to malignant glioma cell growth and invasion. Notch1 and ligand DII4 are key components that contribute GSC stemness.

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