scholarly journals Satellitosis, a Crosstalk between Neurons, Vascular Structures and Neoplastic Cells in Brain Tumours; Early Manifestation of Invasive Behaviour

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3720
Author(s):  
Prospero Civita ◽  
Ortenzi Valerio ◽  
Antonio Giuseppe Naccarato ◽  
Mark Gumbleton ◽  
Geoffrey J. Pilkington
Keyword(s):  
Brain Tumours ◽  
Current Knowledge ◽  
Glioma Cells ◽  
Tumour Microenvironment ◽  
High Grade ◽  
Critical Knowledge ◽  
Glioma Growth ◽  
Vascular Structures ◽  
Early Manifestation

The secondary structures of Scherer commonly known as perineuronal and perivascular satellitosis have been identified as a histopathological hallmark of diffuse, invasive, high-grade gliomas. They are recognised as perineuronal satellitosis when clusters of neoplastic glial cells surround neurons cell bodies and perivascular satellitosis when such tumour cells surround blood vessels infiltrating Virchow–Robin spaces. In this review, we provide an overview of emerging knowledge regarding how interactions between neurons and glioma cells can modulate tumour evolution and how neurons play a key role in glioma growth and progression, as well as the role of perivascular satellitosis into mechanisms of glioma cells spread. At the same time, we review the current knowledge about the role of perineuronal satellitosis and perivascular satellitosis within the tumour microenvironment (TME), in order to highlight critical knowledge gaps in research space.

scholarly journals Satellitosis, a Crosstalk Between Neurons, Vascular Structures and Neoplastic Cells in Brain Tumours; Early Manifestation of Invasive Behaviour

2020 ◽  
Author(s):  
Prospero Civita ◽  
Valerio Ortenzi ◽  
Antonio Giuseppe Naccarato ◽  
Mark Gumbleton ◽  
Geoffry J. Pilkington
Keyword(s):  
Brain Tumours ◽  
Current Knowledge ◽  
Glioma Cells ◽  
Tumour Microenvironment ◽  
High Grade ◽  
Critical Knowledge ◽  
Glioma Growth ◽  
Vascular Structures ◽  
Early Manifestation

The secondary structures of Scherer commonly known as perineuronal and perivascular satellitosis have been identified as a histopathological hallmark of diffuse, invasive, high-grade gliomas. They are recognized as perineuronal satellitosis when clusters of neoplastic glial cells surround neurons cell bodies and perivascular satellitosis when such tumour cells surround blood vessels infiltrating Virchow-Robin spaces. In this review, we provide an overview of emerging knowledge regarding how interactions between neurons and glioma cells can modulate tumour evolution and how neurons play a key role in glioma growth and progression, as well as the role of perivascular satellitosis into mechanisms of glioma cells spread. At the same time, we review the current knowledge about the role of perineuronal satellitosis and perivascular satellitosis within the tumour microenvironment (TME), in order to highlight critical knowledge gaps in research space.

scholarly journals NLGN3 Upregulates Expression of ADAM10 to Promote the Cleavage of NLGN3 via Activating the LYN Pathway in Human Gliomas

2021 ◽  
Vol 9 ◽  
Author(s):  
Ning-Ning Dang ◽  
Xiao-Bing Li ◽  
Mei Zhang ◽  
Chen Han ◽  
Xiao-Yong Fan ◽  
...  
Keyword(s):  
Glioma Cells ◽  
Feedback Regulation ◽  
Feedback Mechanism ◽  
Therapeutic Window ◽  
Migration And Invasion ◽  
Lower Grade ◽  
Lower Grade Glioma ◽  
Glioma Growth ◽  
The Brain

The neuron derived synaptic adhesion molecular neuroligin-3 (NLGN3) plays an important role in glioma growth. While the role of autocrine NLGN3 in glioma has not been well-studied. The expression of NLGN3 in glioma was detected using immunohistochemistry. We further explored its function and regulatory mechanism in U251 and U87 cells with high expression of NLGN3. Knockdown of endogenous NLGN3 significantly reduced the proliferation, migration, and invasion of glioma cells and down-regulated the activity of the PI3K-AKT, ERK1/2, and LYN signaling pathways. In comparison, overexpression of NLGN3 yielded opposite results. Our results further demonstrate that LYN functions as a feedback mechanism to promote NLGN3 cleavage. This feedback regulation was achieved by upregulating the ADAM10 sheddase responsible for NLGN3 cleavage. Inhibition of ADAM10 suppressed the proliferation, migration, and invasion of glioma cells; oppositely, the expression of ADAM10 was correlated with a higher likelihood of lower grade glioma (LGG) in the brain. Our study demonstrates that glioma-derived NLGN3 promotes glioma progression by upregulating activity of LYN and ADAM10, which in turn promote NLGN3 cleavage to form a positive feedback loop. This pathway may open a potential therapeutic window for the treatment of human glioma.

EXTH-21. MECHANISMS OF SYNERGISTIC GROWTH SUPPRESSION BY RADIOTHERAPY AND C-MET INHIBITION IN EXPERIMENTAL GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi167-vi168
Author(s):  
Manuela Silginer ◽  
Eleanna Papa ◽  
Emese Szabo ◽  
Flavio Vasella ◽  
Patrick Roth ◽  
...  
Keyword(s):  
Immune Responses ◽  
Synergistic Effects ◽  
Glioma Cells ◽  
Immunodeficient Mice ◽  
Glioma Growth ◽  
Pathway Inhibition ◽  
Murine Glioma

Abstract Glioblastoma remains to be one of the most lethal solid cancers and novel therapies are urgently needed. There is increasing interest in the role of the HGF/MET pathway in the response of glioblastoma to radiotherapy. c-MET-mediated radioresistance may be partially induced via proinvasive and DNA damageresponse pathways and HGF may be involved in the regulation of immune responses. Here, we explored the role of the c-MET pathway in response to radiotherapy and investigated potential modes of action that mediate synergistic effects of MET pathway inhibition and irradiation in syngeneic murine glioma models in vitro and in vivo. Murine glioma cells express HGF and c-MET and respond with c-MET phosphorylation upon exposure to exogenous HGF. In vitro, glioma cell viability and proliferation are not affected by pharmacological or genetic c-MET pathway interference, and the c-MET inhibitor tepotinib fails to sensitize glioma cells to irradiation. Conversely, in vivo c-MET inhibition combined with focal radiotherapy synergistically prolongs survival in two syngeneic orthotopic glioma models compared with either treatment alone. Complementary studies demonstrated that synergy was lost when gliomas were established and treated in immunodeficient mice, and importantly, also when c-MET gene expression was disrupted in the tumor. Thus, synergistic suppression of experimental syngeneic glioma growth by irradiation and c-MET inhibition requires at least two mechanisms, expression of c-MET in the tumor and a functional immune system. In summary, our data suggest clinical evaluation of c-MET pathway inhibition in combination with radiotherapy in human glioblastoma.

scholarly journals Interactions between Tumor Cells, Neurons, and Microglia in the Glioma Microenvironment

2020 ◽  
Vol 21 (22) ◽  
pp. 8476
Author(s):  
Daniel P. Radin ◽  
Stella E. Tsirka
Keyword(s):  
Tumor Progression ◽  
Synapse Formation ◽  
Myeloid Cells ◽  
Glioma Cells ◽  
Standard Of Care ◽  
Functional Differences ◽  
Glioma Growth ◽  
Excitotoxic Cell Death ◽  
Glioma Microenvironment

Despite significant strides made in understanding the pathophysiology of high-grade gliomas over the past two decades, most patients succumb to these neoplasias within two years of diagnosis. Furthermore, there are various co-morbidities associated with glioma and standard of care treatments. Emerging evidence suggests that aberrant glutamate secretion in the glioma microenvironment promotes tumor progression and contributes to the development of co-morbidities, such as cognitive defects, epilepsy, and widespread neurodegeneration. Recent data clearly illustrate that neurons directly synapse onto glioma cells and drive their proliferation and spread via glutamatergic action. Microglia are central nervous system-resident myeloid cells, modulate glioma growth, and possess the capacity to prune synapses and encourage synapse formation. However, current literature has yet to investigate the potential role of microglia in shaping synapse formation between neurons and glioma cells. Herein, we present the literature concerning glutamate’s role in glioma progression, involving hyperexcitability and excitotoxic cell death of peritumoral neurons and stimulation of glioma proliferation and invasion. Furthermore, we discuss instances in which microglia are more likely to sculpt or encourage synapse formation during glioma treatment and propose studies to delineate the role of microglia in synapse formation between neurons and glioma cells. The sex-dependent oncogenic or oncolytic actions of microglia and myeloid cells, in general, are considered in addition to the functional differences between microglia and macrophages in tumor progression. We also put forth tractable methods to safely perturb aberrant glutamatergic action in the tumor microenvironment without significantly increasing the toxicities of the standard of care therapies for glioma therapy.

Recent Developments of 18F-FET PET in Neuro-oncology

2018 ◽  
Vol 25 (26) ◽  
pp. 3061-3073 ◽  
Author(s):  
Barbara Muoio ◽  
Luca Giovanella ◽  
Giorgio Treglia
Keyword(s):  
Differential Diagnosis ◽  
Brain Tumours ◽  
Recent Literature ◽  
Metabolic Imaging ◽  
Low Grade ◽  
High Grade ◽  
Fet Pet ◽  
Recent Developments ◽  
High Grade Gliomas

Background: From the past decade to date, several studies related to O-(2- [18F]fluoroethyl)-L-tyrosine (18F-FET) positron emission tomography (PET) in brain tumours have been published in the literature. Objective: The aim of this narrative review is to summarize the recent developments and the current role of 18F-FET PET in brain tumours according to recent literature data. Methods: Main findings from selected recently published and relevant articles on the role of 18F-FET PET in neuro-oncology are described. Results: 18F-FET PET may be useful in the differential diagnosis between brain tumours and non-neoplastic lesions and between low-grade and high-grade gliomas. Integration of 18F-FET PET into surgical planning allows better delineation of the extent of resection beyond margins visible with standard MRI. For biopsy planning, 18F-FET PET is particularly useful in identifying malignant foci within non-contrast-enhancing gliomas. 18F-FET PET may improve the radiation therapy planning in patients with gliomas. This metabolic imaging method may be useful to evaluate treatment response in patients with gliomas and it improves the differential diagnosis between brain tumours recurrence and posttreatment changes. 18F-FET PET may provide useful prognostic information in high-grade gliomas. Conclusion: Based on recent literature data 18F-FET PET may provide additional diagnostic information compared to standard MRI in neuro-oncology.

scholarly journals DDRE-18. THE MITOCHONDRIAL PYRUVATE CARRIER—A METABOLIC TARGET OF MALIGNANT GLIOMA

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i10-i10
Author(s):  
Patricia Tiburcio ◽  
Balazs Murnyak ◽  
Kimberly Coffman ◽  
Eric Huang
Keyword(s):  
Malignant Glioma ◽  
Glial Cells ◽  
Glioma Cells ◽  
Metabolic Reprogramming ◽  
Insulin Sensitizer ◽  
Mitochondrial Pyruvate Carrier ◽  
Glioma Growth ◽  
The Mean ◽  
Malignant Glioma Cells

Abstract Metabolic reprogramming has been recognized as crucial to the survival and proliferation of cancer cells through the reduction of glucose oxidation (the Warburg effect) and diversion of pyruvate and glycolytic metabolites to fuel anabolic processes. The mitochondrial pyruvate carrier (MPC) protein complex, consisting of MPC1 and MPC2, has been identified as essential for pyruvate transport into mitochondria. In most human cancers, MPC1 is frequently deleted or downregulated and, therefore, the MPC activity is low. Restoration of MPC levels increases pyruvate oxidation and markedly inhibits tumor growth. Despite being tumor suppressive in general, the role of MPC in malignant glioma seems complex. We reported previously that unlike MPC1 in IDH-mutant glioma, MPC2 expression correlated with worsened survival. Interestingly, MPC2 homo-oligomers have been identified recently as an efficient autonomous pyruvate transporter, which can be inhibited by an insulin sensitizer rosiglitazone but not by the MPC heterotypic oligomer inhibitor UK-5099. In this study, we report that glioma cells show low MPC1 expression but much higher MPC2 expression. Analysis of glioma patient data revealed that the mean MPC2 expression increased in a grade-dependent fashion whereas the mean MPC1 expression remained essentially low, thereby resulting in an increased MPC2/MPC1 ratio in association with glioma progression. Importantly, we show that malignant glioma cells are extremely sensitive to the mitochondrion-specific, PPARγ-sparing insulin sensitizer mitoglitazone but not UK-5099 whereas MPC-proficient glial cells are highly responsive to the latter, indicating MPC2 as an alternative pyruvate transporter in glioma. Furthermore, the addition of glutamate fully rescues the growth arrest of Mpc1-/- murine glial cells, suggesting the involvement of cerebral cortex-specific microenvironment in glioma growth. We are employing newly developed RCAS/tva Mpc1fl/fl mouse models to test therapeutic targeting of Mpc2 in spontaneously developed glioma.

scholarly journals The Role of Radiotherapy and Chemotherapy in the Treatment of Primary Adult High Grade Gliomas: Assessment of Patients for These Treatment Approaches and the Common Immediate Side Effects

ISRN Oncology ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
E. E. Philip-Ephraim ◽  
K. I. Eyong ◽  
U. E. Williams ◽  
R. P. Ephraim
Keyword(s):  
Side Effects ◽  
Brain Tumours ◽  
World Health Organisation ◽  
World Health ◽  
High Grade ◽  
Primary Brain Tumours ◽  
The World ◽  
The Common ◽  
High Grade Gliomas

Gliomas are the commonest primary brain tumours in adults. They are usually classified and graded according to the criteria by the World Health Organisation. High-grade gliomas are the most malignant primary brain tumours. Conventional therapies include surgery, radiotherapy, and chemotherapy. The tumours often demonstrate high levels of resistance to these conventional therapies, and in spite of treatment advances the prognosis remains poor.

scholarly journals HGG-02. NEUROPHYSIOLOGICAL SMALL MOLECULE SCREEN TO TARGET NEURON-GLIOMA INTERACTIONS IN PEDIATRIC HIGH-GRADE GLIOMAS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i17-i17
Author(s):  
David Rogawski ◽  
Sara Mulinyawe ◽  
Craig Thomas ◽  
Michelle Monje
Keyword(s):  
Ion Channels ◽  
Small Molecule ◽  
Glioma Cells ◽  
High Grade Glioma ◽  
High Grade ◽  
In Vivo Experiments ◽  
Target Neuron ◽  
Glioma Cell Proliferation ◽  
Glioma Growth

Abstract Neurons stimulate glioma growth via synaptic and paracrine signaling mechanisms. We recently demonstrated that neurons form AMPA receptor-dependent synapses with glioma cells, and that neuronal activity also induces potassium-evoked currents that are amplified by gap junctions coupling glioma cells. However, our understanding of the neurotransmitters, receptors, and ion channels participating in neuron-glioma signaling remains incomplete. We have recently developed a high-throughput neuron-glioma co-culture strategy to screen small molecules for agents that may disrupt neuron-glioma signaling. Glioma cell proliferation is increased tenfold when cultured together with neurons; this robust biological effect can be probed in a targeted screen of compounds influencing neurotransmitter receptors and ion channels. The neurophysiological small molecule library used was curated to include approved anti-epileptics, neuroleptics, and antidepressants, as well as a variety of other compounds acting on different neurotransmitter types and ion channels. Hits from the primary screen were run through a counter-screen using glioma cells grown alone without neurons, to identify compounds that specifically affect neuron-glioma interactions. Correlation of the screening results with drug mechanisms of action will allow us to map out the key neurotransmitter pathways regulating glioma growth, which can be further validated using genetic and in vivo experiments. Drugs identified in this glioma neuroscience screen may be readily translated into much-needed therapeutics for children with high-grade glioma.

scholarly journals MiR-450a-5p strengthens the drug sensitivity of gefitinib in glioma chemotherapy via regulating autophagy by targeting EGFR

Oncogene ◽  
2020 ◽  
Vol 39 (39) ◽  
pp. 6190-6202 ◽  
Author(s):  
Yu Liu ◽  
Liang Yang ◽  
Fan Liao ◽  
Wei Wang ◽  
Zhi-Fei Wang
Keyword(s):  
Signaling Pathway ◽  
Drug Sensitivity ◽  
Kinase Inhibitor ◽  
Glioma Cells ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Glioma Growth

Abstract Glioma reported to be refractory to EGFR tyrosine kinase inhibitor is the most common malignant tumor in central nervous system. Our research showed the low expression of miR-450a-5p and high expression of EGFR in glioma tissues. MiR-450a-5p was also observed to synergize with gefitinib to inhibit the proliferation, migration and invasion and induce the apoptosis and autophagy of glioma cells. Furthermore, miR-450a-5p was demonstrated to target 3′UTR of EGFR, and regulated EGFR-induced PI3K/AKT/mTOR signaling pathway. Moreover, the above effects induced by miR-450a-5p in glioma cells were reversed by WIPI1 silencing. The inhibition role of miR-450a-5p on glioma growth was also confirmed in vivo by subcutaneous and intracranial tumor xenografts. Therefore, we conclude that miR-450a-5p synergizes with gefitinib to inhibit the glioma tumorigenesis through inducing autophagy by regulating the EGFR-induced PI3K/AKT/mTOR signaling pathway, thereby enhancing the drug sensitivity of gefitinib.

scholarly journals HGG-05. NEURONAL ACTIVITY PROMOTES PEDIATRIC HIGH-GRADE GLIOMA GROWTH THROUGH A NLGN3-CSPG4 SIGNALING AXIS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i18-i18
Author(s):  
Shawn Gillespie ◽  
Yoon Kim ◽  
Anna Geraghty ◽  
Pamelyn Woo ◽  
Michelle Monje
Keyword(s):  
Neuronal Activity ◽  
Glioma Cells ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
High Grade ◽  
Gamma Secretase ◽  
Intracellular Domain ◽  
Glioma Growth ◽  
Pre Treatment

Abstract High-grade gliomas, including diffuse intrinsic pontine glioma (DIPG), are a lethal group of cancers whose progression is strongly regulated by neuronal activity {Venkatesh 2015}{Venkatesh 2017}{Venkatesh 2019}. One way in which glioma cells sense neuronal activity is via interaction with the ectodomain of post-synaptic adhesion protein neuroligin-3 (NLGN3), which is cleaved and released into the tumor microenvironment (TME) by the sheddase ADAM10. This interaction drives glioma growth, but the relevant binding partner of shed NLGN3 (sNLGN3) on glioma cells is currently unknown. Here, we report that sNLGN3 binds to chondroitin sulfate proteoglycan 4 (CSPG4), in turn inducing regulated intramembrane proteolysis (RIP) of CSPG4, and initiating a signaling cascade within DIPG cells to promote tumor growth. CSPG4 RIP involves activity-regulated ectodomain shedding by ADAM10 and subsequent gamma secretase-mediated release of the intracellular domain in healthy oligodendroglial precursor cells (OPCs), putative cells of origin for several forms of high-grade glioma {Sakry 2014}{Nayak 2018}. Incubation of high-grade glioma cells or healthy OPCs with recombinant NLGN3 is sufficient to augment ADAM10-mediated ectodomain release of CSPG4 and subsequent gamma secretase-mediated cleavage of the CSPG4 intracellular domain (ICD). Pre-treatment of glioma cells or OPCs with an ADAM10 inhibitor entirely blocks NLGN3-induced CSPG4 shedding. Acute depletion of CSPG4 via CRISPR gene editing renders glioma cells insensitive to the growth-promoting effects of NLGN3 application in vitro. We are now performing experiments to better discern how the CSPG4 ICD regulates signaling consequences downstream of sNLGN3 binding. In addition, we are using surface plasmon resonance to investigate whether the shed ectodomains of NLGN3 and CSPG4 remain in complex or only transiently interact. Altogether, our data form a critical missing link in understanding how glioma cells sense, translate and respond to neuronal activity in the TME and identify a new therapeutic target to disrupt neuron-glioma interactions.

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