scholarly journals Acetylcholine Receptor Activation as a Modulator of Glioblastoma Invasion

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1203 ◽  
Author(s):  
Thompson ◽  
Sontheimer
Keyword(s):  
Patient Survival ◽  
Treatment Strategies ◽  
Time Lapse ◽  
Receptor Activation ◽  
Brain Regions ◽  
Primary Brain Tumor ◽  
The Cancer Genome Atlas ◽  
Normal Brain ◽  
Autocrine Signaling ◽  
Calcium Dependent

Grade IV astrocytomas, or glioblastomas (GBMs), are the most common malignant primary brain tumor in adults. The median GBM patient survival of 12–15 months has remained stagnant, in spite of treatment strategies, making GBMs a tremendous challenge clinically. This is at least in part due to the complex interaction of GBM cells with the brain microenvironment and their tendency to aggressively infiltrate normal brain tissue. GBMs frequently invade supratentorial brain regions that are richly innervated by neurotransmitter projections, most notably acetylcholine (ACh). Here, we asked whether ACh signaling influences the biology of GBMs. We examined the expression and function of known ACh receptors (AChRs) in large GBM datasets, as well as, human GBM cell lines and patient-derived xenograft lines. Using RNA-Seq data from the “The Cancer Genome Atlas” (TCGA), we confirmed the expression of AChRs and demonstrated the functionality of these receptors in GBM cells with time-lapse calcium imaging. AChR activation did not alter cell proliferation or migration, however, it significantly increased cell invasion through complex extracellular matrices. This was due to the enhanced activity of matrix metalloproteinase-9 (MMP-9) from GBM cells, which we found to be dependent on an intracellular calcium-dependent mechanism. Consistent with these findings, AChRs were significantly upregulated in regions of GBM infiltration in situ (Ivy Glioblastoma Atlas Project) and elevated expression of muscarinic AChR M3 correlated with reduced patient survival (TCGA). Data from the Repository for Molecular Brain Neoplasia Data (REMBRANDT) dataset also showed the co-expression of choline transporters, choline acetyltransferase, and vesicular acetylcholine transporters, suggesting that GBMs express all the proteins required for ACh synthesis and release. These findings identify ACh as a modulator of GBM behavior and posit that GBMs may utilize ACh as an autocrine signaling molecule.

scholarly journals Transient Activity Induces a Long-Lasting Increase in the Excitability of Olfactory Bulb Interneurons

2008 ◽  
Vol 99 (1) ◽  
pp. 187-199 ◽  
Author(s):  
Tsuyoshi Inoue ◽  
Ben W. Strowbridge
Keyword(s):  
Olfactory Bulb ◽  
Granule Cells ◽  
Receptor Activation ◽  
Brain Regions ◽  
Persistent Activity ◽  
Cellular Mechanisms ◽  
Calcium Dependent ◽  
Transient Activity ◽  
Olfactory Bulb Slices ◽  
Processing And Storage

Little is known about the cellular mechanisms that underlie the processing and storage of sensory in the mammalian olfactory system. Here we show that persistent spiking, an activity pattern associated with working memory in other brain regions, can be evoked in the olfactory bulb by stimuli that mimic physiological patterns of synaptic input. We find that brief discharges trigger persistent activity in individual interneurons that receive slow, subthreshold oscillatory input in acute rat olfactory bulb slices. A 2- to 5-Hz oscillatory input, which resembles the synaptic drive that the olfactory bulb receives during sniffing, is required to maintain persistent firing. Persistent activity depends on muscarinic receptor activation and results from interactions between calcium-dependent afterdepolarizations and low-threshold Ca spikes in granule cells. Computer simulations suggest that intrinsically generated persistent activity in granule cells can evoke correlated spiking in reciprocally connected mitral cells. The interaction between the intrinsic currents present in reciprocally connected olfactory bulb neurons constitutes a novel mechanism for synchronized firing in subpopulations of neurons during olfactory processing.

scholarly journals Treatment Strategies Based on Histological Targets against Invasive and Resistant Glioblastoma

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Akira Hara ◽  
Tomohiro Kanayama ◽  
Kei Noguchi ◽  
Ayumi Niwa ◽  
Masafumi Miyai ◽  
...  
Keyword(s):  
Glioma Cell ◽  
Treatment Strategies ◽  
Secondary Structures ◽  
Primary Brain Tumor ◽  
Therapeutic Interventions ◽  
High Recurrence Rate ◽  
Normal Brain ◽  
Biological Targets ◽  
Glioma Cell Migration ◽  
Histopathological Evidence

Glioblastoma (GBM) is the most common and the most malignant primary brain tumor and is characterized by rapid proliferation, invasion into surrounding normal brain tissues, and consequent aberrant vascularization. In these characteristics of GBM, invasive properties are responsible for its recurrence after various therapies. The histomorphological patterns of glioma cell invasion have often been referred to as the “secondary structures of Scherer.” The “secondary structures of Scherer” can be classified mainly into four histological types as (i) perineuronal satellitosis, (ii) perivascular satellitosis, (iii) subpial spread, and (iv) invasion along the white matter tracts. In order to develop therapeutic interventions to mitigate glioma cell migration, it is important to understand the biological mechanism underlying the formation of these secondary structures. The main focus of this review is to examine new molecular pathways based on the histopathological evidence of GBM invasion as major prognostic factors for the high recurrence rate for GBMs. The histopathology-based pharmacological and biological targets for treatment strategies may improve the management of invasive and resistant GBMs.

scholarly journals Data analysis of high-throughput sequencing and microarray to identify key signatures of microribonucleic acids in glioblastoma

2021 ◽  
Vol 8 (3) ◽  
pp. 21-33
Author(s):  
A. A. Pushkin ◽  
E. A. Dzenkova ◽  
N. N. Timoshkina ◽  
D. Yu. Gvaldin
Keyword(s):  
Mirna Expression ◽  
High Throughput Sequencing ◽  
Patient Survival ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Differential Expression Analysis ◽  
The Cancer Genome Atlas ◽  
Normal Brain ◽  
Sequencing Data ◽  
Tissue Samples

Purpose of the study. This research was devoted to study of mRNA and miRNA expression patterns in glioglastomas using The Cancer Genome Atlas (TCGA) data, to search for genetic determinants that determine the prognosis of patient survival and to create of interaction networks for glioblastomas.Materials and methods. Based on the data of the open TCGA database groups of glioblastomas and conventionally normal brain tissue samples were formed. Survival gene and miRNA expression data were extracted for each sample. After the data stratification by groups the differential expression analysis and search the genes affecting patient survival was carried out. The enrichment analysis by functional affiliation and an interactome analysis were performed.Results. A total of 156 glioblastoma samples with mRNA sequencing data, 571 samples with microarray microRNA analysis data, and 15 control samples were analyzed. Networks of mRNA-miRNA interactions were built and expression profiles of genes and miRNAs characteristic of glioblastomas were developed. We have determined the genes which aberrant level is associated with survival and shown the pairwise DEG and DE of microRNA correlations.Conclusion. The microRNA-mRNA regulatory pairs identified for glioblastomas can stimulate the development of new therapeutic approaches based on subtype-specific regulatory mechanisms of oncogenesis.

scholarly journals Association of collagen architecture with glioblastoma patient survival

2016 ◽  
Vol 126 (6) ◽  
pp. 1812-1821 ◽  
Author(s):  
Kelli B. Pointer ◽  
Paul A. Clark ◽  
Alexandra B. Schroeder ◽  
M. Shahriar Salamat ◽  
Kevin W. Eliceiri ◽  
...  
Keyword(s):  
Patient Survival ◽  
Second Harmonic ◽  
Primary Brain Tumor ◽  
Collagen Fibers ◽  
Normal Brain ◽  
Direct Visualization ◽  
Second Harmonic Generation Microscopy ◽  
Multivariate Survival ◽  
Custom Software ◽  
Picrosirius Red

OBJECTIVEGlioblastoma (GBM) is the most malignant primary brain tumor. Collagen is present in low amounts in normal brain, but in GBMs, collagen gene expression is reportedly upregulated. However, to the authors' knowledge, direct visualization of collagen architecture has not been reported. The authors sought to perform the first direct visualization of GBM collagen architecture, identify clinically relevant collagen signatures, and link them to differential patient survival.METHODSSecond-harmonic generation microscopy was used to detect collagen in a GBM patient tissue microarray. Focal and invasive GBM mouse xenografts were stained with Picrosirius red. Quantitation of collagen fibers was performed using custom software. Multivariate survival analysis was done to determine if collagen is a survival marker for patients.RESULTSIn focal xenografts, collagen was observed at tumor brain boundaries. For invasive xenografts, collagen was intercalated with tumor cells. Quantitative analysis showed significant differences in collagen fibers for focal and invasive xenografts. The authors also found that GBM patients with more organized collagen had a longer median survival than those with less organized collagen.CONCLUSIONSCollagen architecture can be directly visualized and is different in focal versus invasive GBMs. The authors also demonstrate that collagen signature is associated with patient survival. These findings suggest that there are collagen differences in focal versus invasive GBMs and that collagen is a survival marker for GBM.

scholarly journals Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0241766
Author(s):  
Young H. Lee ◽  
Molly M. Lee ◽  
Dinuka M. De Silva ◽  
Arpita Roy ◽  
Cara E. Wright ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tyrosine Kinases ◽  
Patient Survival ◽  
Receptor Activation ◽  
The Cancer Genome Atlas ◽  
Transcriptional Activators ◽  
Data Set ◽  
Specific Patient ◽  
Mesenchymal Transition ◽  
Group 1

Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes.

scholarly journals Local autocrine signaling of IGF1 synthesized and released by CA1 pyramidal neurons regulates plasticity of dendritic spines

2021 ◽  
Author(s):  
Xun Tu ◽  
Anant Jain ◽  
Helena Decker ◽  
Ryohei Yasuda
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spines ◽  
Pyramidal Neurons ◽  
Receptor Activation ◽  
Brain Regions ◽  
Dependent Manner ◽  
Autocrine Signaling ◽  
Ca1 Pyramidal Neurons ◽  
Igf1 Receptor ◽  
Activity Dependent

Insulin-like growth factor 1 (IGF1) regulates hippocampal plasticity, learning, and memory. While circulating, liver-derived IGF1 is known to play an essential role in hippocampal function and plasticity, IGF1 is also synthesized in multiple brain regions, including the hippocampus. However, little is known about the role of hippocampus-derived IGF1 in synaptic plasticity, the type of cells that may provide relevant IGF1, and the spatiotemporal dynamics of IGF1 signaling. Here, using a new FRET sensor for IGF1 signaling, we show that IGF1 in the hippocampus is primarily synthesized in CA1 pyramidal neurons and released in an activity-dependent manner in mice. The local IGF1 release from dendritic spines triggers local autocrine IGF1 receptor activation on the same spine, regulating structural and electrophysiological plasticity of the activated spine. Thus, our study demonstrates a novel mechanism underlying synaptic plasticity by the synthesis and autocrine signaling of IGF1 specific to CA1 pyramidal neurons.

BIOM-33. EV-ASSOCIATED IL13Ra2 AS A LIQUID BIOPSY BIOMARKER FOR GBM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi18-vi18
Author(s):  
Vladimir Khristov ◽  
Darya Nesterova ◽  
Brad Zacharia ◽  
James Connor ◽  
Achuthamangalam Madhankumar
Keyword(s):  
Extracellular Vesicles ◽  
Liquid Biopsy ◽  
Clinical Characteristics ◽  
Patient Survival ◽  
Disease Status ◽  
Primary Brain Tumor ◽  
Response To Therapy ◽  
Diagnostic Methods ◽  
Normal Brain ◽  
Normal Brain Tissue

Abstract Glioblastoma (GBM) is both the most common and deadly malignant primary brain tumor with a 1-year survival of 37.2% and a 5-year survival of just 5.1%. Despite advances in imaging technology, distinguishing between pseudoprogression and pseudoresponse remains problematic and there is a dire need for additional diagnostic methods. Tumor-derived extracellular vesicles are found in a variety of biofluids and are good candidates for a liquid biopsy. A unique characteristic of GBM is the overexpression of the α2 variant of IL-13 receptor (IL13Rα2) in 78-96% of patients while virtually undetectable in normal brain tissue. We hypothesize that biofluids of patients with GBM contains sufficient IL13Rα2-positive extracellular vesicles (EV) to inform the clinical picture regarding disease status such as tumor recurrence and response to therapy. We have measured the levels of IL13Rα2 in the EV fraction of plasma from GBM patients and correlated these levels to patient survival, and patient clinical characteristics (n=35). We have demonstrated that the EV fraction of some patients with GBM is enriched for the IL13Rα2 receptor. The plasma level of IL13Rα2 could also predict the level of IL13Rα2 in the GBM tumor (n=9). Further, IL13Rα2 positive EVs from patient-derived GBM cell lines could be immunoprecipitated for further interrogation of genomic and proteomic molecular markers. These exciting findings lay the groundwork for a GBM liquid biopsy based on tumor-specific EVs in patient biofluids.

scholarly journals Autocrine Signaling by Receptor Tyrosine Kinases in Urothelial Carcinoma of the Bladder

2020 ◽  
Author(s):  
Young H. Lee ◽  
Molly M. Lee ◽  
Dinuka M. De Silva ◽  
Arpita Roy ◽  
Cara Wright ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tyrosine Kinases ◽  
Patient Survival ◽  
Receptor Activation ◽  
The Cancer Genome Atlas ◽  
Transcriptional Activators ◽  
Data Set ◽  
Specific Patient ◽  
Mesenchymal Transition ◽  
Group 1

AbstractComprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes.

Radiotherapy for Brain Tumors: Current Practice and Future Directions

2020 ◽  
Vol 16 (3) ◽  
pp. 182-195
Author(s):  
Sarah Baker ◽  
Natalie Logie ◽  
Kim Paulson ◽  
Adele Duimering ◽  
Albert Murtha
Keyword(s):  
Brain Tumors ◽  
Treatment Strategies ◽  
Brain Parenchyma ◽  
Benign Tumors ◽  
Tumor Control ◽  
Normal Brain ◽  
Neurocognitive Deficits ◽  
Close Proximity ◽  
Recent Developments ◽  
High Level

Radiotherapy is an important component of the treatment for primary and metastatic brain tumors. Due to the close proximity of critical structures and normal brain parenchyma, Central Nervous System (CNS) radiotherapy is associated with adverse effects such as neurocognitive deficits, which must be weighed against the benefit of improved tumor control. Advanced radiotherapy technology may help to mitigate toxicity risks, although there is a paucity of high-level evidence to support its use. Recent advances have been made in the treatment for gliomas, meningiomas, benign tumors, and metastases, although outcomes remain poor for many high grade tumors. This review highlights recent developments in CNS radiotherapy, discusses common treatment toxicities, critically reviews advanced radiotherapy technologies, and highlights promising treatment strategies to improve clinical outcomes in the future.

scholarly journals CSIG-03. RECONCILING TUMOR HETEROGENEITY IN GLIOBLASTOMA USING A PATHWAY-BASED APPROACH

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii28-ii28
Author(s):  
Alvaro Alvarado ◽  
Kaleab Tessema ◽  
Kunal Patel ◽  
Riki Kawaguchi ◽  
Richard Everson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Patient Survival ◽  
Molecular Subtype ◽  
Gene List ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Molecular Architecture ◽  
Survival Pathways ◽  
Cancer Genome Atlas

Abstract Despite efforts to gain a deeper understanding of its molecular architecture, glioblastoma (GBM) remains uniformly fatal. While genome-based molecular subtyping has revealed that GBMs may be parsed into several molecularly distinct categories, this insight has yielded little progress towards extending patient survival. In particular, the great phenotypic heterogeneity of GBM – both inter and intratumorally – has hindered therapeutic efforts. To this end, we interrogated tumor samples using a pathway-based approach to resolve tumoral heterogeneity. Gene set enrichment analysis (GSEA) was applied to gene expression data and used to provide an overview of each sample that can be compared to other samples by generating sample clusters based on overall patterns of enrichment. The Cancer Genome Atlas (TCGA) samples were clustered using the canonical and oncogenic signatures and in both cases the clustering was distinct from the molecular subtype previously reported and clusters were informative of patient survival. We also analyzed single cell RNA sequencing datasets and uniformly found two clusters of cells enriched for cell cycle regulation and survival pathways. We have validated our approach by generating gene lists from common elements found in the top contributing genesets for a particular cluster and testing the top targets in appropriate gliomasphere patient-derived lines. Samples enriched for cell cycle related genesets showed a decrease in sphere formation capacity when E2F1, out top target, was silenced and when treated with fulvestrant and calcitriol, which were identified as potential drugs targeting this genelist. Conversely, no changes were observed in samples not enriched for this gene list. Finally, we interrogated spatial heterogeneity and found higher enrichment of the proliferative signature in contrast enhancing compared with non-enhancing regions. Our studies relate inter- and intratumoral heterogeneity to critical cellular pathways dysregulated in GBM, with the ultimate goal of establishing a pipeline for patient- and tumor-specific precision medicine.

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