-
Cancers Dec 2020The secondary structures of Scherer commonly known as perineuronal and perivascular satellitosis have been identified as a histopathological hallmark of diffuse,... (Review)
Review
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.
PubMed: 33322379
DOI: 10.3390/cancers12123720 -
Neuro-oncology Advances 2021Gliomas typically escape surgical resection and recur due to their "diffuse invasion" phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma....
BACKGROUND
Gliomas typically escape surgical resection and recur due to their "diffuse invasion" phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the "diffuse invasion" phenotype, designated the Scherer's secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown.
METHODS
We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients.
RESULTS
Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients.
CONCLUSIONS
Targeting the transporter Glut1 suppresses the unique phenotype, "diffuse invasion" in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.
PubMed: 33506198
DOI: 10.1093/noajnl/vdaa150 -
Neuro-oncology Sep 2018Perineuronal satellitosis, the microanatomical clustering of glioma cells around neurons in the tumor microenvironment, has been recognized as a histopathological... (Review)
Review
Perineuronal satellitosis, the microanatomical clustering of glioma cells around neurons in the tumor microenvironment, has been recognized as a histopathological hallmark of high-grade gliomas since the seminal observations of Scherer in the 1930s. In this review, we explore the emerging understanding that neuron‒glioma cell interactions regulate malignancy and that neuronal activity is a critical determinant of glioma growth and progression. Elucidation of the interplay between normal and malignant neural circuitry is critical to realizing the promise of effective therapies for these seemingly intractable diseases. Here, we review current knowledge regarding the role of neuronal activity in the glioma microenvironment and highlight critical knowledge gaps in this burgeoning research space.
Topics: Animals; Brain Neoplasms; Disease Progression; Glioma; Humans; Neurons; Tumor Microenvironment
PubMed: 29788372
DOI: 10.1093/neuonc/noy083 -
Journal of Oncology 2019Glioblastoma (GBM) is the most common and the most malignant primary brain tumor and is characterized by rapid proliferation, invasion into surrounding normal brain... (Review)
Review
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.
PubMed: 31320900
DOI: 10.1155/2019/2964783 -
The American Journal of Pathology Jun 2023Because of their ability to infiltrate normal brain tissue, gliomas frequently evade microscopic surgical excision. The histologic infiltrative property of human glioma... (Review)
Review
Because of their ability to infiltrate normal brain tissue, gliomas frequently evade microscopic surgical excision. The histologic infiltrative property of human glioma has been previously characterized as Scherer secondary structures, of which the perivascular satellitosis is a prospective target for anti-angiogenic treatment in high-grade gliomas. However, the mechanisms underlying perineuronal satellitosis remain unclear, and therapy remains lacking. Our knowledge of the mechanism underlying Scherer secondary structures has improved over time. New techniques, such as laser capture microdissection and optogenetic stimulation, have advanced our understanding of glioma invasion mechanisms. Although laser capture microdissection is a useful tool for studying gliomas that infiltrate the normal brain microenvironment, optogenetics and mouse xenograft glioma models have been extensively used in studies demonstrating the unique role of synaptogenesis in glioma proliferation and identification of potential therapeutic targets. Moreover, a rare glioma cell line is established that, when transplanted in the mouse brain, can replicate and recapitulate the human diffuse invasion phenotype. This review discusses the primary molecular causes of glioma, its histopathology-based invasive mechanisms, and the importance of neuronal activity and interactions between glioma cells and neurons in the brain microenvironment. It also explores current methods and models of gliomas.
Topics: Humans; Mice; Animals; Brain Neoplasms; Glioma; Brain; Neurons; Cell Line; Disease Models, Animal; Neoplasm Invasiveness; Tumor Microenvironment
PubMed: 37286277
DOI: 10.1016/j.ajpath.2023.02.018 -
Frontiers in Oncology 2019Laser capture microdissection (LCM) coupled with RNA-seq is a powerful tool to identify genes that are differentially expressed in specific histological tumor subtypes....
Laser capture microdissection (LCM) coupled with RNA-seq is a powerful tool to identify genes that are differentially expressed in specific histological tumor subtypes. To better understand the role of single tumor cell populations in the complex heterogeneity of glioblastoma, we paired microdissection and NGS technology to study intra-tumoral differences into specific histological regions and cells of human GBM FFPE tumors. We here isolated astrocytes, neurons and endothelial cells in 6 different histological contexts: tumor core astrocytes, pseudopalisading astrocytes, perineuronal astrocytes in satellitosis, neurons with satellitosis, tumor blood vessels, and normal blood vessels. A customized protocol was developed for RNA amplification, library construction, and whole transcriptome analysis of each single portion. We first validated our protocol comparing the obtained RNA expression pattern with the gene expression levels of RNA-seq raw data experiments from the BioProject NCBI database, using Spearman's correlation coefficients calculation. We found a good concordance for pseudopalisading and tumor core astrocytes compartments (0.5 Spearman correlation) and a high concordance for perineuronal astrocytes, neurons, normal, and tumor endothelial cells compartments (0.7 Spearman correlation). Then, Principal Component Analysis and differential expression analysis were employed to find differences between tumor compartments and control tissue and between same cell types into distinct tumor contexts. Data consistent with the literature emerged, in which multiple therapeutic targets significant for glioblastoma (such as Integrins, Extracellular Matrix, transmembrane transport, and metabolic processes) play a fundamental role in the disease progression. Moreover, specific cellular processes have been associated with certain cellular subtypes within the tumor. Our results are promising and suggest a compelling method for studying glioblastoma heterogeneity in FFPE samples and its application in both prospective and retrospective studies.
PubMed: 31231613
DOI: 10.3389/fonc.2019.00482 -
PeerJ 2013Glia have been implicated in a variety of functions in the central nervous system, including the control of the neuronal extracellular space, synaptic plasticity and...
Perineuronal satellite neuroglia in the telencephalon of New Caledonian crows and other Passeriformes: evidence of satellite glial cells in the central nervous system of healthy birds?
Glia have been implicated in a variety of functions in the central nervous system, including the control of the neuronal extracellular space, synaptic plasticity and transmission, development and adult neurogenesis. Perineuronal glia forming groups around neurons are associated with both normal and pathological nervous tissue. Recent studies have linked reduction in the number of perineuronal oligodendrocytes in the prefrontal cortex with human schizophrenia and other psychiatric disorders. Therefore, perineuronal glia may play a decisive role in homeostasis and normal activity of the human nervous system. Here we report on the discovery of novel cell clusters in the telencephala of five healthy Passeriforme, one Psittaciform and one Charadriiforme bird species, which we refer to as Perineuronal Glial Clusters (PGCs). The aim of this study is to describe the structure and distribution of the PGCs in a number of avian species. PGCs were identified with the use of standard histological procedures. Heterochromatin masses visible inside the nuclei of these satellite glia suggest that they may correspond to oligodendrocytes. PGCs were found in the brains of nine New Caledonian crows, two Japanese jungle crows, two Australian magpies, two Indian mynah, three zebra finches (all Passeriformes), one Southern lapwing (Charadriiformes) and one monk parakeet (Psittaciformes). Microscopic survey of the brain tissue suggests that the largest PGCs are located in the hyperpallium densocellulare and mesopallium. No clusters were found in brain sections from one Gruiform (purple swamphen), one Strigiform (barn owl), one Trochiliform (green-backed firecrown), one Falconiform (chimango caracara), one Columbiform (pigeon) and one Galliform (chick). Our observations suggest that PGCs in Aves are brain region- and taxon-specific and that the presence of perineuronal glia in healthy human brains and the similar PGCs in avian gray matter is the result of convergent evolution. The discovery of PGCs in the zebra finch is of great importance because this species has the potential to become a robust animal model in which to study the function of neuron-glia interactions in healthy and diseased adult brains.
PubMed: 23904989
DOI: 10.7717/peerj.110 -
The American Journal of Surgical... Aug 2014Oligodendrogliomas are an important adult form of diffuse gliomas with a distinctive clinical and genetic profile. Histologically similar tumors occurring rarely in...
Oligodendrogliomas are an important adult form of diffuse gliomas with a distinctive clinical and genetic profile. Histologically similar tumors occurring rarely in children are incompletely characterized. We studied 50 patients with oligodendrogliomas (median age at diagnosis 8 y, range 7 mo to 20 y). Tumors resembling dysembryoplastic neuroepithelial tumors or pilocytic astrocytomas or those having a "mixed" histology were excluded. Tumors at first diagnosis were low grade (n=38) or anaplastic (n=12). Histologic features included uniform round cells with perinuclear halos (100%), secondary structures (predominantly perineuronal satellitosis) (90%), calcifications (46%), and microcysts (44%). Sequential surgical specimens were obtained in 8 low-grade oligodendroglioma patients, with only 1 progressing to anaplasia. Studies for 1p19q performed in 40 cases demonstrated intact 1p19q loci in 29 (73%), 1p19q codeletion in 10 (25%), and 1p deletion with intact 19q in 1 (2%). Except for 2 young patients (3 and 11 y of age), patients with 1p19q codeletion were older than 16 years at diagnosis. Mutant IDH1 (R132H) protein immunohistochemistry was positive in 4 (of 22) (18%) cases, 3 of which also had 1p19q codeletion, whereas 1p19q status was not available on the fourth case. There was a nonsignificant trend for worse overall survival in grade III tumors, but no significant association with age, extent of resection, or 1p19q status. In summary, oligodendrogliomas with classic histology occur in the pediatric population but lack 1p19q codeletion and IDH1 (R132H) mutations in most instances. They are predominantly low grade, recur/clinically progress in a subset, but demonstrate a relatively low frequency of histologic progression.
Topics: Adolescent; Brain Neoplasms; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 1; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Infant; Kaplan-Meier Estimate; Male; Oligodendroglioma; Polymerase Chain Reaction; Young Adult
PubMed: 24805856
DOI: 10.1097/PAS.0000000000000221 -
Brain Sciences Jan 2023The extent of resection beyond the enhancing core (EC) in glioblastoma IDH-wild type (GBM, IDHwt) is one of the most debated topics in neuro-oncology. Indeed, it has...
The extent of resection beyond the enhancing core (EC) in glioblastoma IDH-wild type (GBM, IDHwt) is one of the most debated topics in neuro-oncology. Indeed, it has been demonstrated that local disease recurrence often arises in peritumoral areas and that radiologically-defined FLAIR hyperintensity areas of GBM IDHwt are often visible beyond the conventional EC. Therefore, the need to extend the surgical resection also to the FLAIR hyperintensity areas is a matter of debate. Since little is known about the histological composition of FLAIR hyperintensity regions, in this study we aimed to provide a comprehensive description of the histological features of EC and FLAIR hyperintensity regions sampled intraoperatively using neuronavigation and 5-aminolevulinic acid (5-ALA) fluorescence, in 33 patients with GBM, IDHwt. Assessing a total 109 histological samples, we found that FLAIR areas consisted in: (i) fragments of white matter focally to diffusely infiltrated by tumor cells in 76% of cases; (ii) a mixture of white matter with reactive astrogliosis and grey matter with perineuronal satellitosis in 15% and (iii) tumor tissue in 9%. A deeper knowledge of the histology of FLAIR hyperintensity areas in GBM, IDH-wt may serve to better guide neurosurgeons on the choice of the most appropriate surgical approach in patients with this neoplasm.
PubMed: 36831791
DOI: 10.3390/brainsci13020248 -
Patterns of brain infiltration and secondary structure formation in supratentorial ependymal tumors.Journal of Neuropathology and... Sep 2008Ependymomas are generally considered to be noninfiltrative tumors that have discrete borders with adjacent brain tissue. Most occur in the posterior fossa or spinal...
Ependymomas are generally considered to be noninfiltrative tumors that have discrete borders with adjacent brain tissue. Most occur in the posterior fossa or spinal cord. Supratentorial ependymal tumors arise near the ventricular system or, more rarely, within the cerebral white matter or cortex. Presented here are 6 supratentorial ependymal tumors, 3 that primarily involve the cerebral cortex and 3 that extend into the cortex from the underlying white matter. By microscopy, all of these tumors locally infiltrate the cortex and/or white matter along small blood vessels and axonal fiber tracts. They also form other glioma secondary structures including perineuronal tumor cell satellitosis and subpial tumor cell mounds. The 3 cortical ependymal tumors show a spectrum of features ranging from conventional and clear-cell ependymoma-like patterns to more angiocentric glioma-like histology. Because ependymal tumors generally have a significantly better prognosis than other infiltrating gliomas, recognition of their capacity to infiltrate adjacent cortex and white matter is important to prevent the misdiagnosis of oligodendroglioma, astrocytoma, or infiltrating glioma, not otherwise specified. Cortical ependymomas and angiocentric gliomas may comprise a group of locally infiltrative ependymal tumors that are associated with an excellent prognosis after gross total surgical resection.
Topics: Adult; Brain; Child; Child, Preschool; Ependymoma; Female; Humans; Immunohistochemistry; Infant; Male; Supratentorial Neoplasms
PubMed: 18716554
DOI: 10.1097/NEN.0b013e31818521cd