ABSTRACT
Cell commitment to tumourigenesis and the onset of uncontrolled growth are critical determinants in cancer development but the early events directing tumour initiating cell (TIC) fate remain unclear. We reveal a single-cell transcriptome profile of brain TICs transitioning into tumour growth using the brain tumour (brat) neural stem cell-based Drosophila model. Prominent changes in metabolic and proteostasis-associated processes including ribogenesis are identified. Increased ribogenesis is a known cell adaptation in established tumours. Here we propose that brain TICs boost ribogenesis prior to tumour growth. In brat-deficient TICs, we show that this dramatic change is mediated by upregulated HEAT-Repeat Containing 1 (HEATR1) to promote ribosomal RNA generation, TIC enlargement and onset of overgrowth. High HEATR1 expression correlates with poor glioma patient survival and patient-derived glioblastoma stem cells rely on HEATR1 for enhanced ribogenesis and tumourigenic potential. Finally, we show that HEATR1 binds the master growth regulator MYC, promotes its nucleolar localisation and appears required for MYC-driven ribogenesis, suggesting a mechanism co-opted in ribogenesis reprogramming during early brain TIC development.
Subject(s)
Brain Neoplasms , Glioblastoma , Minor Histocompatibility Antigens , Proto-Oncogene Proteins c-myc , RNA-Binding Proteins , Animals , Humans , Brain/metabolism , Brain Neoplasms/metabolism , Carcinogenesis/pathology , Cell Transformation, Neoplastic/pathology , DNA-Binding Proteins/metabolism , Drosophila/genetics , Drosophila/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Glioblastoma/metabolism , Glioma/pathology , Minor Histocompatibility Antigens/metabolism , Neoplastic Stem Cells/metabolism , RNA-Binding Proteins/metabolism , Proto-Oncogene Proteins c-myc/metabolismABSTRACT
AIMS: The question of how to handle clinically actionable outcomes from retrospective research studies is poorly explored. In neuropathology, this problem is exacerbated by ongoing refinement in tumour classification. We sought to establish a disclosure threshold for potential revised diagnoses as determined by the neuro-oncology speciality. METHODS: As part of a previous research study, the diagnoses of 73 archival paediatric brain tumour samples were reclassified according to the WHO 2016 guidelines. To determine the disclosure threshold and clinical actionability of pathology-related findings, we conducted a result-evaluation approach within the ethical framework of BRAIN UK using a surrogate clinical multidisciplinary team (MDT) of neuro-oncology specialists. RESULTS: The MDT identified key determinants impacting decision-making, including anticipated changes to patient management, time elapsed since initial diagnosis, likelihood of the patient being alive and absence of additional samples since cohort inception. Ultimately, none of our research findings were considered clinically actionable, largely due to the cohort's historic archival and high-risk nature. From this experience, we developed a decision-making framework to determine if research findings indicating a change in diagnosis require reporting to the relevant clinical teams. CONCLUSIONS: Ethical issues relating to the use of archival tissue for research and the potential to identify actionable findings must be carefully considered. We have established a structured framework to assess the actionability of research data relating to patient diagnosis. While our specific findings are most applicable to the pathology of poor prognostic brain tumour groups in children, the model can be adapted to a range of disease settings, for example, other diseases where research is dependent on retrospective tissue cohorts, and research findings may have implications for patients and families, such as other tumour types, epilepsy-related pathology, genetic disorders and degenerative diseases.
Subject(s)
Brain Neoplasms , Humans , Brain Neoplasms/pathology , Brain Neoplasms/diagnosis , Child , Decision Making , Retrospective Studies , Biomedical ResearchABSTRACT
There is an unmet need for the identification of biomarkers to aid in the diagnosis, clinical management, prognosis and follow-up of meningiomas. There is currently no consensus on the optimum management of WHO grade II meningiomas. In this study, we identified the calcium binding extracellular matrix glycoprotein, Fibulin-2, via mass-spectrometry-based proteomics, assessed its expression in grade I and II meningiomas and explored its potential as a grade II biomarker. A total of 87 grade I and 91 grade II different meningioma cells, tissue and plasma samples were used for the various experimental techniques employed to assess Fibulin-2 expression. The tumours were reviewed and classified according to the 2016 edition of the Classification of the Tumours of the central nervous system (CNS). Mass spectrometry proteomic analysis identified Fibulin-2 as a differentially expressed protein between grade I and II meningioma cell cultures. Fibulin-2 levels were further evaluated in meningioma cells using Western blotting and Real-time Quantitative Polymerase Chain Reaction (RT-qPCR); in meningioma tissues via immunohistochemistry and RT-qPCR; and in plasma via Enzyme-Linked Immunosorbent Assay (ELISA). Proteomic analyses (p < 0.05), Western blotting (p < 0.05) and RT-qPCR (p < 0.01) confirmed significantly higher Fibulin-2 (FBLN2) expression levels in grade II meningiomas compared to grade I. Fibulin-2 blood plasma levels were also significantly higher in grade II meningioma patients compared to grade I patients. This study suggests that elevated Fibulin-2 might be a novel grade II meningioma biomarker, when differentiating them from the grade I tumours. The trend of Fibulin-2 expression observed in plasma may serve as a useful non-invasive biomarker.
Subject(s)
Biomarkers, Tumor/blood , Calcium-Binding Proteins/blood , Extracellular Matrix Proteins/blood , Meningeal Neoplasms/blood , Meningioma/blood , Adult , Aged , Aged, 80 and over , Female , Gene Expression Regulation, Neoplastic/genetics , Humans , Male , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Meningioma/genetics , Meningioma/pathology , Middle Aged , Neoplasm Grading , Prognosis , ProteomicsABSTRACT
Widespread dietary exposure of the population of Britain to bovine spongiform encephalopathy (BSE) prions in the 1980s and 1990s led to the emergence of variant Creutzfeldt-Jakob Disease (vCJD) in humans. Two previous appendectomy sample surveys (Appendix-1 and -2) estimated the prevalence of abnormal prion protein (PrP) in the British population exposed to BSE to be 237 per million and 493 per million, respectively. The Appendix-3 survey was recommended to measure the prevalence of abnormal PrP in population groups thought to have been unexposed to BSE. Immunohistochemistry for abnormal PrP was performed on 29,516 samples from appendices removed between 1962 and 1979 from persons born between 1891 through 1965, and from those born after 1996 that had been operated on from 2000 through 2014. Seven appendices were positive for abnormal PrP, of which two were from the pre-BSE-exposure era and five from the post BSE-exposure period. None of the seven positive samples were from appendices removed before 1977, or in patients born after 2000 and none came from individuals diagnosed with vCJD. There was no statistical difference in the prevalence of abnormal PrP across birth and exposure cohorts. Two interpretations are possible. Either there is a low background prevalence of abnormal PrP in human lymphoid tissues that may not progress to vCJD. Alternatively, all positive specimens are attributable to BSE exposure, a finding that would necessitate human exposure having begun in the late 1970s and continuing through the late 1990s.
Subject(s)
Creutzfeldt-Jakob Syndrome/epidemiology , Encephalopathy, Bovine Spongiform/epidemiology , Prion Proteins/metabolism , Prions/metabolism , Animals , Appendix/metabolism , Brain/metabolism , Brain/virology , Cattle , Creutzfeldt-Jakob Syndrome/metabolism , Encephalopathy, Bovine Spongiform/metabolism , Humans , PrevalenceABSTRACT
A 36-year-old woman with relapsing remitting multiple sclerosis (MS) presented with right-sided spasms, focal seizures and neuropsychiatric symptoms 10 months after her first course of alemtuzumab. Magnetic resonance imaging (MRI) brain imaging revealed multiple foci of T2 hyperintensity. Subsequent blood and cerebrospinal fluid (CSF) testing for progressive multifocal leukoencephalopathy (PML), vasculitis and infective causes was negative. A brain biopsy was performed, revealing a prominent perivascular inflammatory infiltrate with multiple immune cells including eosinophils, suggesting eosinophilic vasculitis. The patient was treated successfully with cyclophosphamide. The potential sequelae of alemtuzumab treatment are discussed; this treatable complication should be considered when tests for JC virus are negative.
Subject(s)
JC Virus , Leukoencephalopathy, Progressive Multifocal , Multiple Sclerosis, Relapsing-Remitting , Vasculitis, Central Nervous System , Adult , Alemtuzumab/adverse effects , Female , Humans , Magnetic Resonance Imaging , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Vasculitis, Central Nervous System/chemically induced , Vasculitis, Central Nervous System/diagnostic imaging , Vasculitis, Central Nervous System/drug therapyABSTRACT
The majority of meningiomas are grade I, but some grade I tumours are clinically more aggressive. Recent advances in the genetic study of meningiomas has allowed investigation into the influence of genetics on the tumour microenvironment, which is important for tumorigenesis. We have established that the endpoint genotyping method Kompetitive Allele Specific PCR (KASP™) is a fast, reliable method for the screening of meningioma samples into different non-NF2 mutational groups using a standard real-time PCR instrument. This genotyping method and four-colour flow cytometry has enabled us to assess the variability in the largest immune cell infiltrate population, M2 macrophages (CD45+HLA-DR+CD14+CD163+) in 42 meningioma samples, and to suggest that underlying genetics is relevant. Further immunohistochemistry analysis comparing AKT1 E17K mutants to WHO grade I NF2-negative samples showed significantly lower levels of CD163-positive activated M2 macrophages in meningiomas with mutated AKT1 E17K, signifying a more immunosuppressive tumour microenvironment in NF2 meningiomas. Our data suggested that underlying tumour genetics play a part in the development of the immune composition of the tumour microenvironment. Stratifying meningiomas by mutational status and correlating this with their cellular composition will aid in the development of new immunotherapies for patients.
Subject(s)
Macrophages/metabolism , Meningioma/genetics , Proto-Oncogene Proteins c-akt/genetics , Tumor Microenvironment/genetics , Alleles , Antigens, CD/genetics , Antigens, Differentiation, Myelomonocytic/genetics , Cell Lineage/genetics , Female , Genotype , HLA-DR Antigens/genetics , Humans , Leukocyte Common Antigens/genetics , Lipopolysaccharide Receptors/genetics , Macrophages/classification , Macrophages/pathology , Male , Meningioma/classification , Meningioma/pathology , Middle Aged , Mutation/genetics , Neurofibromin 2/genetics , Receptors, Cell Surface/geneticsABSTRACT
Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. ß-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.
Subject(s)
Craniopharyngioma/metabolism , MAP Kinase Signaling System , Pituitary Neoplasms/metabolism , Transcriptome , Tumor Microenvironment/physiology , Animals , Computational Biology , Craniopharyngioma/pathology , Craniopharyngioma/therapy , Cytokines/metabolism , Disease Models, Animal , Humans , Inflammation/metabolism , Inflammation/therapy , Laser Capture Microdissection , Mice , Neuroglia/metabolism , Odontogenesis/physiology , Pituitary Gland/embryology , Pituitary Gland/pathology , Pituitary Neoplasms/pathology , Pituitary Neoplasms/therapy , Sequence Analysis, RNA , Tissue Culture TechniquesABSTRACT
A minority of meningiomas are difficult to treat with surgery or radiotherapy, and chemotherapeutic alternatives are limited. This study aims to better understand pathways that are active in meningiomas, in order to direct future treatment strategies. We investigated the expression and activation of multiple growth factor receptors, their ligands and downstream signalling pathways in 30 meningiomas using immunohistochemistry. Expression was correlated with chromosome 22q loss. Membrane expression of VEGF receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR)ß was seen in 83% of tumors, Axl in 70%, EGFR in 50% and insulin-like growth factor receptor in 47%. Expression was similar in low- and high-grade tumors, but membrane EGFR expression was not seen in tumors showing chromosome 22q loss (P < 0.05). Expression of ligands (IGF, NRG, VEGF, Gas 6), and signalling proteins (Mek, Erk, Jnk, Akt) and pS6RP, was widespread. Western blot confirmed widespread Axl expression and supported selective expression of EGFR in NF2-intact meningiomas. The majority of meningiomas express and show activation of multiple growth factor receptors and their signalling pathways, irrespective of tumor grade. In addition to previously reported receptors, Axl offers a new therapeutic target. The findings also suggest that anti-EGFR based therapies may be less effective in meningiomas with 22q loss.
Subject(s)
Intercellular Signaling Peptides and Proteins/metabolism , Meningeal Neoplasms/metabolism , Meningioma/metabolism , Receptors, Growth Factor/metabolism , Signal Transduction , Chromosomes, Human, Pair 22 , Humans , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Meningioma/genetics , Meningioma/pathology , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Axl Receptor Tyrosine KinaseABSTRACT
Familial cases of frontotemporal dementia (FTD) provide an opportunity to study the pathophysiology of this clinically diverse condition. The C9ORF72 mutation is the most common cause of familial FTD, recent pathological descriptions challenge existing TDP-43 based hypotheses of sporadic FTD pathogenesis. Non-ATG dependent translation of the hexanucleotide expansion into aggregating dipeptide repeat (DPR) proteins may represent a novel pathomechanism. We report detection of the DPR aggregates very early in C9ORF72 FTD development and also describe childhood intellectual disability as a clinical feature preceding dementia. The index case presented with psychiatric symptoms, progressing into typical FTD. Autopsy revealed extensive neuronal DPR aggregates but only minimal TDP-43 pathology. Her intellectually disabled elder son, also carrying the C9ORF72 mutation, died aged 26 years and at autopsy only DPR aggregates without TDP-43 were found. A second son also has intellectual disability, his C9ORF72 status is unknown, but chromosomal microarray revealed no other cause of disability. These cases both extend the existing phenotype of C9ORF72 mutation and highlight the potential significance of DPR translation early in disease development.
Subject(s)
DNA Repeat Expansion , Frontotemporal Dementia/genetics , Intellectual Disability/genetics , Proteins/genetics , Adult , Brain/metabolism , Brain/pathology , C9orf72 Protein , Disease Progression , Family , Fatal Outcome , Female , Frontotemporal Dementia/complications , Frontotemporal Dementia/pathology , Humans , Immunohistochemistry , Intellectual Disability/complications , Intellectual Disability/pathology , Male , Middle Aged , Mothers , Pedigree , White People/geneticsSubject(s)
Antineoplastic Agents/pharmacology , Neurofibromatosis 2/metabolism , Sorafenib/pharmacology , Adult , Antineoplastic Agents/metabolism , Blotting, Western , Caspase 3/drug effects , Caspase 3/metabolism , Cyclin D1/drug effects , Cyclin D1/metabolism , Humans , Immunohistochemistry , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Mitogen-Activated Protein Kinase 1/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/drug effects , Mitogen-Activated Protein Kinase 3/metabolism , Molecular Targeted Therapy , Neurofibromatosis 2/drug therapy , Proto-Oncogene Proteins c-akt/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Receptor, Platelet-Derived Growth Factor beta/drug effects , Receptor, Platelet-Derived Growth Factor beta/metabolism , Ribosomal Protein S6/drug effects , Ribosomal Protein S6/metabolism , Sorafenib/metabolismABSTRACT
Anonymous screening of lymphoreticular tissues removed during routine surgery has been applied to estimate the UK population prevalence of asymptomatic vCJD prion infection. The retrospective study of Hilton et al (J Pathol 2004; 203: 733-739) found accumulation of abnormal prion protein in three formalin-fixed appendix specimens. This led to an estimated UK prevalence of vCJD infection of â¼1 in 4000, which remains the key evidence supporting current risk reduction measures to reduce iatrogenic transmission of vCJD prions in the UK. Confirmatory testing of these positives has been hampered by the inability to perform immunoblotting of formalin-fixed tissue. Animal transmission studies offer the potential for 'gold standard' confirmatory testing but are limited by both transmission barrier effects and known effects of fixation on scrapie prion titre in experimental models. Here we report the effects of fixation on brain and lymphoreticular human vCJD prions and comparative bioassay of two of the three prevalence study formalin-fixed, paraffin-embedded (FFPE) appendix specimens using transgenic mice expressing human prion protein (PrP). While transgenic mice expressing human PrP 129M readily reported vCJD prion infection after inoculation with frozen vCJD brain or appendix, and also FFPE vCJD brain, no infectivity was detected in FFPE vCJD spleen. No prion transmission was observed from either of the FFPE appendix specimens. The absence of detectable infectivity in fixed, known positive vCJD lymphoreticular tissue precludes interpreting negative transmissions from vCJD prevalence study appendix specimens. In this context, the Hilton et al study should continue to inform risk assessment pending the outcome of larger-scale studies on discarded surgical tissues and autopsy samples.
Subject(s)
Appendix/metabolism , Brain/metabolism , Creutzfeldt-Jakob Syndrome/metabolism , Prions/metabolism , Animals , Appendix/pathology , Biological Assay/methods , Brain/pathology , Creutzfeldt-Jakob Syndrome/pathology , Creutzfeldt-Jakob Syndrome/transmission , Humans , Mice , Mice, Transgenic , PrPSc Proteins/metabolism , Retrospective Studies , Tissue Fixation/methodsABSTRACT
Deficiency of the tumor suppressor Merlin causes development of schwannoma, meningioma, and ependymoma tumors, which can occur spontaneously or in the hereditary disease neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Surgery and radiotherapy are current first-line treatments; however, tumors frequently recur with limited treatment options. Here, we use human Merlin-negative schwannoma and meningioma primary cells to investigate the involvement of the endogenous retrovirus HERV-K in tumor development. HERV-K proteins previously implicated in tumorigenesis were overexpressed in schwannoma and all meningioma grades, and disease-associated CRL4DCAF1 and YAP/TEAD pathways were implicated in this overexpression. In normal Schwann cells, ectopic overexpression of HERV-K Env increased proliferation and upregulated expression of c-Jun and pERK1/2, which are key components of known tumorigenic pathways in schwannoma, JNK/c-Jun, and RAS/RAF/MEK/ERK. Furthermore, FDA-approved retroviral protease inhibitors ritonavir, atazanavir, and lopinavir reduced proliferation of schwannoma and grade I meningioma cells. These results identify HERV-K as a critical regulator of progression in Merlin-deficient tumors and offer potential strategies for therapeutic intervention. SIGNIFICANCE: The endogenous retrovirus HERV-K activates oncogenic signaling pathways and promotes proliferation of Merlin-deficient schwannomas and meningiomas, which can be targeted with antiretroviral drugs and TEAD inhibitors.
Subject(s)
Anti-Retroviral Agents/pharmacology , Cell Proliferation/drug effects , Cell Proliferation/genetics , Endogenous Retroviruses/metabolism , Meningeal Neoplasms/metabolism , Meningioma/metabolism , Neurilemmoma/metabolism , Neurofibromin 2/metabolism , Viral Proteins/metabolism , Carcinogenesis/genetics , Carcinogenesis/metabolism , HEK293 Cells , Humans , Meningeal Neoplasms/complications , Meningeal Neoplasms/pathology , Meningeal Neoplasms/virology , Meningioma/complications , Meningioma/pathology , Meningioma/virology , Neurilemmoma/complications , Neurilemmoma/pathology , Neurilemmoma/virology , Neurofibromatosis 2/complications , Neurofibromin 2/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Transfection , Viral Proteins/antagonists & inhibitors , Viral Proteins/geneticsABSTRACT
INTRODUCTION: Muscle biopsy is used in the diagnosis of mitochondrial disorders. There are limited data on the normal ranges, so interpretation of findings can be difficult. METHODS: We evaluated the percentage of fibers showing mitochondrial abnormalities using Gomori trichrome staining, succinate dehydrogenase, and cytochrome oxidase histochemistry in autopsy samples taken from 45 individuals without evidence of muscle disease and biopsies from 17 patients with mitochondrial disorders. RESULTS: In controls, mitochondrial abnormalities were rare before the fifth decade, and most had <0.1% abnormal fibers. The proportion of abnormal fibers increased with age and was higher in deltoid than quadriceps. Most patients with mitochondrial disorders had >0.5% abnormal fibers. CONCLUSIONS: Although some patients with mitochondrial disease have very few muscle fibers that show mitochondrial abnormalities, a rate of abnormality of >0.5% fibers, in the absence of a primary muscle disease this should raise the possibility of a mitochondrial disorder.
Subject(s)
Mitochondria/pathology , Mitochondrial Diseases/pathology , Muscle Fibers, Skeletal/pathology , Muscle, Skeletal/pathology , Muscular Diseases/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Mitochondria/metabolism , Mitochondrial Diseases/diagnosis , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/metabolism , Muscle, Skeletal/physiopathology , Muscular Diseases/diagnosis , Prospective Studies , Retrospective Studies , Young AdultABSTRACT
Deficiency of the tumor suppressor merlin leads to the development of multiple tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas. Due to the benign character of these tumors, classical chemotherapy is ineffective. Current therapies, surgery, and radiosurgery are local and quite invasive, thus new systemic treatments are required. We have previously described the Raf/mitogen-activated kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway activation and its role in schwannoma growth. Here, we targeted MEK1/2 known as a convergence point for multiple cascades towards ERK1/2 activation and cell proliferation, using MEK1/2 inhibitor AZD6244 (ARRY-142886; Astra Zeneca). We show that AZD6244 at low concentration completely abolished platelet-derived growth factor-DD-mediated ERK1/2 activation and cell proliferation in human primary schwannoma cells. Moreover, this drug was not toxic for either schwannoma or Schwann cells and has been reported to be safe with tolerable side effects. Thus, AZD6244 can be considered as a drug candidate for schwannoma treatment.
Subject(s)
Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , MAP Kinase Kinase 2/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Neurilemmoma/drug therapy , Neurilemmoma/physiopathology , Antineoplastic Agents/pharmacology , Bromodeoxyuridine , Cell Proliferation/drug effects , Cells, Cultured , Humans , Immunoblotting , Immunohistochemistry , MAP Kinase Kinase 2/antagonists & inhibitors , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Phosphorylation , Platelet-Derived Growth Factor/metabolism , Schwann Cells/drug effects , Schwann Cells/physiologySubject(s)
Meningeal Neoplasms/pathology , Meningioma/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Immunohistochemistry , Male , Meningeal Neoplasms/physiopathology , Meningeal Neoplasms/surgery , Meningioma/physiopathology , Meningioma/surgery , Microscopy, Electron , Middle Aged , Neoplasm GradingABSTRACT
Creutzfeldt-Jakob disease (CJD) is a fatal disease presenting with rapidly progressive dementia, and most patients die within a year of clinical onset. CJD poses a potential risk of iatrogenic transmission, as it can incubate asymptomatically in humans for decades before becoming clinically apparent. In this Review, we sought evidence to understand the current iatrogenic risk of CJD to public health by examining global evidence on all forms of CJD, including clinical incidence and prevalence of subclinical disease. We found that although CJD, particularly iatrogenic CJD, is rare, the incidence of sporadic CJD is increasing. Incubation periods as long as 40 years have been observed, and all genotypes have now been shown to be susceptible to CJD. Clinicians and surveillance programmes should maintain awareness of CJD to mitigate future incidences of its transmission. Awareness is particularly relevant for sporadic CJD, which occurs in older people in whom clinical presentation could resemble rapidly developing dementia.
Subject(s)
Creutzfeldt-Jakob Syndrome/epidemiology , Creutzfeldt-Jakob Syndrome/pathology , Iatrogenic Disease/epidemiology , Infectious Disease Incubation Period , Adult , Aged , Aged, 80 and over , Creutzfeldt-Jakob Syndrome/transmission , Female , Humans , Incidence , Male , Middle Aged , Prevalence , Risk Assessment , Young AdultABSTRACT
BACKGROUND: Rosai-Dorfman disease (RDD) is a rare idiopathic benign proliferative disorder of histiocytes, predominantly affecting the lymph nodes. RDD can also present in extranodal tissues and is occasionally found within the central nervous system. CASE DESCRIPTION: We report the case of a 52-year-old man presenting with a short episode of dizziness. Imaging identified a right frontal, extraaxial, dural-based lesion, suspicious for a meningioma. The patient underwent a craniotomy for tumor resection and, although not entirely typical, the pathology was consistent with RDD. No other evidence of RDD was identified. CONCLUSIONS: RDD should be considered as a differential diagnosis of dural-based lesions, more commonly meningiomas.
Subject(s)
Brain Neoplasms/pathology , Histiocytosis, Sinus/pathology , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/surgery , Craniotomy , Diagnosis, Differential , Dizziness/etiology , Histiocytes/pathology , Histiocytosis, Sinus/diagnostic imaging , Histiocytosis, Sinus/surgery , Humans , Lymph Nodes/pathology , Male , Meningioma/diagnosis , Meningioma/diagnostic imaging , Middle Aged , Neurosurgical Procedures , Treatment OutcomeABSTRACT
Meningioma are the most frequent primary intracranial tumour. Management of aggressive meningioma is complex, and development of effective biomarkers or pharmacological interventions is hampered by an incomplete knowledge of molecular landscape. Here, we present an integrated analysis of two complementary omics studies to investigate alterations in the "transcriptome-proteome" profile of high-grade (III) compared to low-grade (I) meningiomas. We identified 3598 common transcripts/proteins and revealed concordant up- and downregulation in grade III vs. grade I meningiomas. Concordantly upregulated genes included FABP7, a fatty acid binding protein and the monoamine oxidase MAOB, the latter of which we validated at the protein level and established an association with Food and Drug Administration (FDA)-approved drugs. Notably, we derived a plasma signature of 21 discordantly expressed genes showing positive changes in protein but negative in transcript levels of high-grade meningiomas, including the validated genes CST3, LAMP2, PACS1 and HTRA1, suggesting the acquisition of these proteins by tumour from plasma. Aggressive meningiomas were enriched in processes such as oxidative phosphorylation and RNA metabolism, whilst concordantly downregulated genes were related to reduced cellular adhesion. Overall, our study provides the first transcriptome-proteome characterisation of meningioma, identifying several novel and previously described transcripts/proteins with potential grade III biomarker and therapeutic significance.
ABSTRACT
BACKGROUND: Meningiomas are the most common primary intracranial tumours. They are classified as grade I, II, and III based on their histopathological features. While most meningiomas can be managed by surgery alone, adjuvant treatment may be required in case of recurrent, or high-grade tumours. To date, chemotherapy has proven ineffective in meningioma patients, reinforcing the need for novel therapeutic targets and molecular biomarkers. METHODS: Using meningioma tissues and in vitro models, we investigated microRNA levels in meningioma samples of different grades, as well as their regulation. Based on this, we also investigated candidate miRNAs expression in serum, and their potential as biomarkers. FINDINGS: We found that miR-497~195 cluster expression in meningioma decreases with increasing malignancy grade, and that Cyclin D1 overexpression correlated with downregulation of the miR-497~195 cluster. GATA binding protein 4, a transcription factor upregulated in malignant meningioma, caused increased cell viability by controlling the expression of the miR-497~195 cluster, resulting in increased Cyclin D1 expression. Accordingly, GATA-4 inhibition via the small-molecule inhibitor NSC140905 restored miR-497~195 cluster expression, resulting in decreased viability, and Cyclin D1 downregulation. Analysis of the miR-497~195 cluster expression in serum exosomes derived from high-grade meningioma patients, revealed lower levels of miR-497 compared to those of benign origin. INTERPRETATION: Our data suggest that GATA-4 could be a novel potential therapeutic target, and miR-497 could serve as a potential non-invasive biomarker for high-grade meningioma.
Subject(s)
Biomarkers, Tumor , Circulating MicroRNA , GATA4 Transcription Factor/metabolism , Gene Expression Regulation, Neoplastic , Meningioma/genetics , Meningioma/metabolism , MicroRNAs/genetics , Apoptosis/genetics , Cell Line, Tumor , Female , Humans , Liquid Biopsy , Male , Meningioma/diagnosis , Meningioma/therapy , MicroRNAs/blood , Multigene Family , Neoplasm Grading , Prognosis , ROC CurveABSTRACT
BACKGROUND: Meningiomas are the most frequent primary brain tumors of the central nervous system. The standard of treatment is surgery and radiotherapy, but effective pharmacological options are not available yet. The well-characterized genetic background stratifies these tumors in several subgroups, thus increasing diversification. We identified epidermal growth factor receptor-signal transducer and activator of transcription 1 (EGFR-STAT1) overexpression and activation as a common identifier of these tumors. METHODS: We analyzed STAT1 overexpression and phosphorylation in 131 meningiomas of different grades and locations by utilizing several techniques, including Western blots, qPCR, and immunocytochemistry. We also silenced and overexpressed wild-type and mutant forms of the gene to assess its biological function and its network. Results were further validated by drug testing. RESULTS: STAT1 was found widely overexpressed in meningioma but not in the corresponding healthy controls. The protein showed constitutive phosphorylation not dependent on the JAK-STAT pathway. STAT1 knockdown resulted in a significant reduction of cellular proliferation and deactivation of AKT and ERK1/2. STAT1 is known to be activated by EGFR, so we investigated the tyrosine kinase and found that EGFR was also constitutively phosphorylated in meningioma and was responsible for the aberrant phosphorylation of STAT1. The pharmaceutical inhibition of EGFR caused a significant reduction in cellular proliferation and of overall levels of cyclin D1, pAKT, and pERK1/2. CONCLUSIONS: STAT1-EGFR-dependent constitutive phosphorylation is responsible for a positive feedback loop that causes its own overexpression and consequently an increased proliferation of the tumor cells. These findings provide the rationale for further studies aiming to identify effective therapeutic options in meningioma.