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International Journal of Molecular... Nov 2021Malignant brain tumors are responsible for catastrophic morbidity and mortality globally. Among them, glioblastoma multiforme (GBM) bears the worst prognosis. The...
Malignant brain tumors are responsible for catastrophic morbidity and mortality globally. Among them, glioblastoma multiforme (GBM) bears the worst prognosis. The GrpE-like 2 homolog () plays a crucial role in regulating mitochondrial protein import and redox homeostasis. However, the role of in human glioblastoma has yet to be clarified. In this study, we investigated the function of in glioma. Based on bioinformatics analyses from the Cancer Gene Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), we inferred that expression positively correlates with WHO tumor grade ( < 0.001), IDH mutation status ( < 0.001), oligodendroglial differentiation ( < 0.001), and overall survival ( < 0.001) in glioma datasets. Functional validation in LN229 and GBM8401 GBM cells showed that knockdown efficiently inhibited cellular proliferation. Moreover, GRPEL2 suppression induced cell cycle arrest at the sub-G1 phase. Furthermore, silencing decreased intracellular reactive oxygen species (ROS) without impending mitochondria membrane potential. The cellular oxidative respiration measured with a Seahorse XFp analyzer exhibited a reduction of the oxygen consumption rate (OCR) in GBM cells by , which subsequently enhanced autophagy and senescence in glioblastoma cells. Taken together, GRPEL2 is a novel redox regulator of mitochondria bioenergetics and a potential target for treating GBM in the future.
Topics: Apoptosis; Brain Neoplasms; Case-Control Studies; Cell Cycle; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Intracellular Signaling Peptides and Proteins; Membrane Potential, Mitochondrial; Mitochondria; Oxidation-Reduction; Prognosis; Protein Transport; Reactive Oxygen Species; Survival Rate; Tumor Cells, Cultured
PubMed: 34884508
DOI: 10.3390/ijms222312705 -
Turkish Neurosurgery 2022To evaluate the clinical features, treatment approaches, and outcomes of glial tumors in children.
AIM
To evaluate the clinical features, treatment approaches, and outcomes of glial tumors in children.
MATERIAL AND METHODS
Files (2006 to 2020) of children diagnosed with glial tumors and followed-up were reviewed retrospectively. Information regarding demographic and clinical characteristics, treatment approaches, and outcomes were retrieved from the patients? files.
RESULTS
Of the total of 180 pediatric patients diagnosed with brain tumors, 73 (40.6%) had glial tumors. The children with astrocytoma were in the age range of 2?18 years (median age: 8.7 years), while the ages of children with ependymoma ranged from three months to 10 years (median age: 3 years). This difference was statistically significant (p < 0.0001). The male to female ratio was 1.6. The most common symptoms or signs were headaches (n=34, 46.6%), abnormal gait or coordination (n=22, 30.2%), vomiting (n=21, 28.8%), and cranial nerve palsies (n=20, 27.4%). The pathological diagnoses were astrocytomas (n=53, 72.6%), oligodendroglial tumors (n=2, 2.7%), ependymoma (n=15, 20.7%), and other glial tumors (n=3, 4.1%). The most common tumor location was supratentorial (n=42, 57.5%), while midline glioma was detected in seven patients. The 5-year overall survival (OS) rate of all glial tumors, astrocytoma, and ependymoma was 42%, 40%, and 55%, respectively. The 5-year OS rate of the tumor Grade I, II, III, and IV was 77.2%, 45%, 32%, and 0%, respectively (p < 0.0001). The 5-year OS rate of supratentorial, infratentorial, and spinal tumors was 25.6%, 63.6%, and 50%, respectively (p=0.021). In Cox regression analysis, it was found that the tumor resection and grade had an effect on the tumor prognosis.
CONCLUSION
Treatment results are not satisfactory in high-grade astrocytomas. There is a need for new treatment approaches that would take cognizance of molecular features and adopt multidisciplinary approaches.
Topics: Astrocytoma; Brain Neoplasms; Child; Child, Preschool; Ependymoma; Female; Glioma; Humans; Infant; Male; Prognosis; Retrospective Studies; Treatment Outcome
PubMed: 34751424
DOI: 10.5137/1019-5149.JTN.34801-21.2 -
Medicine Oct 2021Astroblastoma is a rare tumor of the central nervous system with uncertain biological behavior and origin. Its histopathological features have been well established,...
RATIONALE
Astroblastoma is a rare tumor of the central nervous system with uncertain biological behavior and origin. Its histopathological features have been well established, while, to our knowledge, astroblastoma with oligodendroglial-like cells have not been reported.
PATIENT CONCERNS
A 15-year-old girl presented with nausea, vomiting, headache, and visual disturbance.
DIAGNOSIS
Magnetic resonance imaging revealed a large neoplasm in the left temporal. Histologically, the tumor showed solid and pseudopapillary structure. Immunohistochemical staining showed that the tumor cells were positive for glial fibrillary acidic protein and vimentin. The oligodendroglial-like cells were positive for glial fibrillary acidic protein, vimentin, and oligodendrocyte transcription factor 2. The antigen KI67 labeling index was about 4%. Sequencing for isocitrate dehydrogenase (IDH) 1 codon 132 and IDH2 codon 172 gene mutations showed negative results. Furthermore, fluorescent analysis revealed neither 1p nor 19q deletion in the lesion. Based on these findings, the girl was finally diagnosed as astroblastoma.
INTERVENTIONS
A craniotomy with total excision of the tumor was performed.
OUTCOMES
The follow-up time was 1 year, no evidence of disease recurrence was found in magnetic resonance imaging.
LESSONS
Cerebral astroblastoma with oligodendroglial-like cells is a clinically rare tumor of central nervous system. Clear distinction and diagnosis are critical.
Topics: Adolescent; Brain Neoplasms; Craniotomy; Female; Humans; Neoplasms, Neuroepithelial
PubMed: 34713831
DOI: 10.1097/MD.0000000000027570 -
Hematology/oncology Clinics of North... Feb 2022Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute... (Review)
Review
Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute myeloid leukemia, and other human malignancies. Cancer-associated mutations alter the function of the enzyme, resulting in production of R(-)-2-hydroxyglutarate and broad epigenetic dysregulation. Small molecule IDH inhibitors have received regulatory approval for the treatment of IDH mutant (mIDH) leukemia and are under development for the treatment of mIDH solid tumors. This article provides a current view of mIDH adult astrocytic and oligodendroglial tumors, including their clinical presentation and treatment, and discusses novel approaches and challenges toward improving the treatment of these tumors.
Topics: Adult; Brain Neoplasms; Glioma; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Mutation
PubMed: 34711457
DOI: 10.1016/j.hoc.2021.08.008 -
Ideggyogyaszati Szemle Sep 2021Aberrant activation of the Wnt pathway contributes to differentiation and maintenance of cancer stem cells underlying gliomagenesis. The aim of our research was to...
BACKGROUND AND PURPOSE
Aberrant activation of the Wnt pathway contributes to differentiation and maintenance of cancer stem cells underlying gliomagenesis. The aim of our research was to determine as to what degrees some Wnt markers are expressed in gliomas of different grades, lineages and molecular subtypes.
METHODS
Nine grade II, 10 grade III and 72 grade IV surgically removed, formalin-fixed paraffin-embedded glioma specimens were included. Mutation status of IDH1 codon 132 was defined by immunohistochemistry and pyrosequencing in all tumors. Grade II and III astrocytic and oligodendroglial tumors were further tested for the expression of p53 and ATRX by immunohistochemistry, and codeletion of 1p19q by fluorescent in situ hybridization. Expression levels of the non-canonical Wnt5a and Fzd2, and the canonical Wnt3a and beta-catenin Wnt pathway markers were determined by immunohistochemistry, and compared between subgroups stratified according to grade, lineage and the presence or absence of IDH1 R132H/C mutations.
RESULTS
In the normal brain - grade II-IV glioma comparisons, a gradual increase was observed for the expressions of Wnt5a, Wnt3a, Fzd2 and beta-catenin. In the astroglial and oligodendroglial lineages of grade II and III gliomas, only the Wnt5a expression was significantly higher in the astroglial subgroup. Stratification according to the IDH1 status resulted in a significant increase of the Wnt3 expression in the wild type grade II-IV gliomas.
CONCLUSION
These data extend previous observations and show a correlation of Wnt pathway activity with glioma grade. Further investigations of the Wnt marker expression regulation according to glioma lineage or IDH gene mutational status are in progress by using more exact molecular approaches.
Topics: Brain Neoplasms; Glioma; Humans; In Situ Hybridization, Fluorescence; Isocitrate Dehydrogenase; Wnt Signaling Pathway
PubMed: 34657400
DOI: 10.18071/isz.74.0349 -
Folia Neuropathologica 2021This study has assessed the diagnostic ability of oligodendrocyte-2 (Olig2), CD99, and epithelial membrane antigen (EMA) immunohistochemical stains to diagnose...
INTRODUCTION
This study has assessed the diagnostic ability of oligodendrocyte-2 (Olig2), CD99, and epithelial membrane antigen (EMA) immunohistochemical stains to diagnose oligodendroglial-like neoplasms as central neurocytoma, ependymoma, or oligodendroglioma.
MATERIAL AND METHODS
An immunohistochemistry (IHC) panel of Olig2, EMA, and CD99 was performed on 18 central neurocytomas, 46 ependymomas, and 28 oligodendrogliomas. A quantitative labelling index of stained tumor cells was assessed using a scoring system, and its diagnostic predictability was evaluated with multinomial logistic regression.
RESULTS
Significant differences in IHC expression patterns were observed between all tumor groups (p < 0.001). The labeling indices of the histochemical expression of Olig2, EMA, and CD99 were related to diagnostic predictability. Olig2 was unlikely to differentiate ependymoma from central neurocytoma (p = 0.154), while EMA and CD99 were significant in diagnosing these two tumors (p < 0.05). Olig2 was a specific marker of oligodendroglioma, differentiating it from ependymoma and central neurocytoma (p 0.05), but CD99 significantly differentiated ependymoma from oligodendroglioma (p = 0.022). These labelling indices were used to re-assess the diagnostic accuracy, regardless of tumor location and histology, and yielded significantly different tumor diagnoses.
CONCLUSIONS
The IHC panel of Olig2, EMA, and CD99 should be used to differentiate oligodendroglial-like neoplasms. Olig2 is a specific IHC marker to diagnose oligodendroglioma and differentiate it from ependymoma and central neurocytoma. Lack of Olig2 expression rules out oligodendroglioma and suggests the diagnosis of ependymoma rather than central neurocytoma if the EMA labelling index shows diffuse/partial expression. CD99 is considered a sensitive marker for ependymoma but not central neurocytoma.
Topics: 12E7 Antigen; Biomarkers, Tumor; Brain Neoplasms; Ependymoma; Humans; Mucin-1; Neurocytoma; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Oligodendroglioma
PubMed: 34628794
DOI: 10.5114/fn.2021.108526 -
Turk Patoloji Dergisi 2022Diffuse gliomas, the most common primary malignant brain tumors, have been classified by the World Health Organization as class II-IV gliomas. After 2016, two mutations...
OBJECTIVE
Diffuse gliomas, the most common primary malignant brain tumors, have been classified by the World Health Organization as class II-IV gliomas. After 2016, two mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene were identified in addition to the IDH, 1p / 19q, and ATRX status.
MATERIAL AND METHOD
We identified 84 patients with grade II-IV glioma with IDH, ATRX, 1p / 19q and TERT status. All tumor samples were subjected to molecular genetic screening (Sanger sequencing for IDH and TERT mutations, fluorescence in situ hybridization for 1p/19q status) after histological diagnosis (immunohistochemistry for IDH1 R132H, ATRX, and p53) for a more precise molecular diagnosis. The confidence intervals were calculated at the 95% confidence level, and differences at p < 0.05 were considered statistically significant.
RESULTS
Primary glioblastomas had the highest frequency of TERT promoter mutations (25 of 28, 89.2%, p=0.006) followed by oligodendrogliomas (29 of 35, 82.8%, p < 0.001) while astrocytomas showed the lowest frequency (3 of 15, 20%, p=0.107), and the positivity significantly differed among these three groups (p < 0.001). TERT promoter mutations were more frequent in patients older than 55 years of age at diagnosis (p=0.023). The group with TERT promoter mutations, and without IDH mutations showed the worst overall survival. However, the presence of both TERT promoter and IDH mutations, which resembled oligodendroglial progression, showed best overall survival (p=0.042).
CONCLUSION
The discovery of TERT promoter mutations in numerous gliomas has opened the door for a better molecular classification of gliomas, and TERT status is associated with survival. Further studies will help in elucidating the value of TERT promoter mutations as biomarkers in clinical practice, and eventual therapeutic targets.
Topics: Brain Neoplasms; Glioblastoma; Glioma; Humans; In Situ Hybridization, Fluorescence; Isocitrate Dehydrogenase; Mutation; Prognosis; Promoter Regions, Genetic; Telomerase
PubMed: 34558656
DOI: 10.5146/tjpath.2021.01555 -
Neuro-oncology Apr 2022Microtubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network...
BACKGROUND
Microtubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular, glioblastomas (GBMs), while they are uncommon in chemosensitive IDH-mutant and 1p/19q co-deleted oligodendrogliomas. The aim of this study was to identify potential signaling pathways involved in MT formation.
METHODS
Bioinformatics analysis of TCGA was performed to analyze differences between GBM and oligodendroglioma. Patient-derived GBM stem cell lines were used to investigate MT formation under transforming growth factor-beta (TGF-β) stimulation and inhibition in vitro and in vivo in an orthotopic xenograft model. RNA sequencing and proteomics were performed to detect commonalities and differences between GBM cell lines stimulated with TGF-β.
RESULTS
Analysis of TCGA data showed that the TGF-β pathway is highly activated in GBMs compared to oligodendroglial tumors. We demonstrated that TGF-β1 stimulation of GBM cell lines promotes enhanced MT formation and communication via calcium signaling. Inhibition of the TGF-β pathway significantly reduced MT formation and its associated invasion in vitro and in vivo. Downstream of TGF-β, we identified thrombospondin 1 (TSP1) as a potential mediator of MT formation in GBM through SMAD activation. TSP1 was upregulated upon TGF-β stimulation and enhanced MT formation, which was inhibited by TSP1 shRNAs in vitro and in vivo.
CONCLUSION
TGF-β and its downstream mediator TSP1 are important mediators of the MT network in GBM and blocking this pathway could potentially help to break the complex MT-driven invasion/resistance network.
Topics: Glioblastoma; Glioma; Humans; Oligodendroglioma; Thrombospondin 1; Transforming Growth Factor beta
PubMed: 34543427
DOI: 10.1093/neuonc/noab212 -
Pathology Oncology Research : POR 2021Secretogranin III (SCG3) physiologically participates in neurotransmitter storage/transport and is widely expressed in neuroendocrine tumors. However, there is no...
Secretogranin III (SCG3) physiologically participates in neurotransmitter storage/transport and is widely expressed in neuroendocrine tumors. However, there is no report on SCG3 protein expression in gliomas. The method of immunohistochemical staining on a glioma tissue microarray was utilized to detect SCG3 protein expression and investigate the correlations of its expression with clinicopathological and genetic features in gliomas. The RNA-seq data of SCG3 in The Cancer Genome Atlas database was exploited to explore these correlations at the transcriptional level. There were 57.5% (130/226) glioma cases having SCG3 cytoplasmic staining in the tissue microarray. SCG3 expression inversely correlated with malignancy grade at both transcriptional and protein levels. The highest level was observed in oligodendroglial tumors, especially in oligodendrogliomas (ODs) with IDH-mutation/1p19q-codeletion. The lowest SCG3 expression was observed in glioblastomas (GBMs), especially in the mesenchymal subtype. Nearly a half of GBM cases (44.4%, 64/144) had any discernible SCG3 staining, and were defined as SCG3-positive by the microarray study. SCG3-positive GBM cases exhibited improved overall survival as compared with the SCG3-negative cases (29.3 vs. 14.5 months; Hazard ratio, 0.364; 95% CI, 0.216-0.612; < 0.001). A multivariate Cox regression analysis also revealed SCG3 positivity as an independent favorable prognosticator in GBM patients. SCG3 protein expression inversely correlates with glioma malignancy and predicts favorable outcomes in GBM patients.
Topics: Biomarkers, Tumor; Brain Neoplasms; Chromogranins; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Glioma; Humans; Mutation; Prognosis; Retrospective Studies; Survival Rate
PubMed: 34257545
DOI: 10.3389/pore.2021.594931 -
Veterinary Pathology Sep 2021Gliomas are relatively common tumors in aged dogs (especially brachycephalic breeds), and the dog is proving to be useful as a translational model for humans with brain...
Gliomas are relatively common tumors in aged dogs (especially brachycephalic breeds), and the dog is proving to be useful as a translational model for humans with brain tumors. Hitherto, there is relatively little prognostic data for canine gliomas and none on outcome related to specific histological features. Histologic sections of tumor biopsies from 33 dogs with glioma treated with surgical resection and immunotherapy and 21 whole brains obtained postmortem were reviewed. Tumors were diagnosed as astrocytic, oligodendroglial, or undefined glioma using Comparative Brain Tumor Consortium criteria. Putative features of malignancy were evaluated, namely, mitotic counts, glomeruloid vascularization, and necrosis. For biopsies, dogs with astrocytic tumors lived longer than those with oligodendroglial or undefined tumor types (median survival 743, 205, and 144 days, respectively). Dogs with low-grade gliomas lived longer than those with high-grade gliomas (median survival 734 and 194 days, respectively). Based on analysis of tumor biopsies, low mitotic counts, absence of glomeruloid vascularization, and absence of necrosis correlated with increased survival (median 293, 223, and 220 days, respectively), whereas high mitotic counts, glomeruloid vascularization, and necrosis correlated with poor survival (median 190, 170, and 154 days, respectively). Mitotic count was the only histological feature in biopsy samples that significantly correlated with survival ( < .05). Whole-brain analyses for those same histologic features had similar and more robust correlations, and were statistically significant for all features ( < .05). The small size of biopsy samples may explain differences between biopsy and whole-brain tumor data. These findings will allow more accurate prognosis for gliomas.
Topics: Animals; Astrocytoma; Brain Neoplasms; Dog Diseases; Dogs; Glioma; Prognosis; Retrospective Studies
PubMed: 34219560
DOI: 10.1177/03009858211025795