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Neuro-oncology May 2024Over the past 2 decades, the cancer stem cell (CSC) hypothesis has provided insight into many malignant tumors, including glioblastoma (GBM). Cancer stem cells have been... (Review)
Review
Over the past 2 decades, the cancer stem cell (CSC) hypothesis has provided insight into many malignant tumors, including glioblastoma (GBM). Cancer stem cells have been identified in patient-derived tumors and in some mouse models, allowing for a deeper understanding of cellular and molecular mechanisms underlying GBM growth and therapeutic resistance. The CSC hypothesis has been the cornerstone of cellular heterogeneity, providing a conceptual and technical framework to explain this longstanding phenotype in GBM. This hypothesis has evolved to fit recent insights into how cellular plasticity drives tumor growth to suggest that CSCs do not represent a distinct population but rather a cellular state with substantial plasticity that can be achieved by non-CSCs under specific conditions. This has further been reinforced by advances in genomics, including single-cell approaches, that have used the CSC hypothesis to identify multiple putative CSC states with unique properties, including specific developmental and metabolic programs. In this review, we provide a historical perspective on the CSC hypothesis and its recent evolution, with a focus on key functional phenotypes, and provide an update on the definition for its use in future genomic studies.
Topics: Glioblastoma; Humans; Neoplastic Stem Cells; Animals; Brain Neoplasms
PubMed: 38394444
DOI: 10.1093/neuonc/noae011 -
Neuro-oncology Aug 2023Resolving the differential diagnosis between brain metastases (BM), glioblastomas (GBM), and central nervous system lymphomas (CNSL) is an important dilemma for the...
BACKGROUND
Resolving the differential diagnosis between brain metastases (BM), glioblastomas (GBM), and central nervous system lymphomas (CNSL) is an important dilemma for the clinical management of the main three intra-axial brain tumor types. Currently, treatment decisions require invasive diagnostic surgical biopsies that carry risks and morbidity. This study aimed to utilize methylomes from cerebrospinal fluid (CSF), a biofluid proximal to brain tumors, for reliable non-invasive classification that addresses limitations associated with low target abundance in existing approaches.
METHODS
Binomial GLMnet classifiers of tumor type were built, in fifty iterations of 80% discovery sets, using CSF methylomes obtained from 57 BM, GBM, CNSL, and non-neoplastic control patients. Publicly-available tissue methylation profiles (N = 197) on these entities and normal brain parenchyma were used for validation and model optimization.
RESULTS
Models reliably distinguished between BM (area under receiver operating characteristic curve [AUROC] = 0.93, 95% confidence interval [CI]: 0.71-1.0), GBM (AUROC = 0.83, 95% CI: 0.63-1.0), and CNSL (AUROC = 0.91, 95% CI: 0.66-1.0) in independent 20% validation sets. For validation, CSF-based methylome signatures reliably distinguished between tumor types within external tissue samples and tumors from non-neoplastic controls in CSF and tissue. CSF methylome signals were observed to align closely with tissue signatures for each entity. An additional set of optimized CSF-based models, built using tumor-specific features present in tissue data, showed enhanced classification accuracy.
CONCLUSIONS
CSF methylomes are reliable for liquid biopsy-based classification of the major three malignant brain tumor types. We discuss how liquid biopsies may impact brain cancer management in the future by avoiding surgical risks, classifying unbiopsiable tumors, and guiding surgical planning when resection is indicated.
Topics: Humans; Epigenome; Brain Neoplasms; Central Nervous System Neoplasms; Liquid Biopsy; Brain; Glioblastoma; Biomarkers, Tumor
PubMed: 36455236
DOI: 10.1093/neuonc/noac264 -
PloS One 2023This study compared the dynamic susceptibility contrast (DSC) magnetic resonance imaging parameters and apparent diffusion coefficient (ADC) between pilocytic...
Dynamic susceptibility contrast perfusion-weighted and diffusion-weighted magnetic resonance imaging findings in pilocytic astrocytoma and H3.3 and H3.1 variant diffuse midline glioma, H3K27-altered.
OBJECTIVE
This study compared the dynamic susceptibility contrast (DSC) magnetic resonance imaging parameters and apparent diffusion coefficient (ADC) between pilocytic astrocytoma (PA) and diffuse midline glioma, H3K27-altered (DMG) variants.
METHODS
The normalized relative cerebral blood volume (nrCBV), normalized relative flow (nrCBF), percentile signal recovery (PSR), and normalized mean ADC (nADCmean) of 23 patients with midline PAs (median age, 13 years [range, 1-71 years]; 13 female patients) and 40 patients with DMG (8.5 years [1-35 years]; 19 female patients), including 35 patients with H3.3- and five patients with H3.1-mutant tumors, treated between January 2016 and May 2022 were statistically compared.
RESULTS
DMG had a significantly lower nADCmean (median: 1.48 vs. 1.96; p = 0.00075) and lower PSR (0.97 vs. 1.23, p = 0.13) but higher nrCBV and nrCBF (1.66 vs. 1.17, p = 0.058, respectively, and 1.87 vs. 1.19, p = 0.028, respectively) than PA. The H3.3 variant had a lower nADCmean than the H3.1 variant (1.46 vs. 1.80, p = 0.10).
CONCLUSION
DMG had lower ADC and PSR and higher rCBV and rCBF than PA. The H3.3 variant had a lower ADC than the H3.1 variant. Recognizing the differences and similarities in the DSC parameters and ADC between these tumors may help presurgical diagnosis.
Topics: Humans; Female; Adolescent; Brain Neoplasms; Astrocytoma; Diffusion Magnetic Resonance Imaging; Magnetic Resonance Imaging; Perfusion
PubMed: 37450487
DOI: 10.1371/journal.pone.0288412 -
Cells Oct 2023Glioblastoma (GBM) stands as the most prevalent primary malignant brain tumor, typically resulting in a median survival period of approximately thirteen to fifteen...
Glioblastoma (GBM) stands as the most prevalent primary malignant brain tumor, typically resulting in a median survival period of approximately thirteen to fifteen months after undergoing surgery, chemotherapy, and radiotherapy. Nucleobindin-2 (NUCB2) is a protein involved in appetite regulation and energy homeostasis. In this study, we assessed the impact of NUCB2 expression on tumor progression and prognosis of GBM. We further evaluated the relationship between NUCB2 expression and the sensitivity to chemotherapy and radiotherapy in GBM cells. Additionally, we compared the survival of mice intracranially implanted with GBM cells. High NUCB2 expression was associated with poor prognosis in patients with GBM. Knockdown of NUCB2 reduced cell viability, migration ability, and invasion ability of GBM cells. Overexpression of NUCB2 resulted in reduced apoptosis following temozolomide treatment and increased levels of DNA damage repair proteins after radiotherapy. Furthermore, mice intracranially implanted with NUCB2 knockdown GBM cells exhibited longer survival compared to the control group. NUCB2 may serve as a prognostic biomarker for poor outcomes in patients with GBM. Additionally, NUCB2 not only contributes to tumor progression but also influences the sensitivity of GBM cells to chemotherapy and radiotherapy. Therefore, targeting NUCB2 protein expression may represent a novel therapeutic approach for the treatment of GBM.
Topics: Humans; Animals; Mice; Glioblastoma; Nucleobindins; Cell Line, Tumor; Temozolomide
PubMed: 37830634
DOI: 10.3390/cells12192420 -
Journal of Translational Medicine Jun 2024The adaptability of glioblastoma (GBM) cells, encouraged by complex interactions with the tumour microenvironment (TME), currently renders GBM an incurable cancer.... (Review)
Review
The adaptability of glioblastoma (GBM) cells, encouraged by complex interactions with the tumour microenvironment (TME), currently renders GBM an incurable cancer. Despite intensive research, with many clinical trials, GBM patients rely on standard treatments including surgery followed by radiation and chemotherapy, which have been observed to induce a more aggressive phenotype in recurrent tumours. This failure to improve treatments is undoubtedly a result of insufficient models which fail to incorporate components of the human brain TME. Research has increasingly uncovered mechanisms of tumour-TME interactions that correlate to worsened patient prognoses, including tumour-associated astrocyte mitochondrial transfer, neuronal circuit remodelling and immunosuppression. This tumour hijacked TME is highly implicated in driving therapy resistance, with further alterations within the TME and tumour resulting from therapy exposure inducing increased tumour growth and invasion. Recent developments improving organoid models, including aspects of the TME, are paving an exciting future for the research and drug development for GBM, with the hopes of improving patient survival growing closer. This review focuses on GBMs interactions with the TME and their effect on tumour pathology and treatment efficiency, with a look at challenges GBM models face in sufficiently recapitulating this complex and highly adaptive cancer.
Topics: Humans; Glioblastoma; Tumor Microenvironment; Drug Resistance, Neoplasm; Neoplasm Recurrence, Local; Brain Neoplasms; Animals
PubMed: 38844944
DOI: 10.1186/s12967-024-05301-9 -
Seminars in Cell & Developmental Biology Mar 2024Glioblastoma (GB), the most malignant subtype of diffuse glioma, is highly aggressive, invasive and vascularized. Its median survival is still short even with maximum... (Review)
Review
Glioblastoma (GB), the most malignant subtype of diffuse glioma, is highly aggressive, invasive and vascularized. Its median survival is still short even with maximum standard care. There is a need to identify potential new molecules and mechanisms, that are involved in the interactions of GB cells with the tumor microenvironment (TME), for therapeutic intervention. Thrombospondin-1 (TSP1) is a multi-faceted matricellular protein which plays a significant role in development, physiology and pathology including cancer. Recent studies have pinpoint an important role of TSP1 in GB development which will be summarized and discussed herein. We will discuss studies, mainly from preclinical research, which should lead to a deeper understanding of TSP1's role in GB development. We will also discuss some issues with regard to the use of this knowledge for the clinic.
Topics: Humans; Glioblastoma; Brain Neoplasms; Tumor Microenvironment
PubMed: 37690904
DOI: 10.1016/j.semcdb.2023.09.001 -
The Neuroradiology Journal Nov 2023The T2-Fluid-Attenuated Inversion Recovery (T2-FLAIR) mismatch sign is a radiogenomic marker that is easily discernible on preoperative conventional MR imaging.... (Review)
Review
The T2-Fluid-Attenuated Inversion Recovery (T2-FLAIR) mismatch sign is a radiogenomic marker that is easily discernible on preoperative conventional MR imaging. Application of strict criteria (adult population, cerebral hemisphere location, and classic imaging morphology) permits the noninvasive preoperative diagnosis of isocitrate dehydrogenase (IDH)-mutant 1p/19q-non-codeleted diffuse astrocytoma with near-perfect specificity, albeit with variably low sensitivity. This leads to improved preoperative planning and patient counseling. More recent research has shown that the application of less strict criteria compromises the near-perfect specificity of the sign but remains adequate for ruling out IDH-wildtype (glioblastoma) phenotype, which bears a far grimmer prognosis compared to IDH-mutant diffuse astrocytic disease. In this review, we elaborate on the various definitions of the T2-FLAIR mismatch sign present in the literature, illustrate these with images obtained at a comprehensive cancer center, discuss the potential of the mismatch sign for application to certain pediatric-type brain tumors, namely dysembryoplastic neuroepithelial tumor and diffuse midline glioma, and elaborate upon the clinical, histologic, and molecular associations of the T2-FLAIR mismatch sign as recognized to date. Finally, the sign's correlates in diffusion- and perfusion-weighted imaging are presented, and opportunities to further maximize the diagnostic and prognostic applications of the sign in the context of the 2021 revision of the WHO Classification of Central Nervous System Tumors are discussed.
PubMed: 37924213
DOI: 10.1177/19714009231212375 -
Neurology Jan 2024Tumor-related epilepsy is a well-known symptom of glioblastoma. However, the particular characteristics of epileptic seizures related to glioblastoma, ()-wild-type is... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
Tumor-related epilepsy is a well-known symptom of glioblastoma. However, the particular characteristics of epileptic seizures related to glioblastoma, ()-wild-type is almost unexplored longitudinally during the whole course of the disease. We assessed tumor-related epilepsy and seizure control during tumor evolution and the prognostic significance of tumor-related epilepsy.
METHODS
We performed an observational, retrospective single-center study at one tertiary referral neuro-oncology surgical center (2000-2020). We included adult patients treated for a newly diagnosed supratentorial glioblastoma, -wild-type with available preoperative and postoperative MRI and with available epileptic seizure status at diagnosis. To determine factors associated with tumor-related epilepsy or seizure control, univariate analyses were performed using the χ or Fisher exact tests for categorical variables and the unpaired test or Mann-Whitney rank-sum test for continuous variables. Predictors associated with tumor-related epilepsy and seizure control in unadjusted analysis were entered into backward stepwise logistic regression models.
RESULTS
One thousand six patients were enrolled. The cumulative incidence of tumor-related epilepsy increased during tumor evolution (33.1% at diagnosis, 44.7% after oncologic treatment, 52.4% at progression, and 51.8% at the end-of-life phase) and is related to tumor features (cortex involvement, no necrosis, and small volume). Uncontrolled epileptic seizures increased during tumor evolution (20.1% at diagnosis, 32.0% after oncologic treatment, 46.7% at progression, and 41.1% at the end-of-life phase). Epileptic seizure control after oncologic treatment was related to seizure features (uncontrolled before oncologic treatment and focal-to-bilateral tonic-clonic seizures) and to the extent of resection. Epileptic seizure control at tumor progression was related to seizure features (presence at diagnosis and uncontrolled after oncologic treatment) and to the time to progression. Tumor-related epilepsy at diagnosis was a predictor of a longer overall survival (adjusted hazard ratio, 0.78; 95% CI 0.67-0.90; < 0.001) independent of age, Karnofsky Performance Status score, tumor location and volume, extent of resection, standard combined chemoradiotherapy, levetiracetam use, and promoter methylation.
DISCUSSION
The progression of tumor-related epilepsy with the evolution of glioblastoma, -wild-type and the effects of surgery on seizure control argue for proper antiseizure medication and maximal safe resection. Tumor-related epilepsy is an independent predictor of a longer survival.
Topics: Adult; Humans; Death; Epilepsy; Glioblastoma; Isocitrate Dehydrogenase; Medical Oncology; Prognosis; Retrospective Studies; Seizures
PubMed: 38165369
DOI: 10.1212/WNL.0000000000207902 -
Brain Pathology (Zurich, Switzerland) Jan 2024The 2021 WHO Classification of Central Nervous System Tumors recommended evaluation of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion in addition to...
The 2021 WHO Classification of Central Nervous System Tumors recommended evaluation of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion in addition to codeletion of 1p/19q to characterize IDH-mutant gliomas. Here, we demonstrated the use of a nanopore-based copy-number variation sequencing (nCNV-seq) approach to simultaneously identify deletions of CDKN2A/B and 1p/19q. The nCNV-seq approach was initially evaluated on three distinct glioma cell lines and then applied to 19 IDH-mutant gliomas (8 astrocytomas and 11 oligodendrogliomas) from patients. The whole-arm 1p/19q codeletion was detected in all oligodendrogliomas with high concordance among nCNV-seq, FISH, DNA methylation profiling, and whole-genome sequencing. For the CDKN2A/B deletion, nCNV-seq detected the loss in both astrocytoma and oligodendroglioma, with strong correlation with the CNV profiles derived from whole-genome sequencing (Pearson correlation (r) = 0.95, P < 2.2 × 10 to r = 0.99, P < 2.2 × 10 ) and methylome profiling. Furthermore, nCNV-seq can differentiate between homozygous and hemizygous deletions of CDKN2A/B. Taken together, nCNV-seq holds promise as a new, alternative approach for a rapid and simultaneous detection of the molecular signatures of IDH-mutant gliomas without capital expenditure for a sequencer.
Topics: Humans; Oligodendroglioma; Brain Neoplasms; Nanopore Sequencing; Mutation; Glioma; Astrocytoma; Isocitrate Dehydrogenase; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19
PubMed: 37574201
DOI: 10.1111/bpa.13203 -
Oncogene Jan 2024The molecular mechanism of glioblastoma (GBM) radiation resistance remains poorly understood. The aim of this study was to elucidate the potential role of Melanophilin...
The molecular mechanism of glioblastoma (GBM) radiation resistance remains poorly understood. The aim of this study was to elucidate the potential role of Melanophilin (MLPH) O-GlcNAcylation and the specific mechanism through which it regulates GBM radiotherapy resistance. We found that MLPH was significantly upregulated in recurrent GBM tumor tissues after ionizing radiation (IR). MLPH induced radiotherapy resistance in GBM cells and xenotransplanted human tumors through regulating the NF-κB pathway. MLPH was O-GlcNAcylated at the conserved serine 510, and radiation-resistant GBM cells showed higher levels of O-GlcNAcylation of MLPH. O-GlcNAcylation of MLPH protected its protein stability and tripartite motif containing 21(TRIM21) was identified as an E3 ubiquitin ligase promoting MLPH degradation whose interaction with MLPH was affected by O-GlcNAcylation. Our data demonstrate that MLPH exerts regulatory functions in GBM radiation resistance by promoting the NF-κB signaling pathway and that O-GlcNAcylation of MLPH both stabilizes and protects it from TRIM21-mediated ubiquitination. These results identify a potential mechanism of GBM radiation resistance and suggest a potential therapeutic strategy for GBM treatment.
Topics: Humans; NF-kappa B; Cell Line, Tumor; Glioblastoma; Neoplasm Recurrence, Local; Ubiquitination
PubMed: 37950039
DOI: 10.1038/s41388-023-02881-6