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Cancer Metastasis Reviews Mar 2022In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient... (Review)
Review
In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas' grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma.
Topics: Brain Neoplasms; Glioblastoma; Glioma; Humans; Prognosis; Tumor Microenvironment
PubMed: 34687436
DOI: 10.1007/s10555-021-09997-9 -
Cancer Science Feb 2022Glioblastoma is a paradigm of cancer-associated immunosuppression, limiting the effects of immunotherapeutic strategies. Thus, identifying the molecular mechanisms...
BACKGROUND
Glioblastoma is a paradigm of cancer-associated immunosuppression, limiting the effects of immunotherapeutic strategies. Thus, identifying the molecular mechanisms underlying immune surveillance evasion is critical. Recently, the preferential expression of inhibitory natural killer (NK) cell receptor CD161 on glioma-infiltrating cytotoxic T cells was identified. Focusing on the molecularly annotated, large-scale clinical samples from different ethnic origins, the data presented here provide evidence of this immune modulator's essential roles in brain tumor biology.
METHODS
Retrospective RNA-seq data analysis was conducted in a cohort of 313 patients with glioma in the Chinese Glioma Genome Atlas (CGGA) database and 603 patients in The Cancer Genome Atlas (TCGA) database. In addition, single-cell sequencing data from seven surgical specimens of glioblastoma patients and a model in which patient-derived glioma stem cells were cocultured with peripheral lymphocytes, were used to analyze the molecular evolution process during gliomagenesis.
RESULTS
CD161 was enriched in high-grade gliomas and isocitrate dehydrogenase (IDH)-wildtype glioma. CD161 acted as a potential biomarker for the mesenchymal subtype of glioma and an independent prognostic factor for the overall survival (OS) of patients with glioma. In addition, CD161 played an essential role in inhibiting the cytotoxicity of T cells in glioma patients. During the process of gliomagenesis, the expression of CD161 on different lymphocytes dynamically evolved.
CONCLUSION
The expression of CD161 was closely related to the pathology and molecular pathology of glioma. Meanwhile, CD161 promoted the progression and evolution of gliomas through its unique effect on T cell dysfunction. Thus, CD161 is a promising novel target for immunotherapeutic strategies in glioma treatment.
Topics: Biomarkers, Tumor; Databases, Genetic; Disease Progression; Glioma; Humans; Immune Checkpoint Inhibitors; Inflammation; Isocitrate Dehydrogenase; Lymphocytes, Tumor-Infiltrating; NK Cell Lectin-Like Receptor Subfamily B; Prognosis; Receptors, Antigen, T-Cell; T-Lymphocytes, Cytotoxic; Transcriptome; Tumor Escape
PubMed: 34881489
DOI: 10.1111/cas.15236 -
Cells Mar 2021Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic... (Review)
Review
Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and soon after in solid malignancies. CSCs have attracted remarkable research interest due to their role in tumor resistance to chemotherapy and radiation treatment as well as recurrence. Extensive research has been devoted to the role of CSCs in glioblastoma multiforme (GBM), the most common primary brain tumor in adults, which is characterized by a dismal prognosis because of its aggressive course and poor response to treatment. The aim of the current paper is to provide an overview of current knowledge on the role of cancer stem cells in the pathogenesis and treatment resistance of glioblastoma. The six regulatory mechanisms of glioma stem cells (GSCs)-tumor microenvironment, niche concept, metabolism, immunity, genetics, and epigenetics-are reviewed. The molecular markers used to identify GSCs are described. The role of GSCs in the treatment resistance of glioblastoma is reviewed, along with future treatment options targeting GSCs. Stem cells of glioblastoma thus represent both a driving mechanism of major treatment difficulties and a possible target for more effective future approaches.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; Cell Lineage; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Neoplastic Stem Cells; Phenotype; Radiation Tolerance; Tumor Microenvironment
PubMed: 33799798
DOI: 10.3390/cells10030621 -
Nature Mar 2022Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system....
Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 10 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.
Topics: Astrocytoma; Brain Stem Neoplasms; Child; Gangliosides; Gene Expression Profiling; Glioma; Histones; Humans; Immunotherapy, Adoptive; Mutation; Receptors, Chimeric Antigen; Spinal Cord Neoplasms
PubMed: 35130560
DOI: 10.1038/s41586-022-04489-4 -
Cancer Cell May 2020Glioma stem cells (GSCs) are thought to underlie glioma initiation, evolution, and resistance to existing therapies. Although functional evidence for GSCs is abundant,... (Review)
Review
Glioma stem cells (GSCs) are thought to underlie glioma initiation, evolution, and resistance to existing therapies. Although functional evidence for GSCs is abundant, tumor heterogeneity and intrinsic limitations in GSC assays have represented barriers for the field. In this perspective, we revisit the GSC model in light of recent single-cell expression profiling studies. We highlight how classes of glioma differ in their cellular architecture and relate the observed cellular states to established GSC markers. We additionally propose a set of single-cell informed definitions as a framework for our understanding of the cellular architecture of gliomas and a potential therapeutic outlook.
Topics: Animals; Brain Neoplasms; Genomics; Glioma; Humans; Neoplastic Stem Cells; Single-Cell Analysis
PubMed: 32396858
DOI: 10.1016/j.ccell.2020.04.001 -
Journal of Hematology & Oncology Oct 2021Glioma represents a fast proliferating and highly invasive brain tumor which is resistant to current therapies and invariably recurs. Despite some advancements in... (Review)
Review
Glioma represents a fast proliferating and highly invasive brain tumor which is resistant to current therapies and invariably recurs. Despite some advancements in anti-glioma therapies, patients' prognosis remains poor. Toll-like receptors (TLRs) act as the first line of defense in the immune system being the detectors of those associated with bacteria, viruses, and danger signals. In the glioma microenvironment, TLRs are expressed on both immune and tumor cells, playing dual roles eliciting antitumoral (innate and adaptive immunity) and protumoral (cell proliferation, migration, invasion, and glioma stem cell maintenance) responses. Up to date, several TLR-targeting therapies have been developed aiming at glioma bulk and stem cells, infiltrating immune cells, the immune checkpoint axis, among others. While some TLR agonists exhibited survival benefit in clinical trials, it attracts more attention when they are involved in combinatorial treatment with radiation, chemotherapy, immune vaccination, and immune checkpoint inhibition in glioma treatment. TLR agonists can be used as immune modulators to enhance the efficacy of other treatment, to avoid dose accumulation, and what brings more interests is that they can potentiate immune checkpoint delayed resistance to PD-1/PD-L1 blockade by upregulating PD-1/PD-L1 overexpression, thus unleash powerful antitumor responses when combined with immune checkpoint inhibitors. Herein, we focus on recent developments and clinical trials exploring TLR-based treatment to provide a picture of the relationship between TLR and glioma and their implications for immunotherapy.
Topics: Animals; Brain Neoplasms; Glioma; Humans; Immunologic Factors; Immunotherapy; Models, Molecular; Toll-Like Receptors
PubMed: 34715891
DOI: 10.1186/s13045-021-01191-2 -
Signal Transduction and Targeted Therapy Nov 2023Glioma is the most prevalent brain tumor, presenting with limited treatment options, while patients with malignant glioma and glioblastoma (GBM) have poor prognoses. The...
Glioma is the most prevalent brain tumor, presenting with limited treatment options, while patients with malignant glioma and glioblastoma (GBM) have poor prognoses. The physical obstacle to drug delivery imposed by the blood‒brain barrier (BBB) and glioma stem cells (GSCs), which are widely recognized as crucial elements contributing to the unsatisfactory clinical outcomes. In this study, we found a small molecule, gambogic amide (GA-amide), exhibited the ability to effectively penetrate the blood-brain barrier (BBB) and displayed a notable enrichment within the tumor region. Moreover, GA-amide exhibited significant efficacy in inhibiting tumor growth across various in vivo glioma models, encompassing transgenic and primary patient-derived xenograft (PDX) models. We further performed a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen to determine the druggable target of GA-amide. By the combination of the cellular thermal shift assay (CETSA), the drug affinity responsive target stability (DARTS) approach, molecular docking simulation and surface plasmon resonance (SPR) analysis, WD repeat domain 1 (WDR1) was identified as the direct binding target of GA-amide. Through direct interaction with WDR1, GA-amide promoted the formation of a complex involving WDR1, MYH9 and Cofilin, which accelerate the depolymerization of F-actin to inhibit the invasion of patient-derived glioma cells (PDCs) and induce PDC apoptosis via the mitochondrial apoptotic pathway. In conclusion, our study not only identified GA-amide as an effective and safe agent for treating glioma but also shed light on the underlying mechanisms of GA-amide from the perspective of cytoskeletal homeostasis.
Topics: Humans; Molecular Docking Simulation; Cell Line, Tumor; Glioma; Cytoskeleton; Amides; Microfilament Proteins
PubMed: 37935665
DOI: 10.1038/s41392-023-01666-3 -
Nature Communications Feb 2023Diffuse midline glioma-H3K27M mutant (DMG) and glioblastoma (GBM) are the most lethal brain tumors that primarily occur in pediatric and adult patients, respectively....
Diffuse midline glioma-H3K27M mutant (DMG) and glioblastoma (GBM) are the most lethal brain tumors that primarily occur in pediatric and adult patients, respectively. Both tumors exhibit significant heterogeneity, shaped by distinct genetic/epigenetic drivers, transcriptional programs including RNA splicing, and microenvironmental cues in glioma niches. However, the spatial organization of cellular states and niche-specific regulatory programs remain to be investigated. Here, we perform a spatial profiling of DMG and GBM combining short- and long-read spatial transcriptomics, and single-cell transcriptomic datasets. We identify clinically relevant transcriptional programs, RNA isoform diversity, and multi-cellular ecosystems across different glioma niches. We find that while the tumor core enriches for oligodendrocyte precursor-like cells, radial glial stem-like (RG-like) cells are enriched in the neuron-rich invasive niche in both DMG and GBM. Further, we identify niche-specific regulatory programs for RG-like cells, and functionally confirm that FAM20C mediates invasive growth of RG-like cells in a neuron-rich microenvironment in a human neural stem cell derived orthotopic DMG model. Together, our results provide a blueprint for understanding the spatial architecture and niche-specific vulnerabilities of DMG and GBM.
Topics: Adult; Humans; Child; Transcriptome; Ecosystem; Ependymoglial Cells; Glioma; Brain Neoplasms; Glioblastoma; Tumor Microenvironment
PubMed: 36823172
DOI: 10.1038/s41467-023-36707-6 -
Frontiers in Immunology 2022Cuproptosis is a newly discovered unique non-apoptotic programmed cell death distinguished from known death mechanisms like ferroptosis, pyroptosis, and necroptosis.... (Review)
Review
BACKGROUND
Cuproptosis is a newly discovered unique non-apoptotic programmed cell death distinguished from known death mechanisms like ferroptosis, pyroptosis, and necroptosis. However, the prognostic value of cuproptosis and the correlation between cuproptosis and the tumor microenvironment (TME) in lower-grade gliomas (LGGs) remain unknown.
METHODS
In this study, we systematically investigated the genetic and transcriptional variation, prognostic value, and expression patterns of cuproptosis-related genes (CRGs). The CRG score was applied to quantify the cuproptosis subtypes. We then evaluated their values in the TME, prognostic prediction, and therapeutic responses in LGG. Lastly, we collected five paired LGG and matched normal adjacent tissue samples from Sun Yat-sen University Cancer Center (SYSUCC) to verify the expression of signature genes by quantitative real-time PCR (qRT-PCR) and Western blotting (WB).
RESULTS
Two distinct cuproptosis-related clusters were identified using consensus unsupervised clustering analysis. The correlation between multilayer CRG alterations with clinical characteristics, prognosis, and TME cell infiltration were observed. Then, a well-performed cuproptosis-related risk model (CRG score) was developed to predict LGG patients' prognosis, which was evaluated and validated in two external cohorts. We classified patients into high- and low-risk groups according to the CRG score and found that patients in the low-risk group showed significantly higher survival possibilities than those in the high-risk group (<0.001). A high CRG score implies higher TME scores, more significant TME cell infiltration, and increased mutation burden. Meanwhile, the CRG score was significantly correlated with the cancer stem cell index, chemoradiotherapy sensitivity-related genes and immune checkpoint genes, and chemotherapeutic sensitivity, indicating the association with CRGs and treatment responses. Univariate and multivariate Cox regression analyses revealed that the CRG score was an independent prognostic predictor for LGG patients. Subsequently, a highly accurate predictive model was established for facilitating the clinical application of the CRG score, showing good predictive ability and calibration. Additionally, crucial CRGs were further validated by qRT-PCR and WB.
CONCLUSION
Collectively, we demonstrated a comprehensive overview of CRG profiles in LGG and established a novel risk model for LGG patients' therapy status and prognosis. Our findings highlight the potential clinical implications of CRGs, suggesting that cuproptosis may be the potential therapeutic target for patients with LGG.
Topics: Humans; Brain Neoplasms; Glioma; Mutation; Neoplasm Grading; Prognosis; Tumor Microenvironment; Copper; Apoptosis
PubMed: 36045691
DOI: 10.3389/fimmu.2022.933973 -
Journal of Experimental & Clinical... Sep 2019Growing evidences indicate that circular RNAs (circRNAs) play an important role in the regulation of biological behavior of tumor. We aim to explore the role of circRNA...
BACKGROUND
Growing evidences indicate that circular RNAs (circRNAs) play an important role in the regulation of biological behavior of tumor. We aim to explore the role of circRNA in glioma and elucidate how circRNA acts.
METHODS
Real-time PCR was used to examine the expression of circPTN in glioma tissues and normal brain tissues (NBT). Assays of dual- luciferase reporter system, biotin label RNA pull-down and FISH were used to determine that circPTN could sponge miR-145-5p and miR-330-5p. Tumor sphere formation assay was performed to determine self- renewal of glioma stem cell (GSCs). Cell counting Kit-8 (CCK8), EdU assay and flow cytometry were used to investigate proliferation and cell cycle. Intracranial xenograft was established to determine how circPTN impacts in vivo. Tumor sphere formation assay was performed to determine self- renewal of glioma stem cell (GSCs).
RESULTS
We demonstrated circPTN was significantly higher expression in glioma tissues and glioma cell lines, compared with NBT and HEB (human astrocyte). In gain- and loss-of-function experiments, circPTN significantly promoted glioma growth in vitro and in vivo. Furthermore, we performed dual-luciferase reporter assays and RNA pull-down assays to verify that circPTN acts through sponging miR-145-5p and miR-330-5p. Increasing expression of circPTN rescued the inhibition of proliferation and downregulation of SOX9/ITGA5 in glioma cells by miR-145-5p/miR-330-5p. In addition, we found that circPTN promoted self-renewal and increased the expression of stemness markers (Nestin, CD133, SOX9, and SOX2) via sponging miR-145-5p. Moreover, this regulation was disappeared when circPTN binding sites in miR-145-5p were mutated.
CONCLUSIONS
Our results suggest that circPTN is an oncogenic factor that acts by sponging miR-145-5p/miR-330-5p in glioma.
Topics: 3' Untranslated Regions; Animals; Brain Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Gene Expression Profiling; Glioma; Heterografts; Humans; Mice; MicroRNAs; RNA, Circular; Transcriptome
PubMed: 31511040
DOI: 10.1186/s13046-019-1376-8