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Nature Reviews. Neuroscience Jul 2018Gliomas are heterogeneous tumours derived from glial cells and remain the deadliest form of brain cancer. Although the glioma stem cell sits at the apex of the cellular... (Review)
Review
Gliomas are heterogeneous tumours derived from glial cells and remain the deadliest form of brain cancer. Although the glioma stem cell sits at the apex of the cellular hierarchy, how it produces the vast cellular constituency associated with frank glioma remains poorly defined. We explore glioma tumorigenesis through the lens of glial development, starting with the neurogenic-gliogenic switch and progressing through oligodendrocyte and astrocyte differentiation. Beginning with the factors that influence normal glial linage progression and diversity, a pattern emerges that has useful parallels in the development of glioma and may ultimately provide targetable pathways for much-needed new therapeutics.
Topics: Animals; Astrocytes; Brain Neoplasms; Cell Differentiation; Glioma; Humans; Neural Stem Cells; Oligodendroglia
PubMed: 29777182
DOI: 10.1038/s41583-018-0014-3 -
Neuro-oncology Oct 2023Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic...
BACKGROUND
Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tissues, which is potentially limited due to species-specific differences. The aim of this study was to unravel the cellular origins of the 3 most common pediatric brain tumors, ependymoma, pilocytic astrocytoma, and medulloblastoma, using a developing human cerebellar atlas.
METHODS
We used a single-nucleus atlas of the normal developing human cerebellum consisting of 176 645 cells as a reference for an in-depth comparison to 4416 bulk and single-cell transcriptome tumor datasets, using gene set variation analysis, correlation, and single-cell matching techniques.
RESULTS
We find that the astroglial cerebellar lineage is potentially the origin for posterior fossa ependymomas. We propose that infratentorial pilocytic astrocytomas originate from the oligodendrocyte lineage and MHC II genes are specifically enriched in these tumors. We confirm that SHH and Group 3/4 medulloblastomas originate from the granule cell and unipolar brush cell lineages. Radiation-induced gliomas stem from cerebellar glial lineages and demonstrate distinct origins from the primary medulloblastoma. We identify tumor genes that are expressed in the cerebellar lineage of origin, and genes that are tumor specific; both gene sets represent promising therapeutic targets for future study.
CONCLUSION
Based on our results, individual cells within a tumor may resemble different cell types along a restricted developmental lineage. Therefore, we suggest that tumors can arise from multiple cellular states along the cerebellar "lineage of origin."
Topics: Child; Humans; Animals; Mice; Medulloblastoma; Brain Neoplasms; Glioma; Astrocytoma; Ependymoma; Cerebellum; Cerebellar Neoplasms
PubMed: 37534924
DOI: 10.1093/neuonc/noad124 -
Cells Apr 2024Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently... (Review)
Review
Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently available treatments that consist of surgical resection, radiotherapy, and chemotherapy. Recently, the use of mesenchymal stem cells (MSCs) as a possible kind of cell therapy against glioblastoma is gaining great interest due to their immunomodulatory properties, tumor tropism, and differentiation into other cell types. However, MSCs seem to present both antitumor and pro-tumor properties depending on the tissue from which they come. In this work, the possibility of using MSCs to deliver therapeutic genes, oncolytic viruses, and miRNA is presented, as well as strategies that can improve their therapeutic efficacy against glioblastoma, such as CAR-T cells, nanoparticles, and exosomes.
Topics: Humans; Glioblastoma; Mesenchymal Stem Cell Transplantation; Glioma; Brain Neoplasms; Mesenchymal Stem Cells
PubMed: 38607056
DOI: 10.3390/cells13070617 -
Current Oncology Reports Apr 2018In this review, we seek to summarize the literature concerning the use of single-cell RNA-sequencing for CNS gliomas. (Review)
Review
PURPOSE OF REVIEW
In this review, we seek to summarize the literature concerning the use of single-cell RNA-sequencing for CNS gliomas.
RECENT FINDINGS
Single-cell analysis has revealed complex tumor heterogeneity, subpopulations of proliferating stem-like cells and expanded our view of tumor microenvironment influence in the disease process. Although bulk RNA-sequencing has guided our initial understanding of glioma genetics, this method does not accurately define the heterogeneous subpopulations found within these tumors. Single-cell techniques have appealing applications in cancer research, as diverse cell types and the tumor microenvironment have important implications in therapy. High cost and difficult protocols prevent widespread use of single-cell RNA-sequencing; however, continued innovation will improve accessibility and expand our of knowledge gliomas.
Topics: Biomarkers, Tumor; Brain Neoplasms; Glioma; High-Throughput Nucleotide Sequencing; Humans; Prognosis; Single-Cell Analysis; Tumor Microenvironment
PubMed: 29637300
DOI: 10.1007/s11912-018-0673-2 -
Journal of B.U.ON. : Official Journal... 2019Gliomas are tumors with high incidence and poor prognosis among primary brain tumors and they present difficulties in surgical removal, having also high recurrence rate.... (Review)
Review
Gliomas are tumors with high incidence and poor prognosis among primary brain tumors and they present difficulties in surgical removal, having also high recurrence rate. The efficacy of various treatments on high-grade gliomas is not satisfactory. Some studies have found that age, surgery, radiotherapy, chemotherapy and other factors, such as tumor molecular pathology, have a certain impact on the recurrence of high-grade gliomas, and a common concern in the studies of high-grade gliomas is that one single treatment often has low efficacy. However, with the development of molecular biology, there is a deeper understanding of the pathogenesis of these tumors, and molecular targeted therapy has attracked impressive attention. The treatment of recurrent high-grade gliomas is also more abundant , Diversity of treatment options than before. Oncolytic virus therapy, stem cell therapy, immunotherapy and electric field therapy are now available. These emerging treatments are expected to improve the prospect of treating recurrent high-grade gliomas.
Topics: Cell- and Tissue-Based Therapy; Combined Modality Therapy; Glioma; Humans; Immunotherapy; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Oncolytic Virotherapy
PubMed: 31127986
DOI: No ID Found -
Life Sciences May 2023Glioma is the most common tumor of the primary central nervous system, and its malignant phenotype has been shown to be closely related to glioma stem cells (GSCs).... (Review)
Review
Glioma is the most common tumor of the primary central nervous system, and its malignant phenotype has been shown to be closely related to glioma stem cells (GSCs). Although temozolomide has significantly improved the therapeutic outcome of glioma with a high penetration rate of the blood-brain barrier, resistance is often present in patients. Moreover, evidence has shown that the crosstalk between GSCs and tumor-associated microglia/macrophages (TAMs) affect the clinical occurrence, growth, and multi-tolerance of chemoradiotherapy in gliomas. Here, we highlight its vital roles in the maintenance of the stemness of GSCs and the ability of GSCs to recruit TAMs to the tumor microenvironment and promote their polarization into tumor-promoting macrophages, hence providing groundwork for future research into new treatment strategies of cancer.
Topics: Neoplastic Stem Cells; Tumor-Associated Macrophages; Microglia; Humans; Animals; Glioma; Signal Transduction; Macrophage Activation; Brain Neoplasms; Tumor Microenvironment
PubMed: 36889666
DOI: 10.1016/j.lfs.2023.121558 -
Pathology Oncology Research : POR Oct 2014Malignant gliomas are among the deadliest primary brain tumors. Despite multimodal therapy and advances in chemotherapy, imaging, surgical and radiation techniques,... (Review)
Review
Malignant gliomas are among the deadliest primary brain tumors. Despite multimodal therapy and advances in chemotherapy, imaging, surgical and radiation techniques, these tumors remain virtually incurable. Glioma stem cells may be responsible for resistance to traditional therapies and tumor recurrence. Therefore, elimination of glioma stem cells may be crucial for achieving therapeutic efficacy. Metformin, a small molecule drug widely used in the therapy of type 2 diabetes, has shown significant anti-tumor effects in patients with breast cancer and prostate cancer. Recent preclinical data suggest that metformin also has therapeutic effects against glioma. Here we review the markers and hallmarks of glioma stem cells, and the molecular mechanisms involved in therapeutic targeting of glioma stem cells by metformin.
Topics: Biomarkers, Tumor; Glioma; Humans; Hypoglycemic Agents; Metformin; Neoplastic Stem Cells; Prognosis
PubMed: 25168767
DOI: 10.1007/s12253-014-9837-z -
Oncoimmunology 2022Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of pediatric tumors responsible for the majority of childhood brain tumor deaths.... (Review)
Review
Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of pediatric tumors responsible for the majority of childhood brain tumor deaths. Median overall survival is less than 12 months with a 90% mortality rate at 2 years from diagnosis. Research into the underlying tumor biology and numerous clinical trials have done little to change the invariably poor prognosis. Continued development of novel, efficacious therapeutic options for DMGs remains a critically important area of active investigation. Given that DMGs are not amenable to surgical resection, have only limited response to radiation, and are refractory to traditional chemotherapy, immunotherapy has emerged as a promising alternative treatment modality. This review summarizes the various immunotherapy-based treatments for DMG as well as their specific limitations. We explore the use of cell-based therapies, oncolytic virotherapy or immunovirotherapy, immune checkpoint inhibition, and immunomodulatory vaccination strategies, and highlight the recent clinical success of anti-GD2 CAR-T therapy in diffuse intrinsic pontine glioma (DIPG) patients. Finally, we address the challenges faced in translating preclinical and early phase clinical trial data into effective standardized treatment for DMG patients.
Topics: Brain Stem Neoplasms; Child; Glioma; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Receptors, Chimeric Antigen
PubMed: 36185807
DOI: 10.1080/2162402X.2022.2124058 -
Neoplasia (New York, N.Y.) Jun 2022Mutations in IDH1 and IDH2 drive the development of gliomas. These genetic alterations promote tumor cell renewal, disrupt differentiation states, and induce stem-like...
Mutations in IDH1 and IDH2 drive the development of gliomas. These genetic alterations promote tumor cell renewal, disrupt differentiation states, and induce stem-like properties. Understanding how this phenotypic reprogramming occurs remains an area of high interest in glioma research. Previously, we showed that IDH mutation results in the development of a CD24-positive cell population in gliomas. Here, we demonstrate that this CD24-positive population possesses striking stem-like properties at the molecular and phenotypic levels. We found that CD24 expression is associated with stem-like features in IDH-mutant tumors, a patient-derived gliomasphere model, and a neural stem cell model of IDH1-mutant glioma. In orthotopic models, CD24-positive cells display enhanced tumor initiating potency compared to CD24-negative cells. Furthermore, CD24 knockdown results in changes in cell viability, proliferation rate, and gene expression that closely resemble a CD24-negative phenotype. Our data demonstrate that induction of a CD24-positive population is one mechanism by which IDH-mutant tumors acquire stem-like properties. These findings have significant implications for our understanding of the molecular underpinnings of IDH-mutant gliomas.
Topics: Brain Neoplasms; CD24 Antigen; Glioma; Humans; Isocitrate Dehydrogenase; Mutation; Neoplastic Stem Cells; Phenotype
PubMed: 35398668
DOI: 10.1016/j.neo.2022.100790 -
Current Opinion in Neurology Dec 2021Cancer stem cells (CSCs) have been implicated in the hierarchical heterogeneity and treatment resistance of hematologic and solid tumor malignancies, including gliomas,... (Review)
Review
PURPOSE OF REVIEW
Cancer stem cells (CSCs) have been implicated in the hierarchical heterogeneity and treatment resistance of hematologic and solid tumor malignancies, including gliomas, for several decades now but their therapeutic targeting has not been fully realized. Recent studies have uncovered deeper layers of CSC complexity, related to developmental origins, plasticity, cellular states, and interface with the microenvironment.
RECENT FINDINGS
Sequencing and in-vivo lineage-tracing studies in mouse and patient-derived models show evidence of stem and progenitor origin of glioma, at the same time that genomic studies show a relatedness of glioma CSCs with radial glia. The spate of single-cell sequencing analyses demonstrates the diversity of transcriptional cellular states, which are susceptible to transitions, indicating the plasticity of glioma CSCs. The evolution of glioma CSCs and their interactions with niche cells play important roles in CSC treatment resistance and immune evasion, with epigenetic modulation as one of the emerging mechanisms.
SUMMARY
To harness the potential of CSCs for clinical application, there is urgent need to investigate their complex nature and myriad interactions, to better understand the contribution of these self-renewing, stem-like cancer cells in the pathogenesis and therapy resistance of malignant brain tumors.
Topics: Animals; Brain Neoplasms; Glioma; Humans; Mice; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 34581301
DOI: 10.1097/WCO.0000000000000994