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Journal of UOEH 20205-Aminolevulinic acid (ALA) has been widely used as an intravital fluorescence marker in the fluorescence-guided resection of malignant gliomas. Although not a... (Review)
Review
5-Aminolevulinic acid (ALA) has been widely used as an intravital fluorescence marker in the fluorescence-guided resection of malignant gliomas. Although not a photosensitizer itself, 5-ALA is a prodrug that accumulates protoporphyrin IX (PpIX) in the mitochondria of glioma cells; PpIX acts as a photosensitizer. Fluorescence-guided resection for malignant gliomas has some pitfalls. Moreover, 5-ALA is not merely a fluorescence marker but has potential as a mitochondria-targeting drug for malignant glioma therapy. In this article, we review the literature related to 5-ALA, discuss the pitfalls of fluorescence-guided resection using 5-ALA for malignant gliomas, and describe the application of 5-ALA for malignant glioma therapy with personal opinions.
Topics: Aminolevulinic Acid; Brain Neoplasms; Fluorescence; Glioma; Humans; Mitochondria; Photosensitizing Agents; Protoporphyrins; Reactive Oxygen Species; Surgery, Computer-Assisted
PubMed: 32213740
DOI: 10.7888/juoeh.42.27 -
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 -
Cancer Biology & Medicine Nov 2022IDH-mutant lower-grade gliomas (LGGs, grade 2 or 3) eventually transform into secondary grade 4 astrocytomas (sA). Here, we sought to describe the transformation time,...
OBJECTIVE
IDH-mutant lower-grade gliomas (LGGs, grade 2 or 3) eventually transform into secondary grade 4 astrocytomas (sA). Here, we sought to describe the transformation time, risk factors, and outcomes in malignant transformation of IDH-mutant LGGs.
METHODS
We screened data for 108 patients with sA in the Chinese Glioma Genome Atlas who had initial IDH-mutant LGGs and underwent reoperation during 2005-2021. We evaluated the transformation time from IDH-mutant LGGs to sA, and associated risk factors and outcomes. Malignant transformation was defined as pathological confirmation of grade 4 astrocytoma.
RESULTS
The median age of the 108 patients with IDH-mutant LGGs was 35 years (range, 19-54); the median age at transformation was 40 years (range, 25-62); and the median follow-up time for all patients was 146 months (range, 121-171). The average transformation time was 58.8 months for all patients with LGGs (range, 5.9-208.1); 63.5 and 51.9 months for grade 2 and 3 gliomas, respectively; and 58.4 and 78.1 months for IDH-mutant/1p/19q-non-codeleted astrocytomas and IDH-mutant/1p/19q-codeleted oligodendrogliomas, respectively. Univariate and multivariate analysis indicated that radiotherapy [hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.137-0.595; = 0.001] and non-A blood type (HR, 0.37; 95% CI, 0.203-0.680; = 0.001) were protective factors against delayed malignant transformation. Radiotherapy was associated with improved survival after transformation (HR, 0.44; 95% CI, 0.241-0.803; = 0.008), overall survival (HR, 0.50; 95% CI, 0.265-0.972; = 0.041), and progression-free survival (HR, 0.25; 95% CI, 0.133-0.479; < 0.0001) in patients with IDH-mutant gliomas.
CONCLUSIONS
Radiotherapy is associated with delayed malignant transformation and improved survival in patients with IDH-mutant gliomas.
Topics: Humans; Young Adult; Adult; Middle Aged; Isocitrate Dehydrogenase; Brain Neoplasms; Glioma; Oligodendroglioma; Astrocytoma; Glioblastoma; Cell Transformation, Neoplastic
PubMed: 36350001
DOI: 10.20892/j.issn.2095-3941.2022.0472 -
International Journal of Molecular... Nov 2022Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant tumor of the central nervous system. GBM has a very low 5-year survival rate and...
Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant tumor of the central nervous system. GBM has a very low 5-year survival rate and reaching merely a median of ~15 months even with aggressive treatments. PPARγ (Peroxisome proliferator- activated receptor gamma) agonists (ciglitazone), while being widely used on patients of type 2 diabetes mellitus, also have approved anticancer effects. Their action mechanisms on malignant glioma are not fully understood. The aim of this study is to investigate the potential therapeutic effect of PPARγ agonists on maligant glioma. Glioma cell line and in-vivo/ex-vivo animal model intervened by ciglitazone were used to assess the associated mechanism and therapeutic effect. Our results from in vivo and ex vivo experiments showed that ciglitazone not only inhibited tumor growth and its associated angiogenesis, but it also reduced colony formation and migration of tumors. Ciglitazone inhibited the phosphorylation of STAT3 (signal transducer and activator of transcription 3) (at the point of tyrosine 705 by increasing both the amount and activity of SHP-2 (Src homology region 2-containing protein tyrosine phosphatase 2) proteins, based on evidence obtained from immunoprecipitation and immunohistochemistry. Furthermore, ciglitazone activated proteasomes and lysosomes to degrade cell-cycle-related proteins like Cyclin D1, Cyclin E, CDK2 (Cyclin-dependent kinase 2), and CDK4 (Cyclin-dependent kinase 4). Ciglitazone triggered expressions of LC3 (Microtubule-associated protein 1A/1B-light chain 3) and formation of acidic vesicular organelles (AVOs), both of which were implicated in the autophagy pathway. In conclusion, ciglitazone showed the multiple actions to regulate the growth of glioma, which appeared to be a potential candidate for treating malignant glioma.
Topics: Animals; PPAR gamma; Diabetes Mellitus, Type 2; Thiazolidinediones; Glioma; Hypoglycemic Agents; Cell Cycle Proteins; Glioblastoma; Microtubule-Associated Proteins; Cell Line, Tumor
PubMed: 36362294
DOI: 10.3390/ijms232113510 -
Advanced Healthcare Materials Dec 2023Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy is...
Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy is explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia "restorer") and PPA-1 peptide (immune checkpoint blockade) are integrated on a nano-immuno-synergist ( PAM@OA) to work coordinately. The self-assembled OA core is coated with macrophage membrane for efficient blood-brain barrier penetration and microglia targeting, on which PPA-1 peptide is attached via acid-sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, PAM@OA effectively promotes the recruitment and activation of effector T cells by inhibiting aberrant activation of Signal transducer and activator of transcription (STAT-3) pathway in microglia, and assists activated effector T cells in killing tumor cells by blocking elevated immune checkpoint proteins in malignant glioma. Eventually, as adjuvant therapy, the rationally designed nano-immuno-synergist hinders malignant glioma progression and recurrence with or without temozolomide. The work demonstrates the feasibility of a nano-formulation for microglia-based immunotherapy, which may provide a new direction for the treatment of brain tumors.
Topics: Humans; Microglia; Glioma; Brain Neoplasms; Macrophages; Peptides; Tumor Microenvironment
PubMed: 37573475
DOI: 10.1002/adhm.202301861 -
Frontiers in Immunology 2022The tumor immune microenvironment and immunotherapy have become current important tumor research concerns. The unique immune microenvironment plays a crucial role in the... (Review)
Review
The tumor immune microenvironment and immunotherapy have become current important tumor research concerns. The unique immune microenvironment plays a crucial role in the malignant progression of isocitrate dehydrogenase (IDH) mutant gliomas. IDH mutations in glioma can inhibit tumor-associated immune system evasion of NK cell immune surveillance. Meanwhile, mutant IDH can inhibit classical and alternative complement pathways and directly inhibit T-cell responses by metabolizing isocitrate to D-2-Hydroxyglutaric acid (2-HG). IDH has shown clinically relevant efficacy as a potential target for immunotherapy. This article intends to summarize the research progress in the immunosuppressive microenvironment and immunotherapy of IDH-mutant glioma in recent years in an attempt to provide new ideas for the study of occurrence, progression, and treatment of IDH-mutant glioma.
Topics: Brain Neoplasms; Glioma; Humans; Immunologic Factors; Immunotherapy; Isocitrate Dehydrogenase; Mutation; Tumor Microenvironment
PubMed: 35769466
DOI: 10.3389/fimmu.2022.914618 -
Seminars in Cancer Biology Jul 2022Brain tumors remain one of the most difficult tumors to treat and, depending on the diagnosis, have a poor prognosis. Of brain tumors, glioblastoma (GBM) is the most... (Review)
Review
Brain tumors remain one of the most difficult tumors to treat and, depending on the diagnosis, have a poor prognosis. Of brain tumors, glioblastoma (GBM) is the most common malignant glioma and has a dismal prognosis, with only about 5% of patients alive five years after diagnosis. While advances in targeted therapies and immunotherapies are rapidly improving outcomes in a variety of other cancers, the standard of care for GBM has largely remained unaltered since 2005. There are many well-studied challenges that are either unique to brain tumors (i.e., blood-brain barrier and immunosuppressive environment) or amplified within GBM (i.e., tumor heterogeneity at the cellular and molecular levels, plasticity, and cancer stem cells) that make this disease particularly difficult to treat. While we touch on all these concepts, the focus of this review is to discuss the immense inter- and intra-tumoral heterogeneity and advances in our understanding of tumor cell plasticity and epigenetics in GBM. With each improvement in technology, our understanding of the complexity of tumoral heterogeneity and plasticity improves and we gain more clarity on the causes underlying previous therapeutic failures. However, these advances are unlocking new therapeutic opportunities that scientists and physicians are currently exploiting and have the potential for new breakthroughs.
Topics: Brain Neoplasms; Cell Plasticity; Glioblastoma; Glioma; Humans; Neoplastic Stem Cells
PubMed: 33640445
DOI: 10.1016/j.semcancer.2021.02.014 -
Clinical & Translational Oncology :... Sep 2023High-grade gliomas (HGG) are the most common primary brain malignancies and account for more than half of all malignant primary brain tumors. The new 2021 WHO...
High-grade gliomas (HGG) are the most common primary brain malignancies and account for more than half of all malignant primary brain tumors. The new 2021 WHO classification divides adult HGG into four subtypes: grade 3 oligodendroglioma (1p/19 codeleted, IDH-mutant); grade 3 IDH-mutant astrocytoma; grade 4 IDH-mutant astrocytoma, and grade 4 IDH wild-type glioblastoma (GB). Radiotherapy (RT) and chemotherapy (CTX) are the current standard of care for patients with newly diagnosed HGG. Several clinically relevant molecular markers that assist in diagnosis and prognosis have recently been identified. The treatment for recurrent high-grade gliomas is not well defined and decision-making is usually based on prior strategies, as well as several clinical and radiological factors. Whereas the prognosis for GB is grim (5-year survival rate of 5-10%) outcomes for the other high-grade gliomas are typically better, depending on the molecular features of the tumor. The presence of neurological deficits and seizures can significantly impact quality of life.
Topics: Adult; Humans; Quality of Life; Neoplasm Recurrence, Local; Glioma; Brain Neoplasms; Glioblastoma; Mutation
PubMed: 37540408
DOI: 10.1007/s12094-023-03245-y -
Frontiers in Immunology 2023Gliomas, the most prevalent primary malignant tumors of the central nervous system in adults, exhibit slow growth in lower-grade gliomas (LGG). However, the majority of...
BACKGROUND
Gliomas, the most prevalent primary malignant tumors of the central nervous system in adults, exhibit slow growth in lower-grade gliomas (LGG). However, the majority of LGG cases progress to high-grade gliomas, posing challenges for prognostication. The tumor microenvironment (TME), characterized by telomere-related genes and immune cell infiltration, strongly influences glioma growth and therapeutic response. Therefore, our objective was to develop a Telomere-TME (TM-TME) classifier that integrates telomere-related genes and immune cell landscape to assess prognosis and therapeutic response in glioma.
METHODS
This study encompassed LGG patients from the TCGA and CCGA databases. TM score and TME score were derived from the expression signatures of telomere-related genes and the presence of immune cells in LGG, respectively. The TM-TME classifier was established by combining TM and TME scores to effectively predict prognosis. Subsequently, we conducted Kaplan-Meier survival estimation, univariate Cox regression analysis, and receiver operating characteristic curves to validate the prognostic prediction capacity of the TM-TME classifier across multiple cohorts. Gene Ontology (GO) analysis, biological processes, and proteomaps were performed to annotate the functional aspects of each subgroup and visualize the cellular signaling pathways.
RESULTS
The TM_low+TME_high subgroup exhibited superior prognosis and therapeutic response compared to other subgroups (P<0.001). This finding could be attributed to distinct tumor somatic mutations and cancer cellular signaling pathways. GO analysis indicated that the TM_low+TME_high subgroup is associated with the neuronal system and modulation of chemical synaptic transmission. Conversely, the TM_high+TME_low subgroup showed a strong association with cell cycle and DNA metabolic processes. Furthermore, the classifier significantly differentiated overall survival in the TCGA LGG cohort and served as an independent prognostic factor for LGG patients in both the TCGA cohort (P<0.001) and the CGGA cohort (P<0.001).
CONCLUSION
Overall, our findings underscore the significance of the TM-TME classifier in predicting prognosis and immune therapeutic response in glioma, shedding light on the complex immune landscape within each subgroup. Additionally, our results suggest the potential of integrating risk stratification with precision therapy for LGG.
Topics: Adult; Humans; Prognosis; Biomarkers; Telomere; Glioma; Central Nervous System; Tumor Microenvironment
PubMed: 37662954
DOI: 10.3389/fimmu.2023.1220100 -
Neuropathology and Applied Neurobiology Feb 2022The advent of checkpoint immunotherapy, particularly with programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, has provided ground-breaking... (Review)
Review
The advent of checkpoint immunotherapy, particularly with programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, has provided ground-breaking results in several advanced cancers. Substantial efforts are being made to extend these promising therapies to other refractory cancers such as gliomas, especially glioblastoma, which represents the most frequent and malignant glioma and carries an exceptionally grim prognosis. Thus, there is a need for new therapeutic strategies with related biomarkers. Gliomas have a profoundly immunosuppressive tumour micro-environment and evade immunological destruction by several mechanisms, one being the expression of inhibitory immune checkpoint molecules such as PD-L1. PD-L1 is recognised as an important therapeutic target and its expression has been shown to hold prognostic value in different cancers. Several clinical trials have been launched and some already completed, but PD-1/PD-L1 inhibitors have yet to show convincing clinical efficacy in gliomas. Part of the explanation may reside in the vast molecular heterogeneity of gliomas and a complex interplay within the tumour micro-environment. In parallel, critical knowledge about PD-L1 expression is beginning to accumulate including knowledge on expression levels, testing methodology, co-expression with other checkpoint molecules and prognostic and predictive value. This article reviews these aspects and points out areas where biomarker research is needed to develop more successful checkpoint-related therapeutic strategies in gliomas.
Topics: B7-H1 Antigen; Biomarkers, Tumor; Glioma; Humans; Prognosis; Programmed Cell Death 1 Receptor; Tumor Microenvironment
PubMed: 34533233
DOI: 10.1111/nan.12767