Materiały źródłowe

• #1 Glioblastoma: An Update in Pathology, Molecular Mechanisms and Biomarkers

  https://www.mdpi.com/1422-0067/25/5/3040

  Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor in adults. […] Despite important advances in understanding the molecular pathogenesis and biology of this tumor in the past decade, the prognosis for GBM patients remains poor. […] GBM is characterized by aggressive biological behavior and high degrees of inter-tumor and intra-tumor heterogeneity. […] Increased understanding of the molecular and cellular heterogeneity of GBM may not only help more accurately define specific subgroups for precise diagnosis but also lay the groundwork for the successful implementation of targeted therapy. […] Herein, we systematically review the key achievements in the understanding of GBM molecular pathogenesis, mechanisms, and biomarkers in the past decade. […] We discuss the advances in the molecular pathology of GBM, including genetics, epigenetics, transcriptomics, and signaling pathways.

• #2 Current understanding of gliomagenesis: from model to mechanism

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9724244/

  Glioma, a kind of central nervous system (CNS) tumor, is hard to cure and accounts for 32% of all CNS tumors. Establishing a stable glioma model is critically important to investigate the underlying molecular mechanisms involved in tumorigenesis and tumor progression. Various core signaling pathways have been identified in gliomagenesis, such as RTK/RAS/PI3K, TP53, and RB1. Recently, a new classification system for glioma tumors by integrating both tumor morphology and biomolecular features has been introduced. A recent study indicated that the characteristics of gene expression in the gliomas derived from transgenic zebrafish supported the notion that different molecular mutation-selective pressures drive different progression of gliomagenesis. Drug-based curative measures are not ideal for treating glioma because of insufficient understanding of the molecular mechanisms associated with gliomagenesis. In addition, the limited and vague identification of early-stage gliomas also leads to delays in glioma treatment. To date, three core signaling pathways have been identified for high-grade glioma, namely, the receptor tyrosine kinase (RTK)/phosphatidylinositol 3′-kinase (PI3K)/alpha serine-threonine protein kinase (AKT), phosphoprotein53 (TP53), and retinoblastoma (RB1) signaling pathways. Cancer cells have the fundamental features of growth and survival beyond a nominal homeostatic or favorable environment, and their growth, survival, oncogenic proliferation, and apoptosis are governed by signaling pathways. Several methods of genetic modification, including RCAS/t-va, Cre-loxP, zinc finger nucleases (ZFNs), and Tal-effector nuclease (TALENs), have introduced a new dimension in the development of genome manipulation at the molecular level. However, these gene editing techniques have various limitations, such as high cost, difficult design, labor intensiveness, low efficiency, and time consumption. Specifically, CRISPR/Cas9 system, a powerful gene-editing tool, includes a guide RNA (gRNA) and programmable nuclease (Cas9) that can process double-strand breaks (DSBs) at specific target sites efficiently and accurately via homology-directed repair (HDR) or nonhomologous end joining (NHEJ). Therefore, it is essential to highlight the benefits of developing a new glioma model using CRISPR/Cas9 to better understand the molecular mechanisms of gliomagenesis and establish better therapeutic methods. The identification of these molecular features could improve the therapeutic strategies of the treatment of glioma. Although the molecular mechanisms of gliomagenesis were widely investigated in cultured cells, the limitations for modeling invasion, angiogenesis and metastasis still exist. An ideal glioma animal model should have several features, including genetic similarity to human glioma, the invasive and angiogenic-like growth, the imitation of the therapeutic response, to allow for more accurately predict the clinical outcome. The reviewed literature showed that mice, rats and zebrafish are the most widely used glioma animal models with methods such as chemical induction, xenografting, and bioengineering. In gliomas, another commonly identified pathway is TP53 signaling pathway. As the most common tumor suppressor gene, TP53 mutation is critical for the progression of glioma. TP53 regulates multiple genes that control DNA repair, cell cycle, apoptosis, and progression. In addition, primary Tp53-/- astrocytes have an increased susceptibility to tumor transformation and growth. Interestingly, either Tp53 homozygous (Tp53-/-) or heterozygous (Tp53+/-) mice and zebrafish fail to induce gliomagenesis, indicating that the single Tp53 mutation might be insufficient to initiate gliomagenesis. Therefore, this gene editing technology might provide a promising platform for genetically studying tumorigenesis and make it convenient to explore treatment methods for cancer drug targets inspired by CRISPR/Cas9-based genetic screens.

• #3 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0

  Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor in adults, characterized by a poor prognosis and significant resistance to existing treatments. […] A hallmark of GBM is its intricate molecular profile, driven by disruptions in multiple signaling pathways, including PI3K/AKT/mTOR, Wnt, NF-B, and TGF-, critical to tumor growth, invasion, and treatment resistance. […] In GBM, changes and/or increased activity in crucial signaling pathways such as Wnt, TGF-, VEGF, EGFR, CDKN2A, NF-B, and the PI3K/AKT/mTOR pathway are believed to play a role in the disease’s pathogenesis and contribute to the tumor’s aggressive behavior. […] It is crucial to recognize that human malignant gliomas, including glioblastomas, typically do not rely on a single oncogene or tumor suppressor gene for their initiation and progression.

• #4 Molecular Pathogenesis of Glioblastoma in Adults and Future Perspectives: A Systematic Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8910150/

  Glioblastoma (GBM) is the most common and malignant tumour of the central nervous system. Recent appreciation of the heterogeneity amongst these tumours not only changed the WHO classification approach, but also created the need for developing novel and personalised therapies. […] Gliomagenesis, the formation and development of gliomas, is a multistep process in which normal cells undergo genetic alterations that lead to malignant derivatives. Cells progressively acquire genetic and epigenetic changes resulting in inhibiting tumour suppressor genes (TSG) and activation of proto-oncogenes. Together, these changes help cells escape the body’s regulatory mechanisms and lead to rapidly proliferating, undifferentiated cell clusters, known as tumours. These tumours become malignant when they invade and migrate into other tissues.

• #5 Molecular Pathogenesis of Glioblastoma in Adults and Future Perspectives: A Systematic Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8910150/

  At a cellular level, certain tumorigenic processes have been associated with the development and progression of GBMs. These intracellular events include but are not limited to loss of cell cycle control, growth factor over-expression, angiogenesis, invasion migration, genetic instability and disorder of apoptosis. […] The Cancer Genome Atlas (TCGA) network outlines four distinct molecular subtypes of GBM: Neural, Proneural, Classical and Mesenchymal. Each of these subtypes harbours unique molecular and genetic aberrations that drive tumorigenesis. […] Loss of cell cycle control is involved in gliomagenesis. […] The G1 checkpoint has been an important topic of research in GBMs, and it mainly involves cyclins and cyclin-dependent kinases (CDK). […] Not surprisingly, 87% of GBM patients have an associated p53 mutation.

• #6 High grade gliomas: Pathogenesis, management and prognosis | ACNR

  https://acnr.co.uk/articles/high-grade-gliomas-pathogenesis-management-and-prognosis/

  Glioblastomas develop either as primary tumours or arise from pre existing low grade gliomas (Table 1). […] These primary and secondary GBMs constitute separate and distinct disease entities. They affect different epidemiological groups and carry different prognoses. […] Primary gliomas usually are of a de novo manifestation involving older patients with a shorter clinical history. On the other hand, secondary gliomas are usually part of a malignant progression from low grade to high grade involving younger patients with a variable interval between 1 to 10 years. […] Large numbers of genetic abnormalities have been found in gliomas. These genetic abnormalities increase as the grade of glioma increases. Most of these abnormalities affect entry into cell cycle or inhibit apoptosis via multiple pathways, which is discussed in depth elsewhere.

• #7 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0

  Epigenetic modifications play a pivotal role in the development of GBM, with approximately 50% of newly diagnosed cases showing methylation of the MGMT promoter. […] Genomic studies of GBM have unveiled several critical signaling pathways and genetic mutations that drive the tumor’s progression. […] The presence of multiple dysregulated signaling pathways in GBM underscores the idea that tumors rely on the disruption of various molecular targets, which collectively influence tumor biology. […] The PI3K/AKT/mTOR intracellular signaling pathway plays a crucial role in regulating various cellular processes, including growth, proliferation, and metabolism. […] Dysregulation of PI3K/AKT/mTOR signaling is commonly observed in many cancers, contributing to tumorigenesis by promoting uncontrolled cell growth, survival, and resistance to apoptosis.

• #8 Glioblastoma: An Update in Pathology, Molecular Mechanisms and Biomarkers

  https://www.mdpi.com/1422-0067/25/5/3040

  These studies have not only revealed the molecular heterogeneity of GBM at multiple genome-wide levels but also provided useful insights into the fundamental mechanisms for the pathogenesis of GBM. […] The key genetic alterations characterized in GBM include TERT promoter mutation, PTEN tumor suppressor gene deletion, high-level gene amplification of proto-oncogene EGFR, ATRX mutation, and TP53 mutation. […] Epigenetic modifications, including DNA methylation, histone modification, and chromatin remodeling, have been regarded as a hallmark of GBM tumorigenesis and development. […] The transcriptomic features of GBM have been extensively studied with the advance of high-throughput transcriptome profiling methods and computational analysis tools. […] The molecular abnormalities characterized at each dimension (genetics, epigenetics, and transcriptomics) are not isolated but correlate with each other.

• #9 High grade gliomas: Pathogenesis, management and prognosis | ACNR

  https://acnr.co.uk/articles/high-grade-gliomas-pathogenesis-management-and-prognosis/

  Recent data from the Cancer Genome Project suggests genetic abnormalities can classify GBM’s into four categories: CLASSICAL – amplification of EGFR, MESENCHYMAL – NF1 deletion, PRONEURAL – mutations of PDGFR-A and IDH-1, NEURAL – expressed neuronal markers. […] The proneural group showed improved survival, but interestingly showed no survival advantage with chemoradiotherapy vs. radiotherapy alone. Further work is underway to understand the significance of this classification for individual patients.

• #10 Current understanding of gliomagenesis: from model to mechanism

  https://www.medsci.org/v19p2071.htm

  Glioma, a kind of central nervous system (CNS) tumor, is hard to cure and accounts for 32% of all CNS tumors. Establishing a stable glioma model is critically important to investigate the underlying molecular mechanisms involved in tumorigenesis and tumor progression. Various core signaling pathways have been identified in gliomagenesis, such as RTK/RAS/PI3K, TP53, and RB1. […] Recently, genetic markers were proven to be effective clinical signs that can be measured with precision to predict glioma outcome. To date, three core signaling pathways have been identified for high-grade glioma, namely, the receptor tyrosine kinase (RTK)/phosphatidylinositol 3′-kinase (PI3K)/alpha serine-threonine protein kinase (AKT), phosphoprotein53 (TP53), and retinoblastoma (RB1) signaling pathways. […] Several studies have indicated that at least one aberrant pathway among the RTK/PI3K/AKT, TP53 and RB1 signaling pathways was identified in 80-90% of glioblastomas, which highlights their potential as therapeutic targets.

• #11 Current understanding of gliomagenesis: from model to mechanism

  https://www.medsci.org/v19p2071.htm

  The RTK/Ras/PI3K pathways promote cell survival. PI3Ks, a family of heterodimeric kinases, have been reported to contain genetic alterations in 88% of GBM cases. This pathway is also activated via the loss of negative regulators, such as NF1 and PTEN. […] In gliomas, another commonly identified pathway is TP53 signaling pathway. As the most common tumor suppressor gene, TP53 mutation is critical for the progression of glioma. […] RB1 pathway and its downstream effectors were also genetically and epigenetically regulates in various malignant tumors. Specifically, frequent alterations in Rb1 pathway have been observed in 40-70% GBM patients. This pathway plays an important role in DNA repair and replication, cellular development, differentiation, migration, mitosis, and apoptosis. […] The identification of these molecular features could improve the therapeutic strategies of the treatment of glioma.

• #12 The epigenetic dysfunction underlying malignant glioma pathogenesis | Laboratory Investigation

  https://www.nature.com/articles/s41374-022-00741-7

  Comprehensive molecular profiling has dramatically transformed the diagnostic neuropathology of brain tumors. […] Several of the key molecular alterations driving glioma classification involve epigenetic dysregulation at a fundamental level, implicating fields of biology not previously thought to play major roles glioma pathogenesis. […] Moreover, above and beyond tumor classification, these developments have revealed novel pathogenic mechanisms, involving epigenetic regulator genes not previously been implicated in oncogenesis. […] This review will describe recent developments in diffuse glioma classification, including those informing the World Health Organization (WHO) 2021 blue book, with an eye towards molecular abnormalities inducing epigenetic dysregulation, their downstream biological consequences, and strategies for therapeutic targeting.

• #13 The epigenetic dysfunction underlying malignant glioma pathogenesis | Laboratory Investigation

  https://www.nature.com/articles/s41374-022-00741-7

  Many of these key biomarkers, including mutations in genes encoding isocitrate dehydrogenase enzymes (IDH1 and IDH2), H3 histone monomers (H3F3A and HIST1H3B), and the histone chaperone -thalassaemia mental retardation X-linked (ATRX), induce disruptions in normal epigenetic functionality, revealing previously unappreciated oncogenic mechanisms. […] IDH mutations are thought to promote gliomagenesis in part through the disruption of normal chromatin topology. […] The mutation itself appears to bind and restrict the enzymatic activity of the methyltransferase EZH2, a core subunit of the Polycomb Repressive Complex2 (PRC2). […] This inhibition leads to decreased deposition of the normally repressive H3K27me3 chromatin mark, by way of PRC2 sequestration. […] Taken together, these hallmark molecular alterations guide glioma classification and are fundamentally driven by potentially targetable epigenetic dysregulation.

• #14 Fundamental Research Paved the Way for the Development of Vorasidenib – NCI

  https://www.cancer.gov/about-nci/organization/dcb/progress/cancer-biology-and-vorasidenib-development

  During the 2023 American Society of Clinical Oncology (ASCO) annual meeting, a plenary presentation reported that Vorasidenib, a promising new drug to treat IDH-mutant low-grade glioma (a common brain tumor in adults), slows brain tumor growth and delays the need for toxic therapies (i.e., radiation or chemotherapy) in patients. […] This important clinical discovery represents the first new drug treatment for patients with glioma in over 20 years. […] We begin our story tracing back the fundamental research for the development of Vorasidenib to genomic analyses of brain tumors. […] Using genomic sequencing in studies partially supported by the Division of Cancer Biology (DCB), researchers discovered that mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 (key regulators in cellular metabolism) occur in gliomas.

• #15

  https://journals.lww.com/tnoc/fulltext/2019/02030/role_of_natural_killer_cells_in_isocitrate.2.aspx

  Regulation of the immune environment is associated with the genetic profile of the tumors. One of the most prevalent mutations in low-grade gliomas and secondary GBMs is the IDH mutation with IDH1/IDH2 mutations predominating in diffuse astrocytomas and oligodendroglial tumors. This mutation leads to a hypermethylated phenotype, also called glioma CpG island methylation phenotype, resulting in the silencing of numerous immune-regulatory genes. IDH-mutant gliomas are present in younger patients and confer improved, though ultimately dismal, survival outcomes compared to IDH wild-type GBM. […] The mutation in isocitrate dehydrogenase results in the production of (R)-2-hydroxyglutarate (2-HG), a signature on co-metabolite of these tumors. 2-HG acts at the epigenetics to suppress the expression of multiple antitumor immune genes, thereby creating an immune-suppressive microenvironment to allow for the progression to a high-grade tumor.

• #16 Fundamental Research Paved the Way for the Development of Vorasidenib – NCI

  https://www.cancer.gov/about-nci/organization/dcb/progress/cancer-biology-and-vorasidenib-development

  This led to cancer biology studies, including many supported by DCB (described below), that advanced the understanding of the biology of IDH mutations and their mechanistic role in promoting glioma: […] Dr. Yan demonstrated that suppressing the expression of mutant IDH inhibits cancer cell growth and suggested that it could be a target for anti-cancer therapies. […] Biological research also showed that mutant IDH1 and IDH2 produce 2-hydroxyglutarate, an oncometabolite that promotes the development and progression of brain tumors. […] Delving deeper, scientists identified molecular factors involved in the expression levels of the oncometabolite with IDH mutations and revealed a mechanism by which the accumulation of the oncometabolite contributes to IDH mutant glioma pathogenesis. […] Building on the data related to 2-hydroxyglutarate, multiple studies found that IDH mutations induce epigenetic changes (specifically hypermethylation of DNA) and downstream alterations in the gene expression of cancer-related pathways.

• #17 Glioma MOD & VORANIGO® MOA | VORANIGO® (vorasidenib) | HCP

  https://www.voranigohcp.com/about/mod-moa

  2-hydroxyglutarate (2-HG) levels are elevated in mIDH astrocytoma and oligodendroglioma. […] These mutated enzymes lead to the overproduction of 2-HG, which disrupts normal cellular processes, contributing to impaired cellular differentiation and oncogenesis. […] VORANIGO inhibits mIDH1 and mIDH2 enzymes to decrease the production of 2-HG and partially restore cellular differentiation.

• #18 Fundamental Research Paved the Way for the Development of Vorasidenib – NCI

  https://www.cancer.gov/about-nci/organization/dcb/progress/cancer-biology-and-vorasidenib-development

  They further showed that the epigenetic changes create a cell state that is primed for malignancy. […] Next, researchers found that suppressing the gene expression of the enzyme that makes 2-hydroxyglutarate or blocking epigenetic changes (i.e. methylation) caused by IDH mutations inhibits cancer cell growth in preclinical models. […] Subsequent studies with inhibitors of the mutant IDH1 and IDH2, specifically AGI-5198 (in a study partially supported by DCB) and AG-881 (a.k.a Vorasidenib), showed that suppressing the levels of 2-hydroxyglutarate reduces the growth of IDH-mutant cancer cells. […] In a clinical trial, vorasidenib slowed the growth of gliomas in patients whose brain tumors had IDH gene mutations. […] In a surgical study investigating its therapeutic mechanism-of-action, Vorasidenib was found to substantially reduce levels of 2-hydroxyglutarate and associated epigenetic changes related to IDH mutations by reversing gene expression programs associated with the mutant IDH1 enzyme.

• #19 Molecular Pathogenesis of Glioblastoma in Adults and Future Perspectives: A Systematic Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8910150/

  In non-neoplastic cells, DNA repair aims to prevent genetic instability that could lead to tumorigenesis. […] Most notably, p53 mutations leading to impaired apoptotic response have been linked to impaired DNA damage response (DDR) and gliomagenesis. […] Cancer cells adapt DNA repair mechanisms to play a crucial factor in development of therapy resistance and tumour relapse. […] Glioblastoma cells show over-expression of certain growth factors and their receptors. This creates an autocrine growth-promoting loop which provides growth advantage to rapidly proliferating tumour cells. […] The potential role of PI3K in this process has already been discussed above. […] Reprograming CSCs into more differentiated and less oncogenic phenotypes is a novel therapeutic approach in GBM. […] Inducing apoptosis is another potential approach for GBM treatment.

• #20 Chromosomal instability: a key driver in glioma pathogenesis and progression | European Journal of Medical Research | Full Text

  https://eurjmedres.biomedcentral.com/articles/10.1186/s40001-024-02043-8

  Gliomas with significant CIN are associated with increased virulence, correlating with poorer clinical outcomes. […] As CIN continuously modifies the genomic constitution of neoplastic cells, emergent sub-clonal entities have the potential to survive existing treatment options. […] Understanding the genetic complexities of gliomas and CIN’s influence on them, particularly in treatment-resistant glioma subtypes and their responses to currently available interventions, is crucial. […] Recent discoveries of the interaction of CIN and gliomas can reshape oncological care, potentially opening the door to precision-oriented therapy options. […] The cumulative genomic landscape created by CIN gives neoplastic cells an adaptive advantage, allowing them to avoid canonical regulatory checkpoints and sustain uncontrolled proliferation.

• #21 Chromosomal instability: a key driver in glioma pathogenesis and progression | European Journal of Medical Research | Full Text

  https://eurjmedres.biomedcentral.com/articles/10.1186/s40001-024-02043-8

  Chromosomal instability (CIN) is a pivotal factor in gliomas, contributing to their complexity, progression, and therapeutic challenges. CIN influences glioma progression by affecting key oncological pathways, such as tumor suppressor genes (e.g., TP53), oncogenes (e.g., EGFR), and DNA repair mechanisms. It drives tumor evolution, promotes inflammatory signaling, and affects immune interactions, potentially leading to poor clinical outcomes and treatment resistance. […] Emerging evidence, however, links CIN to brain malignancies, specifically gliomas, which are glial progenitor-derived neoplasms. […] Recent findings have highlighted the role of non-coding RNAs (ncRNAs) in modulating CIN, adding another layer of complexity to the regulation of genomic stability. […] CIN-mediated changes commonly intersect critical oncological pathways, affecting key tumor suppressor genes, oncogenes, and DNA repair-centric genes such as TP53, PTEN, and EGFR.

• #22 Molecular Pathogenesis of Glioblastoma in Adults and Future Perspectives: A Systematic Review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8910150/

  Targeting these adaptive mechanisms, which are also involved in developing therapy resistance, could be a novel treatment strategy. […] Glioblastoma cells masterfully manipulate tumour microenvironment (TME) and the cells within to invade brain parenchyma. […] GBM cells can evade the host immune system by modifying TME. […] Multiple immunotherapy strategies have been trialed to train the host immune system against GBM cells. […] Exciting novel immune therapy strategies including dendritic cell vaccines, B-cell vaccines and viral vectors have been developed for the treatment of GBM.

• #23 Microenvironmental Regulation And Epigenetic Control Of Glioma Pathogenesis

  https://digitalcommons.library.uab.edu/etd-collection/1232/

  Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor initiating cell hypothesis. […] The ischemic microenvironment characterized by low oxygen and glucose, and acidic stress occurs in both solid tumors and non-neoplastic tissue injury. […] Standard of care for glioblastoma (GBM) includes the chemotherapy temozolomide, which is not curative due, in part, to residual therapy-resistant brain tumor initiating cells (BTICs). […] By modeling physiologic microenvironments in GBM in vitro, we identified chromodomain helicase DNA binding protein 7 (CHD7) as a novel ischemia-regulated epigenetic modifier. […] Microenvironment-mediated decreases in CHD7 occurred in GBM and neural progenitor cells in vitro, and in perinecrotic niches of GBM patient sections. […] Together, our data provide insight into the molecular responses to ischemia that regulate GBM growth and angiogenesis and provide opportunities for therapeutic intervention.

• #24 Role of miRNA in Glioma Pathogenesis, Diagnosis, and Therapeutic Outcomes | IntechOpen

  https://www.intechopen.com/chapters/1146676

  Growing shreds of evidence suggest that microRNA (miRNA) has a role in the onset and progression of gliomas. […] Different miRNAs have opposing roles as tumor suppressors and oncogenes. Moreover, signaling that promotes chemotherapy resistance and tumor promotion in glioma is also triggered by the alteration or overexpression of oncogenic miRNAs and the downregulation of tumor-suppressing miRNAs. […] Evidence from these investigations shows that aberrant miRNA expression has a major role in tumor cell growth, migration, and invasion. All these findings strengthen the case for miRNAs as a potential therapeutic target in glioma. […] The development of GBM is reliant on the establishment of new blood vessels since gliomas are highly vascularized tumors. […] Several miRNAs have been identified to play a crucial role in angiogenesis, and the transfer of RNAs from GBM cells to brain endothelial cells through extracellular vesicles induces angiogenesis.

• #25 Research Progress on Immune Microenvironment and Molecular Mechanism of Glioma | Frontiers Research Topic

  https://www.frontiersin.org/research-topics/50158/research-progress-on-immune-microenvironment-and-molecular-mechanism-of-glioma

  Glioma, as a primary intracranial tumor, is also the most common malignant brain tumor, leading to significant morbidity and mortality. […] The immune microenvironment of glioma is highly heterogeneous, which is closely related to the occurrence and development of glioma and the effect of anti-tumor immunotherapy. […] Glioma cells secrete a variety of chemokines, cytokines, and growth factors that promote the infiltration of various immune cells, such as macrophages, myeloid-derived suppressor cells, CD4+ T cells, and Treg into the microenvironment. […] Previous studies on the molecular mechanism of glioma have revealed the molecular features associated with different types of glioma, and the diversity of molecular subtypes is often related to patient treatment and prognosis. […] Therefore, studying the molecular mechanisms of gliomagenesis and the regulation of the glioma microenvironment would not only help to better understand the mechanisms of glioma development but also help to improve the sensitivity of glioma chemotherapy as well as develop precise targeted therapy and immunotherapy strategies.

• #26 Research Progress on Immune Microenvironment and Molecular Mechanism of Glioma | Frontiers Research Topic

  https://www.frontiersin.org/research-topics/50158/research-progress-on-immune-microenvironment-and-molecular-mechanism-of-glioma

  Accumulating evidence indicates that the unraveling of tumor molecular mechanisms and the remodeling of the immune microenvironment play crucial roles in the development of glioma. […] This Research Topic aims to reveal the mechanism of the heterogeneity of the glioma immune microenvironment and the mechanism that affects glioma progression and treatment resistance including low-grade gliomas in pediatrics and adults, so as to develop methods that could target the expression of glioma molecular markers and regulate the remodeling of the immune microenvironment, and ultimately provide valuable references for enhancing the immunotherapy, targeted therapy and chemotherapy sensitivity of glioma.

• #27 A New Epigenetic Mechanism of Temozolomide Action in Glioma Cells | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136669

  Temozolomide (TMZ) is an oral alkylating chemotherapeutic agent that prolongs the survival of patients with glioblastoma (GBM). […] Therefore a better understanding of the mechanism of action of this drug is necessary and may allow more durable benefit from its anti-glioma properties. […] The first effect of TMZ action we observed is DNA hypermethylation followed by global demethylation. Therefore an increase of DNA methylation and down regulation of some genes expression can be ascribed to activation of DNA methyltransferases (DNMTs). On the other hand hypomethylation is induced by oxidative stress and causes uncontrolled expression of pathologic protein genes. […] The results of brain tumours treatment with TMZ suggest the new mechanism of modulation epigenetic marker in cancer cells.

• #28 Glioma‑neuronal interactions in tumor progression: Mechanism, therapeutic strategies and perspectives (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2022.5394?text=fulltext

  An increasing body of evidence has become available to reveal the synaptic and functional integration of glioma into the brain network, facilitating tumor progression. […] The novel discovery of gliomaneuronal interactions has fundamentally challenged our understanding of this refractory disease. […] Given that glioma infiltrates extensively within the brain and spinal cord and rarely metastasizes outside the CNS, neurons as a crucial component of the glioma milieu potentially confer important microenvironmental dependencies to the pathogenesis of the tumor. […] The crosstalk between glioma and peritumor neurons may be mediated in different ways, which involve electrochemical synapses, secreted factors, tumor microtubes (TMs) and extracellular vesicles. […] The bidirectional interactions provide plentiful scope for malignant cells to develop; henceforth, the tumor-infiltrated brain becomes physiologically disorganized, a process that eventually facilitates glioma growth.

• #29 Glioma‑neuronal interactions in tumor progression: Mechanism, therapeutic strategies and perspectives (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2022.5394?text=fulltext

  The present review provides an overview of various aspects of the communication between glioma and neurons, and readers will develop further insight into the regulatory mechanisms of glioma-neuronal interactions. […] Neuron-glioma synapses (NGSs), providing a substantial basis for communication between the two entities, are mostly found in the glioma infiltration zone. […] These electrochemical synapses may be regulated by neurotransmitters, ion channels, TMs and gap junctions, which exert a marked influence on glioma. […] The migration of neural progenitor cells and stem cells is influenced by the electric current generated by the local field potential. […] The electrotaxis processes of GBM cell lines are regulated by voltage-gated channels. […] Therefore, targeting ion channels may be a potential therapeutic strategy for glioma.

• #30 Glioma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Glioma_pathophysiology

  The pathogenesis of cerebral glioma involves invasion of the tumor cells into the adjacent normal brain tissue. Although in certain areas the margin of the tumor may seem to be macroscopically well defined from the brain, there are always microscopic nests of tumor cells extending well out into the brain. […] Genes involved in the pathogenesis of glioma include ERCC1, ERCC2, XRCC1, MGMT, IDH1, IDH2, p53, EGFR, TSC1, TSC2, RB1, APC, hMLH1, hMSH2, PMS2, PTEN, NF1, and NF2. […] Astrocytic projections interact with vessels and act as additional elements of the blood brain barrier (BBB). The tumors take advantage of the blood brain barrier to ensure survival and continuous growth. […] Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. […] Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema.

• #31 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Text

  https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0

  The persistent and aberrant activation of the NF-B signaling pathway is a hallmark of GBM. […] The Wnt signaling pathway is an ancient and fundamental genetic program that provides crucial regulatory instructions for cell growth, differentiation, and tissue patterning. […] The TGF- signaling pathway plays a crucial role in regulating key cellular processes, including proliferation, immune response, apoptosis, and adhesion. […] The MAPK signaling pathway plays a pivotal role in various cancers, including GBM, through its hyperactivation, which drives processes such as migration, proliferation, and survival. […] The mechanisms underlying GBM cell migration and invasion are highly complex, involving interrelated biological processes. […] The progression of GBM is driven by a complex network of signaling pathways.

• #32 Exploitation of Astrocytes by Glioma Cells to Facilitate Invasiveness: A Mechanism Involving Matrix Metalloproteinase-2 and the Urokinase-Type Plasminogen Activator–Plasmin Cascade | Journal of Neuroscience

  https://www.jneurosci.org/content/23/10/4034

  We conclude that glioma cells exploit their astrocyte environment to activate MMP-2 and that this leads to the increased invasiveness of glioma cells. […] The family of matrix metalloproteinases (MMPs) is implicated in tumor invasion and metastasis. […] MMP members are classified into subgroups on the basis of structure and substrate preference. […] One category, the gelatinases (MMP-2 and MMP-9), has been associated intimately with tumor invasiveness and metastasis because of its potent ability to degrade the type IV collagen present in basement membrane that surrounds blood vessels. […] With respect to gliomas, the upregulation of MMP-2 and MMP-9 has been observed in cell lines and resected specimens. […] In vivo the expression of MMP-2, determined by in situ hybridization or immunohistochemistry, is principally in glioma cells, whereas MMP-9 expression tends to be predominant in regions of angiogenesis.

• #33 Exploitation of Astrocytes by Glioma Cells to Facilitate Invasiveness: A Mechanism Involving Matrix Metalloproteinase-2 and the Urokinase-Type Plasminogen Activator–Plasmin Cascade | Journal of Neuroscience

  https://www.jneurosci.org/content/23/10/4034

  These analyses implicate MMP-2 in the growth or invasiveness of gliomas in situ, whereas MMP-9 may be associated with angiogenesis. […] Inhibitors of metalloproteinases reduce the invasiveness of glioma cell lines in vitro and attenuate the growth of glioma cells implanted into the flank of severe combined immunodeficient (SCID) mice. […] The mechanism by which gliomas modulate their MMP-2 content or activity remains unclear. […] We have tested the hypothesis that glioma cells exploit their astrocyte environment for MMP-2 production and activation and that the consequence of this interaction is the increased ability of glioma cells to invade. […] The activation of pro-MMPs is facilitated by active forms of other MMPs or by other groups of proteinases. […] A serine proteinase, plasmin, can activate gelatinases without the need for any intermediaries.

• #34 Exploitation of Astrocytes by Glioma Cells to Facilitate Invasiveness: A Mechanism Involving Matrix Metalloproteinase-2 and the Urokinase-Type Plasminogen Activator–Plasmin Cascade | Journal of Neuroscience

  https://www.jneurosci.org/content/23/10/4034

  The presence of reactive astrocytes around glioma cells in the CNS suggests the possibility that these two cell types could be interacting. […] We found that astrocytes in culture produce significant amounts of the pro-form of MMP-2 but undetectable levels of active MMP-2. However, after coculture with the U251N glioma line, astrocyte pro-MMP-2 was converted to the active form. […] The mechanism of pro-MMP-2 activation in glioma-astrocyte coculture was investigated and was found to involve the urokinase-type plasminogen activator (uPA)-plasmin cascade whereby uPA bound to uPA receptor (uPAR), leading to the conversion of plasminogen to plasmin. […] Furthermore, key components (i.e., uPAR, uPA, and pro-MMP-2) were contributed principally by astrocytes, whereas the U251N glioma cells provided plasminogen.

• #35 Molecular pathogenesis of diffuse gliomas – UpToDate

  https://www.uptodate.com/contents/molecular-pathogenesis-of-diffuse-gliomas

  Molecular pathogenesis of diffuse gliomas […] Gliomas are primary brain tumors that display histologic features of glial cells (ie, astrocytes, oligodendrocytes, and ependymal cells). The diffuse gliomas are the most common types and generally affect the cerebral hemispheres of adults. They are classified based upon their molecular features as well as their line of differentiation and are graded according to their histologic degree of malignancy and their molecular characteristics. […] The pathogenesis and biology of diffuse gliomas are reviewed here. […] High-grade gliomas likely arise from neural progenitor cells, but the precise stage of differentiation of such target cells (ie, stem cells versus progenitor cells) has not been clear. […] In isocitrate dehydrogenase (IDH)-wildtype glioblastoma, mouse models and molecular genetic studies of patient tumor tissue, adjacent subventricular zone (SVZ) biopsies, and normal tissue suggest that astrocyte-like neural stem cells in the SVZ, which contain low-level somatic driver mutations, are the cell of origin. […] Over time these cells may migrate and acquire additional somatic mutations, ultimately leading to the development of IDH-wildtype glioblastoma in distant brain regions. […] High-grade gliomas contain multipotent tumor stem cells that are responsible for populating and repopulating the tumors. […] The existence of these tumor stem cells may have therapeutic implications, since therapies that do not ablate the tumor stem cells will be ineffective in eradicating the tumor.

• #36 Role of miRNA in Glioma Pathogenesis, Diagnosis, and Therapeutic Outcomes | IntechOpen

  https://www.intechopen.com/chapters/1146676

  When compared to normal brain samples, GBM contains dysregulated levels of many miRNAs that play a crucial role in the generation of stem cell-like properties. […] Several mechanisms of drug resistance include dysfunctional DNA repair, overexpression of drug efflux transporters, apoptosis inhibition, and increased epithelial-to-mesenchymal transition. The expression levels of MDR transporters are significantly impacted by miRNAs, which play a crucial role in controlling glioblastoma MDR. […] The aforementioned research emphasizes the importance of miRNA in ABC transporter-mediated drug efflux and suggests it as a viable therapeutic target for reestablishing chemosensitivity in gliomas.

• #37 Glioblastoma:: Molecular Mechanisms of Pathogenesis and Current Therapeutic Strategies | SpringerLink

  https://link.springer.com/book/10.1007/978-1-4419-0410-2

  Glioblastoma is the most malignant brain tumor that still remains incurable. […] Our understanding of the histopathology and molecular mechanisms of formation of glioblastoma is rapidly advancing so as to provide us clues for devising rational therapeutic strategies for treatment of this malignancy. […] It is important that we continue to improve our knowledge about the pathogenesis of this devastating disease and explore new areas to find successful therapeutic strategies. […] Various approaches such as sophisticated imaging techniques, improved surgical procedures, ground-breaking strategies for radiotherapy, chemotherapy, immunotherapy, chemoimmunotherapy, and photodynamic therapy are being used for eradicating glioblastoma.

• #38 UCSF Researchers Discover Mechanism Underlying Treatment Resistance in Glioma | UCSF Brain Tumor Center

  https://braintumorcenter.ucsf.edu/news/ucsf-researchers-discover-mechanism-underlying-treatment-resistance-glioma

  Researchers at UC San Francisco have discovered how PGAM1 a protein expressed at high levels in many cancers can contribute to tumor cells resistance to radiation therapy and chemotherapy. […] Published today in Cell Reports, Mukherjee and colleagues report a novel interaction between PGAM1 and another protein WIP1, which underlies glioma cells resistance to DNA damage, and thus treatments like radiation and chemotherapy. […] Ultimately, this leads to overactive DNA damage repair, which protects tumor cells from DNA-damaging agents like radiation and chemotherapy. […] This suggests that loss of PGAM1 sensitizes glioma cells to radiation and TMZ, said Pieper. […] In demonstrating how PGAM1 contributes to overactive DNA damage repair in glioma, the Mukherjee Lab reveals a potential therapeutic target. Downregulation of PGAM1 expression in in vitro and in vivo models appears to increase the efficiency of irradiation and TMZ, the standard treatment regimen for glioma, said Mukherjee.

• #39 Regulation of DNA Repair Mechanism in Human Glioma Xenograft Cells both In Vitro and In Vivo in Nude Mice | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026191

  Glioblastoma Multiforme (GBM) is the most lethal form of brain tumor. Efficient DNA repair and anti-apoptotic mechanisms are making glioma treatment difficult. Proteases such as MMP9, cathepsin B and urokinase plasminogen activator receptor (uPAR) are over expressed in gliomas and contribute to enhanced cancer cell proliferation. Non-homologous end joining (NHEJ) repair mechanism plays a major role in double strand break (DSB) repair in mammalian cells. […] Here we show that silencing MMP9 in combination with uPAR/cathepsin B effects NHEJ repair machinery. Expression of DNA PKcs and Ku70/80 at both mRNA and protein levels in MMP9-uPAR (pMU) and MMP9-cathepsin B (pMC) shRNA-treated glioma xenograft cells were reduced. […] Our results suggest that pMU and pMC shRNA reduce glioma proliferation by DSB accumulation and increase apoptosis under normoxia, hypoxia and in combination with irradiation.

• #40 Regulation of DNA Repair Mechanism in Human Glioma Xenograft Cells both In Vitro and In Vivo in Nude Mice | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026191

  We have demonstrated the role of MMP9 in combination with uPAR/cathepsin B in DDR in glioma xenograft cells. Our results clearly demonstrated that pMU and pMC treatments alter DNA repair efficiency, induces apoptosis and depletes survival signals in normoxic, hypoxic and hypoxic+IR exposed glioma cells. […] NHEJ repair mechanism accounts for more than 75% of DSB repair in mammalian cells. […] Our results showed reduced expressions of these proteins in pMU- and pMC-treated samples at both mRNA and protein levels in 4910 and 5310 cells. […] These findings further strengthen our earlier findings wherein our pMU and pMC treatments lowered DNA PK activity in these glioma xenograft cells. […] We observed a prominent decrease in the expression of NHEJ repair machinery proteins after pMU and pMC treatments. Ku70 and Ku80 DNA binding activity after pMU and pMC treatments were decreased compared to controls. […] Our study clearly demonstrated the potential anti-proliferative effect of bicistronic constructs pMU and pMC by reducing repair of DNA damage and inducing apoptosis.

• #41 Whole Genome Sequencing Unveils Diffuse Glioma Landscape

  https://bioengineer.org/whole-genome-sequencing-unveils-diffuse-glioma-landscape/

  The study identified recurrent disruptions in chromatin-modifying genes and epigenetic regulators, underscoring a vital role for chromatin architecture dysregulation in diffuse glioma pathogenesis. […] The presence of chromothripsis corresponds with more aggressive disease phenotypes and poor prognosis, suggesting its utility as a biomarker for risk stratification. […] Furthermore, the mechanistic links between chromothripsis and defects in DNA repair machinery highlight new pathways for therapeutic exploitation, such as synthetic lethality strategies targeting DNA damage response components. […] Whole genome sequencing enabled the identification of recurrent alterations in regulatory elements, including promoters and enhancers of oncogenes and tumor suppressor genes, advancing our comprehension of how noncoding genomic regions contribute to tumor biology. […] This work exemplifies how cutting-edge genomic technologies coupled with rigorous analytical frameworks can redefine our understanding of devastating cancers, heralding a new chapter of precision neuro-oncology that holds promise for meaningful clinical impact.

• #42 Mechanism Identified for Drug Resistance in Glioblastoma Brain Tumors | Duke Health

  https://corporate.dukehealth.org/news/mechanism-identified-drug-resistance-glioblastoma-brain-tumors

  DURHAM, N.C. Duke Health researchers have identified a unique process within the environment of deadly brain tumors that drives resistance to immune-boosting therapies and could be targeted to promote the effects of those drugs. […] The finding, published in Nature Communications, explains a vexing problem in glioblastoma, a deadly form of brain tumor that has proven notoriously impervious to immune checkpoint inhibitors, a type of immunotherapy which has been highly effective in other cancers. […] Our approach in this work was to find environmental factors that could make glioblastoma more vulnerable to immuno-therapies. […] This molecule is highly active in cancer supporting cells in the glioblastoma environment and is associated with worse survival in humans. […] One surprising finding was that CaMKK2, specifically in neurons, was supporting brain tumor growth and suppressing the function of the immune system.

• #43 Mechanism Identified for Drug Resistance in Glioblastoma Brain Tumors | Duke Department of Neurosurgery

  https://neurosurgery.duke.edu/news/mechanism-identified-drug-resistance-glioblastoma-brain-tumors

  Duke Health researchers have identified a unique process within the environment of deadly brain tumors that drives resistance to immune-boosting therapies and could be targeted to promote the effects of those drugs. […] The finding explains a vexing problem in glioblastoma, a deadly form of brain tumor that has proven notoriously impervious to immune checkpoint inhibitors, a type of immunotherapy which has been highly effective in other cancers. […] Our approach in this work was to find environmental factors that could make glioblastoma more vulnerable to immuno-therapies. […] This molecule is highly active in cancer supporting cells in the glioblastoma environment and is associated with worse survival in humans. […] Not only did CaMMK2 impact T-cell function, but the protein also changed the behavior of macrophages, making these immune cells less helpful to T-cells.

• #44 Mechanism Identified for Drug Resistance in Glioblastoma Brain Tumors | Duke Health

  https://corporate.dukehealth.org/news/mechanism-identified-drug-resistance-glioblastoma-brain-tumors

  Because CaMKK2 is highly expressed in tumor-supporting neurons and macrophages, the researchers said, it promotes resistance to immune-checkpoint inhibitor drugs, which turn off a cellular brake to accelerate the cancer-killing ability of T-cells. […] This suggests that CaMKK2 represents a potential therapeutic target. If we could inhibit CaMMK2, we might be able to unleash the power of the whole class of immunotherapy drugs that have been beneficial in other cancers, but not glioblastoma.

• #45 Mechanism Identified for Drug Resistance in Glioblastoma Brain Tumors | Duke Department of Neurosurgery

  https://neurosurgery.duke.edu/news/mechanism-identified-drug-resistance-glioblastoma-brain-tumors

  One surprising finding was that CaMKK2, specifically in neurons, was supporting brain tumor growth and suppressing the function of the immune system. […] Because CaMKK2 is highly expressed in tumor-supporting neurons and macrophages, the researchers said, it promotes resistance to immune-checkpoint inhibitor drugs, which turn off a cellular brake to accelerate the cancer-killing ability of T-cells. […] This suggests that CaMKK2 represents a potential therapeutic target. If we could inhibit CaMMK2, we might be able to unleash the power of the whole class of immunotherapy drugs that have been beneficial in other cancers, but not glioblastoma.

• #46 Fundamental Research Paved the Way for the Development of Vorasidenib – NCI

  https://www.cancer.gov/about-nci/organization/dcb/progress/cancer-biology-and-vorasidenib-development

  Findings from the study revealed that Vorasidenib delayed the time to disease progression in patients with brain tumors when compared to a placebo (which is an inactive, non-drug substance). […] Dr. Mellinghoff shared the results that showed patients with these brain tumors [i.e., low-grade gliomas], when they took this new pill, the tumors grew significantly slower. […] However, the clinical breakthrough of Vorasidenib would not have been possible without all the research legwork and basic science, stated Dr. Mellinghoff. […] Recent clinical findings built on a culmination of collaborative fundamental, translational, and early clinical discoveries show that Vorasidenib is a promising treatment for IDH-mutant low-grade gliomas. […] Prior cancer biology research funded by DCB showed that mutant IDH reduces the infiltration of immune cells to the tumor and that the IDH oncometabolite of 2-hydroxyglutarate is immunosuppressive. […] These findings suggest that mutant IDH promotes an immunosuppressive brain tumor microenvironment.

• #47 Glioblastoma: An Update in Pathology, Molecular Mechanisms and Biomarkers

  https://www.mdpi.com/1422-0067/25/5/3040

  While the above studies have provided useful insights into the molecular pathogenesis of GBM, they have also revealed the key signaling pathways involved in tumorigenesis and progression of GBM. […] There are three key signaling pathways that are consistently and commonly altered in GBM: (1) RTK pathway, (2) TP53 pathway, and (3) RB pathway. […] Among the abundant molecular biomarkers identified above, three of them have demonstrated the greatest potential in the clinical practice of GBM, including IDH1, MGMT, and EGFR. […] While great strides have been made in the molecular characterization of GBM, there are still many challenges in the implementation of these discoveries into clinical management. […] Taken together, great progress has been made in the molecular characterization of GBM in the past decade.

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