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Biomolecules May 2024Lysophosphatidic acid (LPA) is a well-documented pro-oncogenic factor in different cancers, but relatively little is known on its biological activity in neuroblastoma....
Lysophosphatidic acid (LPA) is a well-documented pro-oncogenic factor in different cancers, but relatively little is known on its biological activity in neuroblastoma. The LPA effects and the participation of the tyrosine kinase receptor anaplastic lymphoma kinase (ALK) in LPA mitogenic signaling were studied in human neuroblastoma cell lines. We used light microscopy and [H]-thymidine incorporation to determine cell proliferation, Western blot to study intracellular signaling, and pharmacological and molecular tools to examine the role of ALK. We found that LPA stimulated the growth of human neuroblastoma cells, as indicated by the enhanced cell number, clonogenic activity, and DNA synthesis. These effects were curtailed by the selective ALK inhibitors NPV-TAE684 and alectinib. In a panel of human neuroblastoma cell lines harboring different ALK genomic status, the ALK inhibitors suppressed LPA-induced phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), which are major regulators of cell proliferation. ALK depletion by siRNA treatment attenuated LPA-induced ERK1/2 activation. LPA enhanced ALK phosphorylation and potentiated ALK activation by the ALK ligand FAM150B. LPA enhanced the inhibitory phosphorylation of the tumor suppressor FoxO3a, and this response was impaired by the ALK inhibitors. These results indicate that LPA stimulates mitogenesis of human neuroblastoma cells through a crosstalk with ALK.
Topics: Humans; Lysophospholipids; Anaplastic Lymphoma Kinase; Neuroblastoma; Cell Proliferation; Cell Line, Tumor; Signal Transduction; Phosphorylation; Piperidines; Carbazoles; Forkhead Box Protein O3; Mitogen-Activated Protein Kinase 3; MAP Kinase Signaling System
PubMed: 38927035
DOI: 10.3390/biom14060631 -
Acta Neuropathologica Communications Jun 2024A novel histomolecular tumor of the central nervous system (CNS), the "diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)," has...
Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC), new name and new problems: an illustration of one case with atypical morphology and biology.
A novel histomolecular tumor of the central nervous system (CNS), the "diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)," has recently been identified, based on a distinct DNA methylation profile and has been added to the 2021 World Health Organization Classification of CNS Tumors. This glioneuronal tumor mainly affects the supratentorial area in children and recurrently presents with a monosomy of chromosome 14. Herein, we report the case of a DNA-methylation based diagnosis of DGONC having atypical features, such as pseudo-rosettes and the absence of a chromosome 14 monosomy, thus rendering its diagnosis very challenging. Because of the wide variety of morphologies harbored by DGONC, a large range of differential diagnoses may be hypothesized from benign to malignant. Interestingly, the current case, like one previously reported, exhibited a co-expression of OLIG2, synaptophysin and SOX10, without GFAP immunopositivity. This particular immunophenotype seems to be a good indicator for a DGONC diagnosis. The classification of DGONC amongst glioneuronal or embryonal tumors is still debated. The clinical (a pediatric supratentorial tumor), morphological (from a benign oligodendroglioma-like tumor with microcalcifications and possible neuropil-like islands to a malignant embryonal tumor with a possible spongioblastic pattern), and immunohistochemical (co-expression of OLIG2 and synaptophsyin) profiles resemble CNS, neuroblastoma, FOXR2-activated and may potentially bring them together in a future classification. Further comprehensive studies are needed to conclude the cellular origin of DGONC and its prognosis.
Topics: Child; Humans; Brain Neoplasms; DNA Methylation; Oligodendroglioma
PubMed: 38926880
DOI: 10.1186/s40478-024-01822-y -
Acta Neuropathologica Communications Jun 2024
Topics: X-linked Nuclear Protein; Humans; Brain Neoplasms; Glioma; Histones; Ataxia Telangiectasia Mutated Proteins; Male
PubMed: 38926805
DOI: 10.1186/s40478-024-01818-8 -
Scientific Reports Jun 2024Our research endeavors are directed towards unraveling the stem cell characteristics of lower-grade glioma patients, with the ultimate goal of formulating personalized...
Our research endeavors are directed towards unraveling the stem cell characteristics of lower-grade glioma patients, with the ultimate goal of formulating personalized treatment strategies. We computed enrichment stemness scores and performed consensus clustering to categorize phenotypes. Subsequently, we constructed a prognostic risk model using weighted gene correlation network analysis (WGCNA), random survival forest regression analysis as well as full subset regression analysis. To validate the expression differences of key genes, we employed experimental methods such as quantitative Polymerase Chain Reaction (qPCR) and assessed cell line proliferation, migration, and invasion. Three subtypes were assigned to patients diagnosed with LGG. Notably, Cluster 2 (C2), exhibiting the poorest survival outcomes, manifested characteristics indicative of the subtype characterized by immunosuppression. This was marked by elevated levels of M1 macrophages, activated mast cells, along with higher immune and stromal scores. Four hub genes-CDCA8, ORC1, DLGAP5, and SMC4-were identified and validated through cell experiments and qPCR. Subsequently, these validated genes were utilized to construct a stemness risk signature. Which revealed that Lower-Grade Glioma (LGG) patients with lower scores were more inclined to demonstrate favorable responses to immune therapy. Our study illuminates the stemness characteristics of gliomas, which lays the foundation for developing therapeutic approaches targeting CSCs and enhancing the efficacy of current immunotherapies. By identifying the stemness subtype and its correlation with prognosis and TME patterns in glioma patients, we aim to advance the development of personalized treatments, enhancing the ability to predict and improve overall patient prognosis.
Topics: Humans; Glioma; Tumor Microenvironment; Prognosis; Biomarkers, Tumor; Neoplastic Stem Cells; Brain Neoplasms; Gene Expression Regulation, Neoplastic; Neoplasm Grading; Male; Cell Line, Tumor; Female; Gene Expression Profiling; Cell Proliferation
PubMed: 38926605
DOI: 10.1038/s41598-024-65717-7 -
Cancer Medicine Jun 2024Neurosurgery is considered the mainstay of treatment for pediatric low-grade glioma (LGG); the extent of resection determines subsequent stratification in current...
INTRODUCTION
Neurosurgery is considered the mainstay of treatment for pediatric low-grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long-term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies.
PATIENTS AND METHODS
Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1-5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1-status, sex, and age.
RESULTS
The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres.
CONCLUSIONS
The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1-status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals.
Topics: Humans; Child; Glioma; Female; Male; Neurosurgical Procedures; Germany; Brain Neoplasms; Adolescent; Child, Preschool; Infant; Neoplasm Grading
PubMed: 38923198
DOI: 10.1002/cam4.7417 -
Current Oncology (Toronto, Ont.) Jun 2024Neuroblastoma is a pediatric cancer with significant clinical heterogeneity. Despite extensive efforts, it is still difficult to cure children with high-risk... (Review)
Review
Neuroblastoma is a pediatric cancer with significant clinical heterogeneity. Despite extensive efforts, it is still difficult to cure children with high-risk neuroblastoma. Immunotherapy is a promising approach to treat children with this devastating disease. We have previously reported that macrophages are important effector cells in high-risk neuroblastoma. In this perspective article, we discuss the potential function of the macrophage inhibitory receptor SIRPA in the homeostasis of tumor-associated macrophages in high-risk neuroblastoma. The ligand of SIRPA is CD47, known as a "don't eat me" signal, which is highly expressed on cancer cells compared to normal cells. CD47 is expressed on both tumor and stroma cells, whereas SIRPA expression is restricted to macrophages in high-risk neuroblastoma tissues. Notably, high expression is associated with better disease outcome. According to the current paradigm, the interaction between CD47 on tumor cells and SIRPA on macrophages leads to the inhibition of tumor phagocytosis. However, data from recent clinical trials have called into question the use of anti-CD47 antibodies for the treatment of adult and pediatric cancers. The restricted expression of SIRPA on macrophages in many tissues argues for targeting SIRPA on macrophages rather than CD47 in CD47/SIRPA blockade therapy. Based on the data available to date, we propose that disruption of the CD47-SIRPA interaction by anti-CD47 antibody would shift the macrophage polarization status from M1 to M2, which is inferred from the 1998 study by Timms et al. In contrast, the anti-SIRPA F(ab') lacking Fc binds to SIRPA on the macrophage, mimics the CD47-SIRPA interaction, and thus maintains M1 polarization. Anti-SIRPA F(ab') also prevents the binding of CD47 to SIRPA, thereby blocking the "don't eat me" signal. The addition of tumor-opsonizing and macrophage-activating antibodies is expected to enhance active tumor phagocytosis.
Topics: CD47 Antigen; Humans; Neuroblastoma; Receptors, Immunologic; Antigens, Differentiation; Macrophages
PubMed: 38920727
DOI: 10.3390/curroncol31060243 -
Cells Jun 2024The world of cancer treatment is evolving rapidly and has improved the prospects of many cancer patients. Yet, there are still many cancers where treatment prospects... (Review)
Review
The world of cancer treatment is evolving rapidly and has improved the prospects of many cancer patients. Yet, there are still many cancers where treatment prospects have not (or hardly) improved. Glioblastoma is the most common malignant primary brain tumor, and even though it is sensitive to many chemotherapeutics when tested under laboratory conditions, its clinical prospects are still very poor. The blood-brain barrier (BBB) is considered at least partly responsible for the high failure rate of many promising treatment strategies. We describe the workings of the BBB during healthy conditions and within the glioblastoma environment. How the BBB acts as a barrier for therapeutic options is described as well as various approaches developed and tested for passing or opening the BBB, with the ultimate aim to allow access to brain tumors and improve patient perspectives.
Topics: Glioblastoma; Humans; Blood-Brain Barrier; Drug Delivery Systems; Brain Neoplasms; Antineoplastic Agents; Animals
PubMed: 38920629
DOI: 10.3390/cells13120998 -
Scientific Reports Jun 2024PTBP1 is an oncogene that regulates the splicing of precursor mRNA. However, the relationship between PTBP1 expression and gene methylation, cancer prognosis, and tumor...
PTBP1 is an oncogene that regulates the splicing of precursor mRNA. However, the relationship between PTBP1 expression and gene methylation, cancer prognosis, and tumor microenvironment remains unclear. The expression profiles of PTBP1 across various cancers were derived from the TCGA, as well as the GTEx and CGGA databases. The CGGA mRNA_325, CGGA mRNA_301, and CGGA mRNA_693 datasets were utilized as validation cohorts. Immune cell infiltration scores were approximated using the TIMER 2.0 tool. Functional enrichment analysis for groups with high and low PTBP1 expression was conducted using Gene Set Enrichment Analysis (GSEA). Methylation data were predominantly sourced from the SMART and Mexpress databases. Linked-omics analysis was employed to perform functional enrichment analysis of genes related to PTBP1 methylation, as well as to conduct protein functional enrichment analysis. Single-cell transcriptome analysis and spatial transcriptome analysis were carried out using Seurat version 4.10. Compared to normal tissues, PTBP1 is significantly overexpressed and hypomethylated in various cancers. It is implicated in prognosis, immune cell infiltration, immune checkpoint expression, genomic variation, tumor neoantigen load, and tumor mutational burden across a spectrum of cancers, with particularly notable effects in low-grade gliomas. In the context of gliomas, PTBP1 expression correlates with WHO grade and IDH1 mutation status. PTBP1 expression and methylation play an important role in a variety of cancers. PTBP1 can be used as a marker of inflammation, progression and prognosis in gliomas.
Topics: Humans; Polypyrimidine Tract-Binding Protein; Heterogeneous-Nuclear Ribonucleoproteins; Prognosis; Biomarkers, Tumor; Glioma; Gene Expression Regulation, Neoplastic; Tumor Microenvironment; DNA Methylation; Gene Expression Profiling; Inflammation; Transcriptome; Brain Neoplasms; Disease Progression; Multiomics
PubMed: 38918441
DOI: 10.1038/s41598-024-64979-5 -
Medical Oncology (Northwood, London,... Jun 2024Glioblastoma (GBM) is the most common malignant brain tumor, which, despite significant progress made in the last years in the field of neuro-oncology, remains an... (Review)
Review
Glioblastoma (GBM) is the most common malignant brain tumor, which, despite significant progress made in the last years in the field of neuro-oncology, remains an incurable disease. GBM has a poor prognosis with a median survival of 12-15 months, and its aggressive clinical course is related to rapid growth, extensive infiltration of adjacent tissues, resistance to chemotherapy, radiotherapy and immunotherapy, and frequent relapse. Currently, several molecular biomarkers are used in clinical practice to predict patient prognosis and response to treatment. However, due to the overall unsatisfactory efficacy of standard multimodal treatment and the remaining poor prognosis, there is an urgent need for new biomarkers and therapeutic strategies for GBM. Recent evidence suggests that GBM tumorigenesis is associated with crosstalk between cancer, immune and stromal cells mediated by various cytokines. One of the key factors involved in this process appears to be interleukin-17 (IL-17), a pro-inflammatory cytokine that is significantly upregulated in the serum and tissue of GBM patients. IL-17 plays a key role in tumorigenesis, angiogenesis, and recurrence of GBM by activating pro-oncogenic signaling pathways and promoting cell survival, proliferation, and invasion. IL-17 facilitates the immunomodulation of the tumor microenvironment by promoting immune cells infiltration and cytokine secretion. In this article we review the latest scientific reports to provide an update on the role of IL-17 role in tumorigenesis, tumor microenvironment, diagnosis, prognosis, and treatment of GBM.
Topics: Humans; Glioblastoma; Brain Neoplasms; Interleukin-17; Tumor Microenvironment; Biomarkers, Tumor; Prognosis
PubMed: 38918274
DOI: 10.1007/s12032-024-02434-1 -
Frontiers in Immunology 2024Glioblastoma (GBM) is a highly malignant, invasive, and poorly prognosed brain tumor. Unfortunately, active comprehensive treatment does not significantly prolong... (Review)
Review
Glioblastoma (GBM) is a highly malignant, invasive, and poorly prognosed brain tumor. Unfortunately, active comprehensive treatment does not significantly prolong patient survival. With the deepening of research, it has been found that gut microbiota plays a certain role in GBM, and can directly or indirectly affect the efficacy of immune checkpoint inhibitors (ICIs) in various ways. (1) The metabolites produced by gut microbiota directly affect the host's immune homeostasis, and these metabolites can affect the function and distribution of immune cells, promote or inhibit inflammatory responses, affect the phenotype, angiogenesis, inflammatory response, and immune cell infiltration of GBM cells, thereby affecting the effectiveness of ICIs. (2) Some members of the gut microbiota may reverse T cell function inhibition, increase T cell anti-tumor activity, and ultimately improve the efficacy of ICIs by targeting specific immunosuppressive metabolites and cytokines. (3) Some members of the gut microbiota directly participate in the metabolic process of drugs, which can degrade, transform, or produce metabolites, affecting the effective concentration and bioavailability of drugs. Optimizing the structure of the gut microbiota may help improve the efficacy of ICIs. (4) The gut microbiota can also regulate immune cell function and inflammatory status in the brain through gut brain axis communication, indirectly affecting the progression of GBM and the therapeutic response to ICIs. (5) Given the importance of gut microbiota for ICI therapy, researchers have begun exploring the use of fecal microbiota transplantation (FMT) to transplant healthy or optimized gut microbiota to GBM patients, in order to improve their immune status and enhance their response to ICI therapy. Preliminary studies suggest that FMT may enhance the efficacy of ICI therapy in some patients. In summary, gut microbiota plays a crucial role in regulating ICIs in GBM, and with a deeper understanding of the relationship between gut microbiota and tumor immunity, it is expected to develop more precise and effective personalized ICI therapy strategies for GBM, in order to improve patient prognosis.
Topics: Humans; Gastrointestinal Microbiome; Glioblastoma; Immune Checkpoint Inhibitors; Brain Neoplasms; Animals; Brain-Gut Axis; Fecal Microbiota Transplantation; Tumor Microenvironment
PubMed: 38915399
DOI: 10.3389/fimmu.2024.1401967