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Cells Dec 2022The fatal clinical course of human glioblastoma (GBM) despite aggressive adjuvant therapies is due to high rates of recurrent tumor growth driven by tumor cells with...
The fatal clinical course of human glioblastoma (GBM) despite aggressive adjuvant therapies is due to high rates of recurrent tumor growth driven by tumor cells with stem-cell characteristics (glioma stem cells, GSCs). The aldehyde dehydrogenase 1 (ALDH1) family of enzymes has been shown to be a biomarker for GSCs, and ALDH1 seems to be involved in the biological processes causing therapy resistance. Ferroptosis is a recently discovered cell death mechanism, that depends on iron overload and lipid peroxidation, and it could, therefore, be a potential therapeutic target in various cancer types. Since both ALDH1 and ferroptosis interact with lipid peroxidation (LPO), we aimed to investigate a possible connection between ALDH1 and ferroptosis. Here, we show that RSL3-induced LPO and ferroptotic cell death revealed RSL3-sensitive and -resistant malignant glioma cell lines. Most interestingly, RSL3 sensitivity correlates with ALDH1a3 expression; only high ALDH1a3-expressing cells seem to be sensitive to ferroptosis induction. In accordance, inhibition of ALDH1a3 enzymatic activity by chemical inhibition or genetic knockout protects tumor cells from RSL3-induced ferroptotic cell death. Both RSL-3-dependent binding of ALDH1a3 to LC3B and autophagic downregulation of ferritin could be completely blocked by ALDH inhibition. Therefore, ALDH1a3 seems to be involved in ferroptosis through the essential release of iron by ferritinophagy. Our results also indicate that ferroptosis induction might be a particularly interesting clinical approach for targeting the highly aggressive cell population of GSC.
Topics: Humans; Aldehyde Dehydrogenase 1 Family; Autophagy; Ferroptosis; Glioblastoma; Glioma; Neoplasm Recurrence, Local
PubMed: 36552781
DOI: 10.3390/cells11244015 -
Cancer Letters Mar 2010Glioblastoma multiforme, the most common primary intracranial malignancy, is associated with very poor outcome despite advances in surgical techniques and chemo- and... (Review)
Review
Glioblastoma multiforme, the most common primary intracranial malignancy, is associated with very poor outcome despite advances in surgical techniques and chemo- and radiation therapy. Many novel treatment modalities are being investigated with varying amount of success. Evolution of cancer stem cell hypothesis provides a new venue for developmental therapeutics. In this review, we highlight the literature regarding the existence of glioma stem cells and their characteristics. We also discuss the potential for virotherapy, a novel therapeutic approach utilizing conditionally replicative viruses, to directly target this population of self-renewing cancer stem cells.
Topics: Cell Proliferation; Glioma; Humans; Neoplasm Staging; Neoplastic Stem Cells; Oncolytic Virotherapy; Virus Replication
PubMed: 19643532
DOI: 10.1016/j.canlet.2009.04.045 -
International Journal of Molecular... Feb 2017Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, is known to play important roles in inhibiting proliferation rate, inducing apoptosis, as well as...
Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, is known to play important roles in inhibiting proliferation rate, inducing apoptosis, as well as hindering the metastasis and invasion of glioma cells, but the underlying mechanisms are still unclear so far. In this study, methyl thiazolyl tetrazolium (MTT), colony-forming, wound healing, invasion, and apoptosis assays were performed to investigate the effect of DHA on malignant glioma cells. Results showed that DHA induced apoptosis of malignant glioma cells through Protein Kinase B (AKT) axis, induced death of malignant glioma cells by downregulating miR-21, and inhibited the invasion of malignant glioma cells corresponding with up-regulation of the reversion-inducing-cysteine-rich protein with kazal motifs (RECK). These results revealed that AKT axis, miR-21, and RECK play pivotal roles in DHA killing malignant glioma cells, suggesting that DHA is a potential agent for treating glioma.
Topics: Adult; Aged; Apoptosis; Artemisinins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; GPI-Linked Proteins; Gene Expression Regulation, Neoplastic; Glioma; Humans; Male; MicroRNAs; Middle Aged; Neoplasm Staging; Proto-Oncogene Proteins c-akt
PubMed: 28208619
DOI: 10.3390/ijms18020350 -
Annals of Oncology : Official Journal... Nov 1998Recent advances in molecular tumor biology and gene technology have provided the possibility to treat patients with malignant brain tumors by altering gene expression in... (Review)
Review
Recent advances in molecular tumor biology and gene technology have provided the possibility to treat patients with malignant brain tumors by altering gene expression in tumor cells. Tumor development and progression involves alterations in a wide spectrum of genes, therefore a variety of gene therapy approaches for malignant gliomas have been proposed. In this review article, we discuss some principles of current gene therapeutic strategies that are under investigation in laboratories and in clinics. In addition, some general issues that remain to be resolved for clinical application of gene therapy in patients with malignant gliomas will be addressed.
Topics: Animals; Brain Neoplasms; Clinical Trials as Topic; Genetic Therapy; Glioma; Humans
PubMed: 9862044
DOI: 10.1023/a:1008488709359 -
BMC Cancer Feb 2023Gliomas are the most common brain tumours with the high-grade glioblastoma representing the most aggressive and lethal form. Currently, there is a lack of specific...
BACKGROUND
Gliomas are the most common brain tumours with the high-grade glioblastoma representing the most aggressive and lethal form. Currently, there is a lack of specific glioma biomarkers that would aid tumour subtyping and minimally invasive early diagnosis. Aberrant glycosylation is an important post-translational modification in cancer and is implicated in glioma progression. Raman spectroscopy (RS), a vibrational spectroscopic label-free technique, has already shown promise in cancer diagnostics.
METHODS
RS was combined with machine learning to discriminate glioma grades. Raman spectral signatures of glycosylation patterns were used in serum samples and fixed tissue biopsy samples, as well as in single cells and spheroids.
RESULTS
Glioma grades in fixed tissue patient samples and serum were discriminated with high accuracy. Discrimination between higher malignant glioma grades (III and IV) was achieved with high accuracy in tissue, serum, and cellular models using single cells and spheroids. Biomolecular changes were assigned to alterations in glycosylation corroborated by analysing glycan standards and other changes such as carotenoid antioxidant content.
CONCLUSION
RS combined with machine learning could pave the way for more objective and less invasive grading of glioma patients, serving as a useful tool to facilitate glioma diagnosis and delineate biomolecular glioma progression changes.
Topics: Humans; Spectrum Analysis, Raman; Glycosylation; Glioma; Brain Neoplasms; Glioblastoma; Neoplasm Grading
PubMed: 36809974
DOI: 10.1186/s12885-023-10588-w -
Neuro-oncology Nov 2011Accumulating evidence has revealed that the tyrosine kinases play a major role in glioma proliferation and invasion. The largest family of tyrosine kinases, the Eph... (Review)
Review
Accumulating evidence has revealed that the tyrosine kinases play a major role in glioma proliferation and invasion. The largest family of tyrosine kinases, the Eph family, and its ligands, the ephrins, are frequently overexpressed in glioma, suggesting important roles for their bidirectional signals in glioma pathobiology. Ephs bind to cell surface-associated ephrin ligands on neighboring cells and have many biological functions during embryonic development of the central nervous system, including axon mapping, cell migration, and angiogenesis. Recent findings suggest that Eph/ephrin signaling affects glioma cell growth, migration, and invasion in vitro and in vivo. However, their roles in glioma seem complex, because both tumor growth promoter and suppressor potentials have been ascribed to Ephs and ephrins. Here, we review recent advances in research on the role of Eph/ephrin signaling in glioma and suggest that the Eph/ephrin system could be a potential target of glioma therapy.
Topics: Animals; Ephrins; Glioma; Humans; Protein-Tyrosine Kinases; Receptors, Eph Family; Signal Transduction
PubMed: 21856686
DOI: 10.1093/neuonc/nor102 -
Brain Pathology (Zurich, Switzerland) Oct 2009The prognosis of patients with malignant glioma is poor in spite of multimodal treatment approaches consisting of neurosurgery, radiochemotherapy and maintenance... (Review)
Review
The prognosis of patients with malignant glioma is poor in spite of multimodal treatment approaches consisting of neurosurgery, radiochemotherapy and maintenance chemotherapy. Among innovative treatment strategies like targeted therapy, antiangiogenesis and gene therapy approaches, immunotherapy emerges as a meaningful and feasible treatment approach for inducing long-term survival in at least a subpopulation of these patients. Setting up immunotherapy for an inherent immunosuppressive tumor located in an immune-privileged environment requires integration of a lot of scientific input and knowledge of both tumor immunology and neuro-oncology. The field of immunotherapy is moving into the direction of active specific immunotherapy using autologous dendritic cells (DCs) as vehicle for immunization. In the translational research program of the authors, the whole cascade from bench to bed to bench of active specific immunotherapy for malignant glioma is covered, including proof of principle experiments to demonstrate immunogenicity of patient-derived mature DCs loaded with autologous tumor lysate, preclinical in vivo experiments in a murine orthotopic glioma model, early phase I/II clinical trials for relapsing patients, a phase II trial for patients with newly diagnosed glioblastoma (GBM) for whom immunotherapy is integrated in the current multimodal treatment, and laboratory analyses of patient samples. The strategies and results of this program are discussed in the light of the internationally available scientific literature in this fast-moving field of basic science and translational clinical research.
Topics: Animals; Antineoplastic Protocols; Brain Neoplasms; Cancer Vaccines; Clinical Trials as Topic; Combined Modality Therapy; Dendritic Cells; Disease Models, Animal; Glioma; Humans; Immunotherapy; Mice; Treatment Outcome
PubMed: 19744041
DOI: 10.1111/j.1750-3639.2009.00316.x -
Brain Pathology (Zurich, Switzerland) Jul 2010Proteomics is increasingly employed in both neurological and oncological research to provide insight into the molecular basis of disease but rarely has a coherent, novel... (Review)
Review
Proteomics is increasingly employed in both neurological and oncological research to provide insight into the molecular basis of disease but rarely has a coherent, novel pathophysiological insight emerged. Gliomas account for >50% of adult primary intracranial tumors, with malignant gliomas (anaplastic astrocytomas and glioblastoma multiforme) being the most common. In glioma, the application of proteomic technology has identified altered protein expression but without consistency of these alterations or their biological significance being established. A systematic review of multiple independent proteomic analyses of glioma has demonstrated alterations of 99 different proteins. Importantly 10 of the 99 proteins found differentially expressed in glioma [PHB, Hsp20, serum albumin, epidermal growth factor receptor (EGFR), EA-15, RhoGDI, APOA1, GFAP, HSP70, PDIA3] were identified in multiple publications. An assessment of protein-protein interactions between these proteins compiled using novel web-based technology, revealed a robust and cohesive network for glioblastoma. The protein network discovered (containing TP53 and RB1 at its core) compliments recent findings in genomic studies of malignant glioma. The novel perspective provided by network analysis indicates that the potential of this technology to explore crucial aspects of glioma pathophysiology can now be realized but only if the conceptual and technical limitations highlighted in this review are addressed.
Topics: Biomarkers, Tumor; Brain Neoplasms; Glioma; Humans; Prohibitins; Proteomics
PubMed: 20175778
DOI: 10.1111/j.1750-3639.2010.00376.x -
Neuroscience Bulletin Feb 2013The matrix-degrading metalloproteinases (MMPs), particularly MMP-9, play important roles in the pathogenesis and development of malignant gliomas. In the present study,...
The matrix-degrading metalloproteinases (MMPs), particularly MMP-9, play important roles in the pathogenesis and development of malignant gliomas. In the present study, the oncogenic role of MMP-9 in malignant glioma cells was investigated via antisense RNA blockade in vitro and in vivo. TJ905 malignant glioma cells were transfected with pcDNA3.0 vector expressing antisense MMP-9 RNA (pcDNA-ASMMP9), which significantly decreased MMP-9 expression, and cell proliferation was assessed. For in vivo studies, U251 cells, a human malignant glioma cell line, were implanted subcutaneously into 4- to 6-week-old BALB/c nude mice. The mice bearing well-established U251 gliomas were treated with intratumoral pcDNA-AS-MMP9-Lipofectamine complex (AS-MMP-9-treated group), subcutaneous injection of endostatin (endostatin-treated group), or both (combined therapy group). Mice treated with pcDNA (empty vector)-Lipofectamine served as the control group. Four or eight weeks later, the volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity were assayed. We demonstrate that pcDNA-AS-MMP9 significantly decreased MMP-9 expression and inhibited glioma cell proliferation. Volume and weight of tumor, MMP-9 expression, microvessel density and proliferative activity in the antisense-MMP-9-treated and therapeutic alliance groups were significantly lower than those in the control group. The results suggest that MMP-9 not only promotes malignant glioma cell invasiveness, but also affects tumor cell proliferation. Blocking the expression of MMP-9 with antisense RNA substantially suppresses the malignant phenotype of glioma cells, and thus can be used as an effective therapeutic strategy for malignant gliomas.
Topics: Animals; Brain Neoplasms; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glioma; Humans; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasm Transplantation; RNA, Antisense; Tumor Cells, Cultured
PubMed: 23307113
DOI: 10.1007/s12264-012-1296-5 -
Journal of Lipid Research Jan 2015Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; however, cellular heterogeneity often... (Review)
Review
Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; however, cellular heterogeneity often precludes the targeted molecules from being found on all glioma cells, thus reducing the efficacy of these treatments. In contrast, one trait shared by virtually all tumor cells is altered (dysregulated) metabolism. Tumor cells have an increased reliance on glucose, suggesting that treatments affecting cellular metabolism may be an effective method to improve current therapies. Indeed, metabolism has been a focus of cancer research in the last few years, as many pathways long associated with tumor growth have been found to intersect metabolic pathways in the cell. The ketogenic diet (high fat, low carbohydrate and protein), caloric restriction, and fasting all cause a metabolic change, specifically, a reduction in blood glucose and an increase in blood ketones. We, and others, have demonstrated that these metabolic changes improve survival in animal models of malignant gliomas and can potentiate the anti-tumor effect of chemotherapies and radiation treatment. In this review we discuss the use of metabolic alteration for the treatment of malignant brain tumors.
Topics: Animals; Brain Neoplasms; Caloric Restriction; Diet, Ketogenic; Glioma; Humans
PubMed: 24503133
DOI: 10.1194/jlr.R046797