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CNS & Neurological Disorders Drug... Sep 2013Diffuse and unstoppable infiltration of brain and spinal cord tissue by neoplastic glial cells is the single most important therapeutic problem posed by the common... (Review)
Review
Diffuse and unstoppable infiltration of brain and spinal cord tissue by neoplastic glial cells is the single most important therapeutic problem posed by the common glioma group of tumors: astrocytoma, oligoastrocytoma, oligodendroglioma, their malignant variants and glioblastoma. These neoplasms account for more than two thirds of all malignant central nervous system tumors. However, most glioma research focuses on an examination of the tumor cells rather than on host-specific, tumor micro-environmental cells and factors. This can explain why existing diffuse glioma therapies fail and why these tumors have remained incurable. Thus, there is a great need for innovation. We describe a novel strategy for the development of a more effective treatment of diffuse glioma. Our approach centers on gaining control over the behavior of the microglia, the defense cells of the CNS, which are manipulated by malignant glioma and support its growth. Armoring microglia against the influences from glioma is one of our research goals. We further discuss how microglia precursors may be genetically enhanced to track down infiltrating glioma cells.
Topics: Animals; Brain Neoplasms; Gene Regulatory Networks; Genetic Therapy; Glioma; Humans; Microglia; Treatment Outcome
PubMed: 24047526
DOI: 10.2174/18715273113126660171 -
Neuro-oncology Feb 2009Malignant glioma is the most commonly occurring primary malignant brain tumor. It is difficult to treat and is usually associated with an inexorable, rapidly fatal... (Review)
Review
Malignant glioma is the most commonly occurring primary malignant brain tumor. It is difficult to treat and is usually associated with an inexorable, rapidly fatal clinical course. Chemotherapy, radiotherapy, and surgical excision are core components in the management of malignant glioma. However, chemotherapy, even with the most active regimens currently available, achieves only modest improvement in overall survival. Novel agents and new approaches to therapy are required to improve clinical outcomes. Irinotecan, a first-line treatment for metastatic colorectal cancer and an agent with high activity against solid tumors of the gastrointestinal tract, is an inhibitor of topoisomerase I, a critical enzyme needed for DNA transcription. Irinotecan crosses the blood-brain barrier and, in preclinical investigations, has demonstrated cytotoxic activity against central nervous system tumor xenografts. Its antitumor activity has also been demonstrated against glioblastoma cells with multidrug resistance. Studies in adult and pediatric patients with recurrent, intractable malignant glioma have evaluated irinotecan as monotherapy and in combination with other agents, including temozolomide, carmustine, thalidomide, and bevacizumab. Studies of irinotecan in combination with other medications, particularly temozolomide and bevacizumab, have yielded promising results. Irinotecan monotherapy has demonstrated efficacy; however, its efficacy appears to be enhanced when used in combination with other chemotherapeutic agents. When administered concurrently with enzyme-inducing antiepileptic drugs, the dosage must be increased to compensate for enhanced cytochrome CY3A4/5 enzyme activity. Toxicities associated with irinotecan have been manageable; the most important dose-limiting toxicities are neutropenia and diarrhea. Irinotecan-based chemotherapy of malignant glioma merits further study.
Topics: Antineoplastic Agents, Phytogenic; Brain Neoplasms; Camptothecin; Clinical Trials as Topic; Glioma; Humans; Irinotecan; Topoisomerase I Inhibitors
PubMed: 18784279
DOI: 10.1215/15228517-2008-075 -
BMJ (Clinical Research Ed.) Dec 1996To explore the experiences of patients and relatives after the diagnosis and treatment of malignant cerebral glioma.
OBJECTIVE
To explore the experiences of patients and relatives after the diagnosis and treatment of malignant cerebral glioma.
DESIGN
Two year prospective study with home interviews.
SETTING
Six neurosurgery and radiotherapy centres in London.
SUBJECTS
75 patients and 66 close relatives interviewed at diagnosis, 58 patients interviewed after radiotherapy, and 27 interviewed after recurrence.
MAIN OUTCOME MEASURES
Awareness of likely prognosis, distress, dissatisfaction with radiotherapy, and perception of severe problems in everyday life.
RESULTS
As they began radiotherapy most patients understood that they suffered from a brain tumour (95%; 71/75), but only one quarter (19/75) seemed fully aware of the poor prognosis. Others were unaware (43%; 32/75) or only partly aware (32%; 24/75). The more aware patients were more distressed. Relatives were three times more likely to be aware of the prognosis (67%; 44/66) and were more distressed. Although 39% (29/75) of patients initially made negative comments about radiotherapy, only 17% (13/75) were completely dissatisfied. The decision to accept radiotherapy could be discussed directly with 19 fully aware patients. Twelve found radiotherapy acceptable if it were medically advised or if it improved survival. Assessed by their own reports of problems only 40% of patients achieved a period of stability or remission, yet dissatisfaction with treatment did not increase.
CONCLUSIONS
Most patients with malignant glioma initially seemed unaware or only partly aware of the poor prognosis. Relatives were more aware, more distressed, and often concerned to protect patients from full awareness, which made it difficult to explore with patients directly the possible trade off between quality and length of life. Conceptualising the question as a rational choice ignores the social and emotional context of life threatening disease.
Topics: Activities of Daily Living; Adult; Aged; Awareness; Brain Neoplasms; Consumer Behavior; Decision Making; Disabled Persons; Family; Female; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Patient Satisfaction; Perception; Prospective Studies; Quality of Life; Stress, Psychological
PubMed: 8978225
DOI: 10.1136/bmj.313.7071.1512 -
British Journal of Cancer May 1999Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic acids are...
Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic acids are phytotherapeutic anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral oedema. Here, we report that boswellic acids are cytotoxic to malignant glioma cells at low micromolar concentrations. In-situ DNA end labelling and electron microscopy reveal that boswellic acids induce apoptosis. Boswellic acid-induced apoptosis requires protein, but not RNA synthesis, and is neither associated with free radical formation nor blocked by free radical scavengers. The levels of BAX and BCL-2 proteins remain unaltered during boswellic acid-induced apoptosis. p21 expression is induced by boswellic acids via a p53-independent pathway. Ectopic expression of wild-type p53 also induces p21, and facilitates boswellic acid-induced apoptosis. However, targeted disruption of the p21 genes in colon carcinoma cells enhances rather than decreases boswellic acid toxicity. Ectopic expression of neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to steroids, subtoxic concentrations of boswellic acids do not interfere with cancer drug toxicity of glioma cells in acute cytotoxicity or clonogenic cell death assays. Also, in contrast to steroids, boswellic acids synergize with the cytotoxic cytokine, CD95 ligand, in inducing glioma cell apoptosis. This effect is probably mediated by inhibition of RNA synthesis and is not associated with changes of CD95 expression at the cell surface. Further studies in laboratory animals and in human patients are required to determine whether boswellic acids may be a useful adjunct to the medical management of human malignant glioma.
Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Drug Resistance, Neoplasm; Drug Synergism; Fas Ligand Protein; Glioma; Humans; Membrane Glycoproteins; Mice; Neoplasm Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Triterpenes; Tumor Cells, Cultured; Tumor Suppressor Protein p53; bcl-2-Associated X Protein
PubMed: 10360653
DOI: 10.1038/sj.bjc.6690419 -
Cold Spring Harbor Perspectives in... Jan 2015Malignant glioma remains incurable despite tremendous advancement in basic research and clinical practice. The identification of the cell(s) of origin should provide... (Review)
Review
Malignant glioma remains incurable despite tremendous advancement in basic research and clinical practice. The identification of the cell(s) of origin should provide deep insights into leverage points for one to halt disease progression. Here we summarize recent studies that support the notion that neural stem cell (NSC), astrocyte, and oligodendrocyte precursor cell (OPC) can all serve as the cell of origin. We also lay out important considerations on technical rigor for further exploring this subject. Finally, we share perspectives on how one could apply the knowledge of cell of origin to develop effective treatment methods. Although it will be a difficult battle, victory should be within reach as along as we continue to assimilate new information and facilitate the collaboration among basic scientists, translational researchers, and clinicians.
Topics: Astrocytes; Brain Neoplasms; Glioma; Humans; Neural Stem Cells; Oligodendroglia
PubMed: 25635044
DOI: 10.1101/cshperspect.a020610 -
Molecular Cancer Feb 2015The poor prognosis and minimally successful treatments of malignant glioma indicate a challenge to identify new therapeutic targets which impact glioma progression....
BACKGROUND
The poor prognosis and minimally successful treatments of malignant glioma indicate a challenge to identify new therapeutic targets which impact glioma progression. Neurotensin (NTS) and its high affinity receptor (NTSR1) overexpression induces neoplastic growth and predicts the poor prognosis in various malignancies. Whether NTS can promote the glioma progression and its prognostic significance for glioma patients remains unclear.
METHODS
NTS precursor (ProNTS), NTS and NTSR1 expression levels in glioma were detected by immunobloting Elisa and immunohistochemistry assay. The prognostic analysis was conducted from internet by R2 microarray platform. Glioma cell proliferation was evaluated by CCK8 and BrdU incorporation assay. Wound healing model and Matrigel transwell assay were utilized to test cellular migration and invasion. The orthotopic glioma implantations were established to analyze the role of NTS and NTSR1 in glioma progression in vivo.
RESULTS
Positive correlations were shown between the expression levels of NTS and NTSR1 with the pathological grade of gliomas. The high expression levels of NTS and NTSR1 indicate a worse prognosis in glioma patients. The proliferation and invasiveness of glioma cells could be enhanced by NTS stimulation and impaired by the inhibition of NTSR1. NTS stimulated Erk1/2 phosphorylation in glioma cells, which could be reversed by SR48692 or NTSR1-siRNA. In vivo experiments showed that SR48692 significantly prolonged the survival length of glioma-bearing mice and inhibited glioma cell invasiveness.
CONCLUSION
NTS promotes the proliferation and invasion of glioma via the activation of NTSR1. High expression levels of NTS and NTSR1 predict a poor prognosis in glioma patients.
Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Glioma; Humans; Mice; Neoplasm Invasiveness; Neurotensin; Phosphorylation; Prognosis; Protein Precursors; Pyrazoles; Quinolines; Receptors, Neurotensin
PubMed: 25644759
DOI: 10.1186/s12943-015-0290-8 -
Medical Science Monitor : International... Sep 2018BACKGROUND The aim of this study was to assess the utility of miR-126 in promoting malignant glioma progression and determine if miR-126 might be a target for malignant...
BACKGROUND The aim of this study was to assess the utility of miR-126 in promoting malignant glioma progression and determine if miR-126 might be a target for malignant glioma treatment. MATERIAL AND METHODS The expression of miR-126 in malignant glioma tissues and cells was detected by reverse transcription polymerase chain reaction (RT-PCR). Western blot analysis was used to detect changes in protein levels. Transwell assay was applied to assess the migration and invasion in vitro. Luciferase reporter assay was used to confirm the binding of miR-126 and mature T cell proliferation 1 (MTCP1). A nude mouse tumor model was used to assess the molecular mechanism in vivo. RESULTS The expression level of miR-126 in patients with stage III~IV malignant glioma was significant lower than that in patients with stage I~II. In different malignant glioma cell lines, the expression was significantly reduced in U87MG. Compared with the control mimics group, the expression of MTCP1 was significantly decreased. The results of Transwell assay showed that the invasiveness and migration in the miR-126 mimics group was significantly lower than in the control mimics groups. miR-126 mimics did not affect luciferase activity in the Mut-miR-126/MTCP1 group, while miR-126 mimics reduced luciferase activity by 54% in the Wt-miR-126/MTCP1 group. The results of invasion showed that the invasion ability in the miR-126 inhibitor group was significantly increased compared with that in the normal control (NC) group, while the invasion and migration abilities in the MTCP1 siRNA group were significantly increased. After 6 weeks, the tumor volume in the miR-126 inhibitor group was significantly increased, while that in the MTCP1 siRNA group was significantly decreased. CONCLUSIONS miR-126 inhibits the migration of malignant glioma cells by inhibiting MTCP1.
Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Glioma; Humans; Male; Mice; Mice, Nude; MicroRNAs; Neoplasm Invasiveness; Proto-Oncogene Proteins; RNA, Messenger; RNA, Small Interfering; Xenograft Model Antitumor Assays
PubMed: 30233082
DOI: 10.12659/MSM.910292 -
CNS Oncology Sep 2012The metabolism of the essential amino acid tryptophan is a key microenvironmental factor shaping the immunobiology of many tumor types. The current concept suggests that... (Review)
Review
The metabolism of the essential amino acid tryptophan is a key microenvironmental factor shaping the immunobiology of many tumor types. The current concept suggests that in the tumor microenvironment, tryptophan is metabolized by specialized dioxygenases, chiefly indoleamine-2,3-dioxygenase (IDO), which is expressed by tumor cells and antigen-presenting cells. High IDO activity leads to the depletion of tryptophan from the local microenvironment, while immediate tryptophan metabolites, particularly kynurenine, accumulate to high micromolar levels. Both the depletion of tryptophan and the accumulation of kynurenine lead to profound suppression of T-cell responses. Orally active IDO inhibitors are currently being explored in clinical trials for their efficacy in enhancing antitumor immune responses. Recent evidence points at alternative routes of tryptophan catabolism via tryptophan-2,3-dioxygenase, which is particularly expressed in malignant gliomas resulting in the production of high amounts of kynurenine. Tryptophan-2,3-dioxygenase-derived kynurenine in turn leads to the promotion of glioma growth and invasiveness and the suppression of antitumor immune responses by binding to the aryl hydrocarbon receptor expressed in glioma cells and glioma-infiltrating T cells. These new data open up novel therapeutic approaches to alleviate glioma-mediated immunosuppression. This review summarizes the current view on the relevance of tryptophan metabolism as an important immunosuppressive, proinvasive and growth-promoting metabolic pathway in malignant glioma.
Topics: Animals; Central Nervous System Neoplasms; Glioma; Humans; Tryptophan
PubMed: 25054303
DOI: 10.2217/cns.12.6 -
Expert Review of Neurotherapeutics 2015Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glioblastoma. They are able to self-renew, recapitulate a whole tumor, and... (Review)
Review
Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glioblastoma. They are able to self-renew, recapitulate a whole tumor, and differentiate into other specific glioblastoma multiforme (GBM) subpopulations. Therefore, they have been held responsible for malignant relapse after primary standard therapy and the poor prognosis of recurrent GBM. The failure of current therapies to eliminate specific GSC subpopulations has been considered a major factor contributing to the inevitable recurrence in GBM patients after treatment. Here, we discuss the molecular mechanisms of chemoresistance of GSCs and the reasons why complete eradication of GSCs is so difficult to achieve. We will also describe the targeted therapies currently available for GSCs and possible mechanisms to overcome such chemoresistance and avoid therapeutic relapse.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Glioblastoma; Glioma; Humans; Neoplasm Recurrence, Local; Neoplastic Stem Cells
PubMed: 26027432
DOI: 10.1586/14737175.2015.1051968 -
Neuron Jun 2008Several years ago, the discovery of a highly tumorigenic subpopulation of stem-like cells embedded within fresh surgical isolates of malignant gliomas lent support to a... (Review)
Review
Several years ago, the discovery of a highly tumorigenic subpopulation of stem-like cells embedded within fresh surgical isolates of malignant gliomas lent support to a new paradigm in cancer biology--the cancer stem cell hypothesis. At the same time, these "glioma stem cells" seemed to resolve a long-standing conundrum on the cell of origin for primary cancers of the brain. However, central tenets of the cancer stem cell hypothesis have recently been challenged, and the cellular origins of stem-like cells within malignant glioma are still contended. Here, we summarize the issues that are still in play with respect to the cancer stem cell hypothesis, and we revisit the developmental origins of malignant glioma. Do glioma stem cells arise from developmentally stalled neural progenitors or from dedifferentiated astrocytes? Five separate predictions of a neural progenitor cell of origin are put to the test.
Topics: Animals; Brain Neoplasms; Glioma; Humans; Neoplastic Stem Cells; Neurons; Stem Cells
PubMed: 18579075
DOI: 10.1016/j.neuron.2008.05.031