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At least 235 records · Page 13Linked to original sources
PubMed2004

Spheroid preparation from hanging drops: characterization of a model of brain tumor invasion.

BACKGROUND: The use of three-dimensional in vitro models of brain tumor invasion has provided a system for reconstructing some of the cellular microenvironments present in the tumor mass. While spheroids of murine and human astrocytoma cells can be prepared using spinning cultures, spheroid preparation using many cell lines is not amenable to this method. We have developed a reproducible system of creating implantable spheroids that is applicable to different cell lines, and is independent of cell line characteristics. METHODS: For murine and human brain tumor cell lines, 20 microl drops containing predetermined cell concentrations were suspended from the lids of culture dishes and the resulting aggregates were transferred to culture dishes base-coated with agar. The two-dimensional aggregates formed three-dimensional spheroids on the non-permissive agar substrate, and were then implanted into three-dimensional collagen I gels and the invasive activity assessed. The invasive activity of C6 and U251 spheroids prepared by hanging drops was compared to spheroids of similar size prepared by spinner culture. RESULTS: The hanging drop method produced implantable spheroids capable of sustained invasion using all cell lines tested. Most cell lines required initial hanging drop cell concentrations of 45,000 cells/drop, suspension times of 48, and 72 h on agar. C6 spheroids had the same invasive capacity regardless of the model utilized, however U251 spheroids produced by hanging drops had significantly increased invasion compared to those prepared by spinner culture. Only spheroids prepared by spinner culture showed histological evidence of central necrosis. CONCLUSIONS: This model represents a reproducible approach to the preparation of implantable spheroids with invasive potential that compares with those produced using spinner culture. The use of hanging drops broadens the applicability of three-dimensional in vitro assays examining brain tumor invasiveness.

Animals↗
PubMed1992

Formation of PC12 tumors after transplantation into rat brains: dependence of time course on host age.

Rat pheochromocytoma PC12 cells form tumors when placed into the brains of Sprague-Dawley rats under specific conditions. We now show that tumorigenic potential is regulated by the microenvironment of the developing cerebrum. PC12 cell aggregates were identified in the periventricular or intraventricular spaces within 24 h after injection of cell suspensions into rat brains. In fetal or young neonatal (1-4-day-old) recipient rat brains, these cell aggregates formed large masses within 21 days. The tumor incidence declined in recipient neonates between the ages of 5 and 8 days. In both cases, tumors spread throughout the ventricular system and subarachnoid and Virchow-Robin spaces as they grew. In contrast, tumors were not generated by injections into adult rat brains or by placement of PC12 cell pellets into preformed cavities. Despite the loss of tumorigenicity, surviving cells were present at the injection site. The presence of surviving cells and the ability of another rat cell line (the C6 rat glioma line) to form tumors in adult rat brains suggest that an immune response is not solely responsible for the lack of PC12 tumorigenicity in adult rat brains. We propose that developmentally increasing local concentrations of specific factors (e.g., nerve growth factor of fibroblast growth factor) may also contribute to the suppression of tumor formation in this system.

Adrenal Gland Neoplasms↗
PubMed1989

Ganglioside function in the development and repair of the nervous system. From basic science to clinical application.

Gangliosides play important roles in the normal physiological operations of the nervous system, in particular that of the brain. Changes in ganglioside composition occur in the mammalian brain not only during development, but also in aging and in several neuropathological situations. Gangliosides may modulate the ability of the brain to modify its response to cues or signals from the microenvironment. For example, cultured neurons are known to respond to exogenous ganglioside with changes characteristic of cell differentiation. Gangliosides can amplify the responses of neurons to extrinsic protein factors (neuronotrophic factors) that are normal constituents of the neuron's environment. The systemic administration of monosialoganglioside also potentiates trophic actions in vivo and improves neural responses following various types of injury to the adult mammalian central nervous system. The possible molecular mechanism(s) underlying the ganglioside effects may reflect an action in modulating ligand-receptor linked transfer of information across the plasma membrane of the cell.

Animals↗
PubMed2006

The TLR-7 agonist, imiquimod, enhances dendritic cell survival and promotes tumor antigen-specific T cell priming: relation to central nervous system antitumor immunity.

Immunotherapy represents an appealing option to specifically target CNS tumors using the immune system. In this report, we tested whether adjunctive treatment with the TLR-7 agonist imiquimod could augment antitumor immune responsiveness in CNS tumor-bearing mice treated with human gp100 + tyrosine-related protein-2 melanoma-associated Ag peptide-pulsed dendritic cell (DC) vaccination. Treatment of mice with 5% imiquimod resulted in synergistic reduction in CNS tumor growth compared with melanoma-associated Ag-pulsed DC vaccination alone. Continuous imiquimod administration in CNS tumor-bearing mice, however, was associated with the appearance of robust innate immune cell infiltration and hemorrhage into the brain and the tumor. To understand the immunological mechanisms by which imiquimod augmented antitumor immunity, we tested whether imiquimod treatment enhanced DC function or the priming of tumor-specific CD8+ T cells in vivo. With bioluminescent, in vivo imaging, we determined that imiquimod dramatically enhanced both the persistence and trafficking of DCs into the draining lymph nodes after vaccination. We additionally demonstrated that imiquimod administration significantly increased the accumulation of tumor-specific CD8+ T cells in the spleen and draining lymph nodes after DC vaccination. The results suggest that imiquimod positively influences DC trafficking and the priming of tumor-specific CD8+ T cells. However, inflammatory responses induced in the brain by TLR signaling must also take into account the local microenvironment in the context of antitumor immunity to induce clinical benefit. Nevertheless, immunotherapeutic targeting of malignant CNS tumors may be enhanced by the administration of the innate immune response modifier imiquimod.

Adjuvants, Immunologic↗
PubMedDate not supplied

[Biological foundations for neurotransplantation].

A review of the mechanisms underlying cytogenesis and of the nervous tissues, the role of microenvironment, cell interactions in differentiation, and plastic rearrangements in the mammalian brain after transplantation of the embryonic nervous tissue. A common concept has been proposed, which unites biological processes involved in neurotransplantation and may serve as a theoretical base for the formation of ideas on pathways of differentiation of the nervous tissue, stimulation of compensatory processes and regeneration in the developing and pathological brain.

Animals↗
PubMed1996

Elevation of amino acids in the interstitial space of the rat brain following infusion of large neutral amino and keto acids by microdialysis: alpha-ketoisocaproate infusion.

alpha-Ketoisocaproate was infused into the brain of free-moving, awake rats by microdialysis to create a microenvironment similar to that found in maple syrup urine disease. The eluate of the probe was analyzed for amino acids to determine if alpha-ketoisocaproate was transaminated to leucine and if the amino acid homeostasis was altered. The interstitial levels of leucine were increased up to 11-fold and other large neutral amino acids were increased 2- to 3-fold indicating an active branched chain keto acid transaminase activity and enhanced hetero-exchange across cell membranes. The elevation of large neutral amino acids in the interstitial space is discussed in terms of the synthesis of leucine and neurotransmitters in maple syrup urine disease.

Amino Acids↗
PubMed2025

Infectious bursal disease virus (IBDV) as a novel oncolytic virotherapy in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most aggressive form of cancer of the central nervous system. Despite advances in immunotherapies and standard-of-care treatments for GBMs, clinical outcomes remain limited-owing to the immunosuppressive tumor microenvironment and the intrinsic resistance of GBM to conventional approaches. As a result, there is growing interest in rational combination strategies, particularly those pairing oncolytic viruses with immune-based therapies or established treatment modalities. Oncolytic viruses, by displaying conditionally enabled tumor cell-restricted replication, while stimulating antitumor immune responses and leaving healthy tissue unharmed, have the potential to reshape the therapeutic landscape in GBM and aid in achieving more durable benefits for patients. This study investigates the use of infectious bursal disease virus (IBDV) as a potential virotherapy for GBM. METHODS AND RESULTS: In vitro, IBDV infects and replicates within murine GBM cells and patient-derived GBM stem cells, inducing direct oncolysis and activating proinflammatory gene expression programs. IBDV also enhances the cytolytic activity of temozolomide (TMZ) in treated GBM cells, complementing TMZ chemotherapeutic activity. In vivo, treatment with IBDV in CT-2A GBM-bearing syngeneic mice significantly reduced tumor growth and improved survival compared with control mice. Intratumoral administration of IBDV induces a deep remodeling of the tumor immune microenvironment, reducing immunosuppressive M2-like macrophages and increasing the ratio of CD8+T cells to regulatory T cells. This reversion of immunosuppression linked to monocyte-derived macrophages has been confirmed on experimental ex vivo infections of explants derived from human GBM donors. CONCLUSION: These findings support further consideration of IBDV as a novel virotherapeutic agent for GBM.

Oncolytic Virotherapy↗
PubMed1981

Rat brain guanylate cyclase. Purification, amphiphilic properties and immunological characterization.

Soluble guanylate cyclase (GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2) has been purified to apparent homogeneity from rat brain by chromatography on Blue-Sepharose CL-6B, precipitation with (NH4)2SO4, preparative isoelectric focusing and gel-filtration on Ultrogel AcA-34. On sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis the purified enzyme showed a single band with an apparent molecular weight 59 000, when stored in buffer without glycerol and 2-mercaptoethanol. Purified enzyme has been found to be very unstable; inactivation can however be partially reversed by an endogenous heat-stable activator fraction. A monospecific antiserum obtained by immunization of rabbits was found to precipitate guanylate cyclase. This antibody also reacted with membrane-bound enzyme, indicating a close similarity to the soluble enzyme. Metal divalent cations were in general found to be strong inhibitors of the enzyme activity, though Ca2+ had no effect. ATP, CTP or UTP were shown to be competitive inhibitors of purified guanylate cyclase. Sodium nitroprusside increased cyclic GMP formation by the purified enzyme. Lysophosphatidylcholine and oleic acid, at low concentration, activated guanylate cyclase. Other unsaturated fatty acids, particularly arachidonic acid, dramatically inhibited the enzyme activity. Lipids may regulate the enzyme activity by binding to an apolar domain, as suggested by charge-shift electrophoresis. The mechanism by which guanylate cyclase is regulated in the cell appears to be a complex phenomenon. It may occur through oxidative reductive processes, and/or depend on other effectors, such as triphospho-nucleotides, divalent cations and lipid microenvironment.

Animals↗
PubMed1998

Impact of protein malnutrition on subcellular nucleic acid and protein status of brain of aluminum-exposed rats.

Nucleic acid and protein content in various cellular fractions of different regions of the brain were investigated in male albino rats following aluminum (Al) exposure (at the dose of 15% of LD50 i.p. for 28 days) on either an adequate or inadequate protein diet. It was observed that there was a decrease in homogenate DNA content in the thalamic area (Th), midbrain-hippocampal region (MH) and cerebellum (CL), but not in the cerebrum (CC) of the protein-restricted group of animals. Increased RNA content was recorded in the ribosomal and soluble fractions of CL of the adequately protein-fed animals compared to pair-fed controls. In the low-protein-fed animals, on the other hand, a decrease in RNA content was observed in the whole homogenate and nuclear fractions of CC, MH and CL, the ribosomal and soluble fractions of MH and CL, and in the mitochondrial fraction of TH. Ribonucleolytic activity was found to be increased only in the Th and CL of the adequately protein-fed group. Protein contents in the subcellular fractions of these four regions remain almost unaltered with the present dose and duration of Al-exposure; only the soluble fraction of CC and microsomal fraction of Th of the low-protein-fed group showed a significant decrease. The results of the present investigation confirm that Al has generally depressive effects on the nucleic acid metabolism of the brain and suggest that these effects are region-specific as well as dependent on dietary protein level. It is further suggested that alterations in the cellular microenvironment, caused by protein malnutrition, may play a significant role in the modification of the effects of Al in the brain.

Aluminum↗
PubMed1977

Significance of multiple forms of brain monoamine oxidase in situ as probed by electron spin resonance.

Spin-labeled hydroxyamphetamine, a competitive reversible inhibitor of brain monoamine oxidase, has been shown to be useful as an electron spin resonance (ESR) probe of the microenvironment of the active sites of the possible monoamine oxidase multiple forms. The ESR spectrum of spin-labeled hydroxyamphetamine was strongly quenched upon binding to the enzyme. The conformation of the active site of rat brain monoamine oxidase existing in various physical states, i.e. monoamine oxidase in situ (intact brain mitochondria), crude solubilized monoamine oxidase (MAOS) and isolated monoamine oxidase fractions (MAOa and MAOb) were critically and systematically examined. Nonlinear least squares regression analyses have been used to fit the binding data (obtained at room temperature with varying spin-labeled hydroxyamphetamine concentrations) to three groups of independent noninteracting ligand-binding models. A Gibbs-Helmholtz relationship was applied to the interpretation of the measured apparent association constant K as a function of temperature ranging from 4-50 degrees with increments of 2 degreesmfrom the extracted intensive parameters, k (intrinsic association constant) and deltaF (intrinsic free energy), as well as the apparent heat, deltaH, it was clear that the microenvironment of the binding sites existing in the more purified enzyme fractions MAOa and MAOb were similar to those found in the crude solubilized enzyme. More importantly, they correlated well with the conformation of the sites characterized in situ. The data suggested that the microenvironment of this multienzyme system was unperturbed in spite of the treatment due to the isolation process. In terms of the composition of binding sites, MAOa appeared to be heterogeneous while MAOb appeared to be more homogeneous. Since the isolated fractions MAOa and MAOb possessed marked different substrate specificities, these observations directly implied that monoamine oxidase multiple forms do exist in situ. The extracted extensive parameters, n (specific binding activity, nanomoles/mg of protein), as well as the measured characteristic transition temperatures, indicated that the relative abundance of the sites which directly affected substrate specificities was indeed altered. The consistency of the characteristic transition temperatures of 21 degrees and 38 degrees for the case of intact membrane preparations was particularly significant. A tenable hypothesis is that the manipulation in the composition of the monoamine oxidase binding forms through intimate lipid-protein interactions, which has been amply demonstrated in many biomembrane systems to be functionally important might be the underlying regulatory mechanism in vivo.

Animals↗
PubMed1978

The blood-brain barrier: its role in contrast studies.

The concept of a blood-brain barrier includes overlapping control mechanisms which work together to produce a constant microenvironment. Most important is the barrier to macromolecule passage located in cerebral capillary endothelium. Many drugs bound to proteins cannot pass this obstruction. Also important are membrane properties shared by all living cells. Lipid soluble molecules pass cell membranes easily; water soluble and ionized molecules do not. Other components include selective ion regulation, facilitated sugar transport, and resorption by the choroid plexus. The bulk flow of cerebrospinal fluid washes all solutes, and even particulate debris, from the system.

Biological Transport↗
PubMed1999

Brain-specific differentiation of mouse yolk sac endothelial cells.

Vascular endothelial cells exhibit diverse functional and biochemical properties that vary among tissues and organs, suggesting that differentiation of endothelial cells is influenced by their microenvironment. In this study, relatively undifferentiated endothelial cells from 9-day embryonic mouse yolk sac were co-cultured with 12-day embryonic mouse brain rudiments. Organ-specific differentiation of the yolk sac endothelial cells was monitored based on the expression and functional activities of two brain-specific endothelial cell markers, glucose transporter 1 (Glut-1) and P-glycoprotein. Immunochemical staining, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and functional assays demonstrated that yolk sac endothelial cells can acquire brain-specific properties after induction by brain rudiments. This result provides support for the hypothesis that endothelial cell heterogeneity is acquired during organogenesis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Role of the supraoptic nucleus in regulation of parturition and milk ejection revisited.

This review will focus on the activity of oxytocin neurons in the supraoptic nucleus (SON) and some factors that regulate their function during parturition and milk ejection in the rat. The level of oxytocin increases in the blood during parturition following a regression of the corpus luteum. The increase in oxytocin secretion is presumably a consequence of releasing the oxytocin neurons from restraining inhibitory influences of endogenous opioids-, nitric oxide-, and GABA-containing neurons following declining blood levels of progesterone on the one hand and increasing levels of estrogen on the other during late pregnancy. However, the principal stimulus for the increased oxytocin release is believed to originate, at least in part, from mechanical stimulation to the uterine cervix by fetuses near term, the resultant uterine contractile activity, and the fetal expulsion reflex. Hence, the contractile activity of the uterus acts through positive feedback mechanisms during parturition to stimulate oxytocin neurons as well, and this further increases the secretion of oxytocin. During suckling in lactating rats, somatosensory stimuli from the pups induce intermittent synchronized burst firing of oxytocin neurons, resulting in pulsatile increases in blood oxytocin concentrations to cause milk ejection. The oxytocin neurons appear to have an intrinsic capability to fire in a bursting fashion as determined by observation of this phenomenon in brain slice or tissue culture preparations. The release of oxytocin within the microenvironment of the SON and paraventricular nucleus coupled with morphological reorganization in these nuclei play important roles in the bursting activity of each oxytocin neuron and synchronization in vivo. However, the mechanism responsible for the synchronization of electrical activity in oxytocin neurons in the four discrete hypothalamic nuclei remains an interesting unanswered question.

Animals↗
PubMed2005

Coculture with endothelial cells reduces the population of cycling LeX neural precursors but increases that of quiescent cells with a side population phenotype.

Neural stem cell proliferation and differentiation are regulated by external cues from their microenvironment. As endothelial cells are closely associated with neural stem cell in brain germinal zones, we investigated whether endothelial cells may interfere with neurogenesis. Neural precursor cells (NPC) from telencephalon of EGFP mouse embryos were cocultured in direct contact with endothelial cells. Endothelial cells did not modify the overall proliferation and apoptosis of neural cells, albeit they transiently delayed spontaneous apoptosis. These effects appeared to be specific to endothelial cells since a decrease in proliferation and a raise in apoptosis were observed in cocultures with fibroblasts. Endothelial cells stimulated the differentiation of NPC into astrocytes and into neurons, whereas they reduced differentiation into oligodendrocytes in comparison to adherent cultures on polyornithine. Determination of NPC clonogenicity and quantification of LeX expression, a marker for NPC, showed that endothelial cells decreased the number of cycling NPC. On the other hand, the presence of endothelial cells increased the number of neural cells having "side population" phenotype, another marker reported on NPC, which we have shown to contain quiescent cells. Thus, we show that endothelial cells may regulate neurogenesis by acting at different level of NPC differentiation, proliferation and quiescence.

Animals↗
PubMed2025

Integrative multi-omics analysis proposes a metabolic classification of gliomas: distinct metabolic states, immune infiltration, and prognosis.

BACKGROUND: The tumor microenvironment (TME) of glioma harbors diverse cell types; however, cell metabolic heterogeneity remains to be explored. This study aims to characterize the metabolic features of different cell types in the TME by integrating multiple datasets, including genomics, bulk and single-cell transcriptomics, and metabolomics. METHODS: Unsupervised machine learning was used to construct an energy metabolic classifier based on the metabolic pathways identified from bulk RNA-seq of gliomas in the TCGA dataset. The classifier was externally validated using multiple datasets, including genomics, bulk RNA-seq, snRNA-seq, and the metabolomics data. Furthermore, metabolic heterogeneity associated with the classifier was further characterized at single-cell resolution. RESULTS: The energy metabolism-based classifier stratified patients into two prognostic clusters: patients in cluster 1 were characterized by high pathway activity of glycolysis, the pentose phosphate pathway (PPP), and fatty acid oxidation (FAO), whereas patients in cluster 2 exhibited higher activity in glutaminolysis. This metabolic classifier revealed both intratumoral and intertumoral metabolic heterogeneity, and the complexity was further validated by the metabolomics profiling and snRNA-seq data from the CPTAC dataset. Notably, OSMR, highly expressed in cluster 1, showed significant co-expression with key glycolytic enzyme genes. The OSM/OSMR/JAK1/STAT3 axis potently drives malignant progression of glioma cells, specially enhancing their invasive and migratory capabilities. Single-cell resolution analyses demonstrated that tumor metabolic heterogeneity is primarily driven by malignant cells rather than non-malignant components, while tumor microenvironment (TME) factors were also found to modulate malignant cell metabolism. Significantly, glycolytic activity in glioma cells increased during the phenotypic transition from PN (proneural) to MES (mesenchymal), with cluster 1 metabolic phenotypes predominating in the tumor core. Compared to cluster 2, cluster 1 patients exhibited higher mRNA expression of immunosuppressive checkpoint genes, which correlated with pronounced immunosuppression in the TME. Furthermore, various immune cells demonstrated distinct metabolic preferences at single-cell resolution. CONCLUSIONS: This study developed an energy metabolic-based classifier for gliomas with prognostic and therapeutic potential. Metabolic reprogramming was linked with the PN-to-MES transition of glioma cells and immunosuppression in the tumor microenvironment. Multi-omics data, especially snRNA-seq, offered insights into metabolism heterogeneity at single-cell resolution, enabling personalized treatment strategies.

Humans↗
PubMed2005

New delivery approaches for pediatric brain tumors.

For many types of childhood brain tumors, including malignant gliomas, disease progression at the primary site is the predominant mode of treatment failure. Accordingly, interest has been directed during the last decade on exploring strategies to enhance the delivery of therapeutically active agents into the tumor microenvironment. Two approaches that have been the focus of considerable attention in the treatment of adult malignant brain tumors include interstitial administration of chemotherapeutic agents using time-release polymers and convection-enhanced delivery of immunotoxin conjugates targeted to receptors overexpressed in brain tumors relative to normal brain cells. Although it remains to be determined whether these approaches will lead to meaningful improvements in disease control and long-term prognosis in children with brain tumors, the encouraging results from studies in adults support the rationale for further exploring these strategies in the pediatric setting.

Antineoplastic Agents↗
PubMed1994

Glial cells derived from aged mouse brain in culture display both mature and immature astrocytic phenotypes.

In earlier studies, we established glial cell cultures derived from aged (18-month-old) mouse cerebral hemispheres (MACH) and have maintained them frozen at various passages. These cultures were characterized immunocytochemically and consist of: 5% oligodendrocytes (GalC+), 75% astrocytes-type 1 (GFAP+ only), 15% astrocytes-type 2 (GFAP+ + A2B5+), and 5% progenitor glial cells (A2B5+ only). In the present study, we isolated colonies from MACH passage 29 cultures and also colonies from MACH passage 19 transfected with the gene for SV40 large T antigen and further subcultured for 8 passages. Using double-staining immunocytochemistry, we found in non-transfected MACH passage 19 colonies consisting primarily of cells exhibiting only vimentin-positive staining and are considered to be immature glioblasts; colonies consisting primarily of cells exhibiting GFAP+ + vimentin+ which are considered to be astrocytes at an intermediate stage of maturation; and colonies consisting predominantly of cells exhibiting GFAP+ only which are considered to be mature astrocytes. In contrast, colonies isolated from transfected MACH cultures consisted primarily of vimentin+ cells. In conclusion, astrocytes in cultures derived from aged brain continue to be variable as they are during development. However, their response to the microenvironment may differ during development and during aging. Thus, the availability of clones of mature and immature astrocytes offers the opportunity to study neuron-glia interactions and the role of mature and immature astrocytes in neuronal aging and regeneration.

Aging↗