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PubMed2006

Hypoxia in the tumorigenesis of gliomas and as a potential target for therapeutic measures.

In this article, the author provides a brief description of the role of hypoxia in the tumorigenesis of gliomas and suggests potential ways of exploiting this role to design treatment modalities. Tumor hypoxia predicts the likelihood of metastases, tumor recurrence, resistance to chemotherapy and radiation therapy, invasive potential, and decreased patient survival for many human malignancies. Various methods of measurement of tumor hypoxia are discussed, including direct measurement and imaging methods. The role of hypoxia-responsive molecules, especially hypoxia-inducible factor-1 (HIF-1), in glioma tumorigenesis is explored. Treatment modalities regulated by hypoxia are proposed and some potential strategies reviewed. The progression of a low-grade astrocytoma to a glioblastoma multiforme may be mediated by hypoxia-induced phenotypic changes and subsequent clonal selection of cells that overexpress hypoxia-responsive molecules, such as HIF-1. In this model, intratumoral hypoxia causes genetic changes that produce a microenvironment that selects for cells of a more aggressive phenotype.

Animals↗
PubMed1998

CTL effector function within the central nervous system requires CD4+ T cells.

CTL responses induced during most viral infections are independent of help derived from the CD4+ T cell population. However, clearance of virus from the central nervous system (CNS) during infection with the neurotropic JHM strain of mouse hepatitis virus is inhibited in the absence of CD4+ T cells. Adoptive transfer of activated CD8+ T cells with virus-specific cytolytic activity into CD4+ T cell-depleted hosts demonstrated that CD4+ T cells were one component of the host response required for expression of CTL effector function(s) within the CNS. Analysis of mice infected with the JHM strain of mouse hepatitis virus demonstrated that, in contrast to CD8+ T cells, few CD4+ T cells entered the brain parenchyma. Although fewer CD8+ T cells entered the brain parenchyma in mice depleted of CD4+ T cells, access of CTL was not inhibited in the absence of CD4+ T cells. The number of apoptotic lymphocytes in the CNS increased in the absence of CD4+ T cells, suggesting that CTL enter the CNS during viral infection in a CD4-independent manner. However, these cells rapidly undergo apoptosis, indicating that expression of CTL effector function with the parenchyma of the CNS is CD4 dependent. These data raise the possibility that programmed cell death of CD8+ T cells within the CNS is due to the increased Ag present in the CNS of infected CD4 depleted mice or that autocrine cytokines, which maintain CTL activity within peripheral tissues, are inhibited in the microenvironment of the CNS.

Animals↗
PubMed2001

Neurons reduce glial responses to lipopolysaccharide (LPS) and prevent injury of microglial cells from over-activation by LPS.

The microenvironment of the CNS has been considered to tonically inhibit glial activities. It has been shown that glia become activated where neuronal death occurs in the aging brain. We have previously demonstrated that neurons tonically inhibit glial activities including their responses to the bacterial endotoxin lipopolysaccharide (LPS). It is not clear whether activation of glia, especially microglia in the aging brain, is the consequence of disinhibition due to neuronal death. This study was designed to determine if glia regain their responsiveness to LPS once the neurons have died in aged cultures. When cultured alone, glia from postnatal day one rat mesencephalons stimulated with LPS (0.1-1000 ng/mL) produced both nitric oxide (NO) and tumor necrosis factor alpha (TNFalpha), yielding a sigmoid and a bell-shaped curve, respectively. When neuron-containing cultures were prepared from embryonic day 14/15 mesencephalons, the shape of the dose-response curve for NO was monotonic and the bell-shaped curve for TNFalpha production was shifted to the right. After 1 month of culture under conditions where neurons die, the production curves for NO and TNFalpha in LPS-stimulated glia shifted back to the left compared to mixed neuron-glia cultures. Immunostaining of rat microglia for the marker CR3 (the receptor for complement component C3) demonstrated that high concentrations of LPS (1 microg/mL) reduced the number of microglia in mixed-glial cultures. In contrast, reduction of CR3 immunostaining was not observed in LPS-stimulated mixed neuron-glia cultures. Taken together, the results demonstrate that disinhibition of the glial response to LPS occurs after neurons die in aged cultures. Once neurons have died, the responsiveness of glia to LPS is restored. Neurons prevented injury to microglia by reducing their responsiveness to LPS. This study broadens our understanding of the ways in which the CNS microenvironment affects cerebral inflammation.

Animals↗
PubMed2025

Axonal injury is a targetable driver of glioblastoma progression.

Glioblastoma (GBM) is an aggressive and highly therapy-resistant brain tumour1,2. Although advanced disease has been intensely investigated, the mechanisms that underpin the earlier, likely more tractable, stages of GBM development remain poorly understood. Here we identify axonal injury as a key driver of GBM progression, which we find is induced in white matter by early tumour cells preferentially expanding in this region. Mechanistically, axonal injury promotes gliomagenesis by triggering Wallerian degeneration, a targetable active programme of axonal death3, which we show increases neuroinflammation and tumour proliferation. Inactivation of SARM1, the key enzyme activated in response to injury that mediates Wallerian degeneration4, was sufficient to break this tumour-promoting feedforward loop, leading to the development of less advanced terminal tumours and prolonged survival in mice. Thus, targeting the tumour-induced injury microenvironment may supress progression from latent to advanced disease, thereby providing a potential strategy for GBM interception and control.

Glioblastoma↗
PubMed2003

Absolute eigenvalue diffusion tensor analysis for human brain maturation.

The absolute eigenvalues of the diffusion tensor of white matter in sixteen normal subjects in two groups representing the early developmental stage (ages 1-10 years, n=8) and young adult stage (ages 18-34 years, n=8) were assessed using a high-field (3.0 T) magnetic resonance (MR) system. All three eigenvalues, including the largest eigenvalue, decreased significantly with brain maturation. The rate of the decline in the two small eigenvalues was, however, much higher than that of the largest eigenvalue, resulting in an actual increase in fractional anisotropy, a commonly measured relative index. The data demonstrate that an increase in anisotropy associated with brain maturation represents a significant decline in the small eigenvalue components, rather than an increase in the largest eigenvalue. The observed pattern of eigenvalue changes is best explained by the simultaneous occurrence of two of several independent phenomena within the axonal microenvironment during the myelination process, namely, (1) decline in unrestricted water content in extra-axonal space, and (2) increase in apparent diffusivity within the axon.

Adolescent↗
PubMed1987

Distribution of transferrin synthesis in brain and other tissues in the rat.

Levels of transferrin mRNA were measured by hybridization to transferrin cDNA in extracts from various areas of rat brain and other tissues. The highest concentrations of transferrin mRNA were found in the liver and the choroid plexus of the lateral and third ventricles. Lower concentrations were observed in the medulla and thalamus, choroid plexus of the fourth ventricle, cortex, hypothalamus, cerebellum, pituitary, testis, placenta, stomach, spleen, kidney, muscle, and heart. Yolk sac, small intestine, and adrenal glands did not contain detectable transferrin mRNA levels. The size of transferrin mRNA was the same in liver, brain, and testis. Upon incubation of choroid plexus pieces with [14C]leucine in vitro, about 4% of the radioactive protein secreted into the medium was found to be transferrin. Together with previous data (Dickson, P.W., Howlett, G.J., and Schreiber, G. (1985) J. Biol. Chem. 260, 8214-8219; Dickson, P.W., Aldred, A.R., Marley, P.D., Bannister, D., and Schreiber (1986) J. Biol. Chem. 261, 3475-3478) the obtained data suggest that the choroid plexus plays a role in maintenance of homeostasis in the microenvironment of the central nervous system by synthesizing and secreting plasma proteins.

Animals↗
PubMed2002

Macrophages relate presynaptic and postsynaptic damage in simian immunodeficiency virus encephalitis.

Neurodegeneration observed in lentiviral-associated encephalitis has been linked to viral-infected and -activated central nervous system macrophages. We hypothesized that lentivirus, macrophages, or both lentivirus and macrophages within distinct microenvironments mediate synaptic damage. Using the simian immunodeficiency virus (SIV)-infected macaque model, we assessed the relationship between virus, macrophages, and neurological damage in multiple brain regions using laser confocal microscopy. In SIV-infected macaques with SIV encephalitis (SIVE), brain tissue concentrations of SIV RNA were 5 orders of magnitude greater than that observed in nonencephalitic animals. In SIVE, staining for postsynaptic protein microtubule-associated protein-2 was significantly decreased in the caudate, hippocampus, and frontal cortical gray matter compared to nonencephalitic controls, whereas staining for presynaptic protein synaptophysin was decreased in SIV-infected macaques with and without encephalitis. These data suggest that presynaptic damage occurs independent of pathological changes associated with SIVE, whereas postsynaptic damage is more tightly linked to regional presence of both activated and infected macrophages.

Animals↗
PubMed2004

Tenascin-R mediates activity-dependent recruitment of neuroblasts in the adult mouse forebrain.

Neuroblasts arising in the adult forebrain that travel to the olfactory bulb use two modes of migration: tangentially, along the rostral migratory stream, and radially, in the core of the olfactory bulb where they start to ascend to the outer layers. Although the mechanisms of tangential migration have been extensively studied, the factors controlling radial migration remain unexplored. Here we report that the extracellular matrix glycoprotein tenascin-R, expressed in the adult mouse olfactory bulb, initiates both the detachment of neuroblasts from chains and their radial migration. Expression of tenascin-R is activity dependent, as it is markedly reduced by odor deprivation. Furthermore, grafting of tenascin-R-transfected cells into non-neurogenic regions reroutes migrating neuroblasts toward these regions. The identification of an extracellular microenvironment capable of directing migrating neuroblasts provides insights into the mechanisms regulating radial migration in the adult olfactory bulb and offers promising therapeutic venues for brain repair.

Animals↗
PubMedDate not supplied

Intracranial neurothekeoma--a rare parenchymal nerve sheath myxoma of the middle cranial fossa.

Neurothekeomas are rare, benign nerve sheath tumors, usually arising from cutaneous nerves in the head and neck region. So far, only 4 cases of the intracranial counterpart have been reported and these were located in the posterior fossa, sellar and parasellar region. We report here the first case of neurothekeoma located deep inside the brain parenchyma. Histologically, the tumor had lobular appearance with bland morphology in spite of cellular pleomorphism, myxoid background and variable S-100 positivity, characteristics of neurothekeomas. The schwannian origin was further confirmed ultrastructurally by demonstrating basal lamina and Luse bodies. Because of its benign nature, the lesion does not need postoperative radiotherapy. Histogenesis of neurothekeoma arising in the parenchyma remains enigmatic. The probable cell of origin could be the Schwann cell or perineurial cell of the nerve twigs around the blood vessels or by extreme differentiation of the precursor cell resting in a suitable microenvironment to the schwannian phenotype.

Adolescent↗
PubMed2026

Downregulated lysyl oxidase in plasma extracellular vesicles: a biomarker linked to brain metastasis risk in lung adenocarcinoma.

BACKGROUND: Brain metastasis (BrM) is a leading cause of mortality in patients with lung adenocarcinoma (LUAD). Extracellular vesicles (EVs), which carry bioactive molecules, play a critical role in tumor microenvironment remodeling and exhibit metastatic organotropism, holding promise as liquid biopsy biomarkers. This study aims to identify plasma EV-derived proteins associated with LUAD-BrM. METHODS: A multi-omics framework was applied. Plasma EVs from 59 stage IV LUAD patients (30 BrM vs 29 non-BrM) were profiled using data-independent acquisition mass spectrometry proteomics. Candidate proteins were screened via bioinformatics and machine learning (LASSO/RF/SVM). Initial validation included tissue proteomics (n = 13), single-cell transcriptomics (TISCH2), and Western blot analysis of a subset of the discovery samples. Functional experiments were conducted in vitro. The lead candidate was ultimately validated in an independent plasma cohort (n = 158) through ELISA. RESULTS: Proteomic analysis implicated collagen-containing extracellular matrix (ECM) pathways. Lysyl oxidase (LOX), a key ECM cross-linking enzyme, was identified as a lead candidate. LOX and its family member LOXL1 were consistently downregulated in BrM tissues and plasma EVs. Single-cell analysis revealed decreased LOX expression specifically in BrM-associated fibroblasts, which showed suppressed ECM-related pathways. In vitro experiments supported a PI3K/AKT-LOX-ECM regulatory axis. Plasma EV-derived LOX demonstrated strong diagnostic performance in the independent cohort, with an AUC of 0.786 (95% CI 0.713iated fi. CONCLUSIONS: Our study establishes plasma EV-derived LOX as a promising non-invasive biomarker for LUAD-BrM through a comprehensive multi-omics validation strategy. We propose a model wherein downregulation of LOX, potentially driven by PI3K/AKT signaling in tumor-associated fibroblasts, contributes to ECM degradation and may promote brain-tropic metastasis. This finding offers new insights for risk stratification and timely intervention in LUAD patients.

Humans↗
PubMed1992

In situ observation of inflammatory cell-tumor cell interaction in human seminomas (germinomas): light, electron microscopic, and immunohistochemical study.

The precise functional significance of the inflammatory cells that infiltrate seminomas remains poorly understood. The present study analyzed 15 cases of testicular and extragonadal seminomas (germinomas) by light and electron microscopy, as well as by immunohistochemical methods, with emphasis on the inflammatory cell-tumor cell interaction. Ultrastructurally, in all 15 cases the lymphocytes (mainly consisting of small lymphocytes) were found to be in intimate contact with the intact tumor cells and with those that displayed damage of varying degree. In particular, relatively early damage, such as local loss of the membrane and/or cytoplasm, occurred at the contact regions. Often, the lymphocytes penetrated deeply into the cytoplasm, even into the nucleus of the tumor cell. In spite of the severe damage to the tumor cells, the lymphocytes were themselves intact. The stromal cells contacted by lymphocytes did not show damage. The tumor cells were in contact with epithelioid cells of granulomas in six cases and scattered macrophages in 11 cases showed damage similar to that seen in tumor cells in contact with lymphocytes. The great majority of the lymphocytes were UCHL1-positive cells. L26- or Leu-7-positive cells were rarely found. The epithelioid cells and scattered macrophages were positive for MAC387. The present morphologic study suggests that the infiltrating lymphocytes, epithelioid cells (probably derived from macrophages), and macrophages may be directly cytotoxic to the tumor cells in the microenvironments of testicular and extragonadal seminomas (germinomas).

Adult↗
PubMed2005

Regulation of YKL-40 expression during genotoxic or microenvironmental stress in human glioblastoma cells.

YKL-40 is a 40 kDa secreted glycoprotein belonging to the family of 'mammalian chitinase-like proteins', but without chitinase activity. YKL-40 has a proliferative effect on fibroblasts, chondrocytes and synoviocytes, and chemotactic effect on endothelium and vascular smooth muscle cells. Elevated YKL-40 levels are found in serum of patients with diseases characterized by inflammation, fibrosis and tissue remodeling. Several studies have reported that high serum YKL-40 levels in patients with cancer are associated with poor prognosis. YKL-40 expression is strongly elevated in serum and biopsy material from glioblastomas patients. We investigated the expression of YKL-40 in three human malignant glioma cell lines exposed to different types of stress. Whereas a polymerase chain reaction transcript was detectable in all three cell lines, only U87 produced measurable amounts of YKL-40 protein. In U87, hypoxia and ionizing radiation induced a significant increase in YKL-40 after 24-48 h. The hypoxic induction of YKL-40 was independent of HIF1. Etoposide, ceramide, serum depletion and confluence all led to elevated YKL-40. Inhibition of p53 augmented the YKL-40 expression indicating that YKL-40 is attenuated by p53. In contrast, both basic fibroblast growth factor and tumor necrosing factor-alpha repressed YKL-40. These are the first data on regulation of YKL-40 in cancer cells. Diverse types of stress resulted in YKL-40 elevation, which strongly supports an involvement of YKL-40 in the malignant phenotype as a cellular survival factor in an adverse microenvironment.

Adipokines↗
PubMed1996

Murine T-lymphocytes express vasoactive intestinal peptide receptor 1 (VIP-R1) mRNA.

Vasoactive intestinal peptide (VIP), a neuropeptide present in primary and secondary lymphoid organs has been previously reported to inhibit IL-2 and IL-4 production as well as the proliferation of mitogen- or antigen-stimulated T-cells. Binding studies suggested that the immunoregulatory effects of VIP are mediated through specific VIP-binding sites present on lymphocyte subpopulations. Here we report on the expression of VIP-R1 mRNA in various murine lymphocyte subpopulations. By using RT-PCR. RNase protection assay, cDNA cloning, and sequence analysis, we show that stimulated and unstimulated murine spleen cells, thymocytes. CD4+ and CD8+ T-cells express VIP-R1. The VIP-R1 fragment amplified from murine brain, thymocytes, spleen cells and CD4+ T-cells share identical nucleotide sequences, and a high degree of homology with the corresponding nonlymphoid rat and human VIP-R1 sequences. The expression of VIP-R1 in thymocytes and peripheral lymphocytes, and especially in the CD4+ T-cell subset supports the idea that VIP produced or released locally in the lymphoid microenvironment could directly affect cytokine production and proliferation of T-lymphocytes.

Animals↗
PubMed1988

[Differentiation and a change in the sensitivity to antibrain serum of circulating colony-forming units under the action of thymic factors].

The rabbit anti-mouse brain serum (RAMBS) that interacts with SC-1 marked cells, rather than with thymocytes and bone marrow cells, inhibits most of the blood and bone marrow colony-forming unit (CFU) population. A commercial thymus preparation thymalin increases the granulocytopoietic activity of the circulating CFU and decreases their sensitivity to RAMBS in thymectomized and normal animals. Differentiation of circulating CFU remains unchanged in thymalin-treated mice after RAMBS administration, while CFU erythroid activity of nontreated animals is lowered. The revealed changes in the CFU differentiation and sensitivity to RAMBS confirm the assumption that SC-1 antigen may mark Thy-1 lymphocytes of their microenvironment, rather than CFU.

Adjuvants, Immunologic↗
PubMed1990

Presence of plasma proteins in spinal nerve roots. An immunohistochemical study in the rat.

The presence of plasma proteins in the spinal nerve roots of normal rats was investigated using an avidin-biotin peroxidase technique on formaldehyde-fixed, paraffin-embedded material. Sections from the roots, exposed to a rabbit-anti rat albumin antiserum showed widespread, intense immunoreactivity which filled the spaces between the nerve fibers. The reaction product usually ended at the junction between the roots and the spinal cord. The sheath enclosing the roots showed the same strong immunoreaction. There was also a marked reaction in the dorsal root ganglia and peripheral nerve. Spinal cord sections, however, showed no extracellular reactivity, but many motor neurons of the ventral horn were distinctly positive, presumably the result of a normally occurring retrograde axonal transport from the periphery. Parallel sections from the roots exposed to rabbit anti rat IgG antiserum, rabbit anti rat IgM antiserum, rabbit anti human fibrinogen antiserum and rabbit anti human fibronectin antiserum revealed no positive immunoreaction. Thus, rat spinal nerve roots normally contain material with albumin antigenic properties. This would indicate that albumin is present in the extracellular fluid of the roots in the same way as in the endoneurium of peripheral nerves. The fluid microenvironment of the roots, therefore, appears to be different from that in the CNS which lacks extracellular albumin due to the impermeability of the blood-brain barrier.

Animals↗
PubMed1987

Ultrastructure of the blood-brain barrier in the dolphin (Stenella coeruleoalba).

Light and electron microscopic methods were used for investigation of angioarchitectonics, glioarchitectonics and the structural basis of the blood-brain barrier in the dolphin Stenella coeruleoalba. It was shown that the cortical plate of the dolphin brain is extremely rich in capillaries and small arteries that are organized into a complicated net of continuous loops surrounding neuronal groups. The density of the capillary loops is related to the cytoarchitectural density of the cortex. It was also found that the neuronal microenvironment in the dolphin cortex is characterized by the presence of a large number of the astroglia-like cells that make a multi-layered investment surrounding capillaries and small arteries. These glial cells, unlike typical astrocytes of terrestrial mammals, have a large number of different organelles and their nuclei are similar to those of the oligocytes. The ultrastructure of the blood-brain barrier in the dolphin is characterized by the presence of extremely long tight junctions between endothelial cells and by specialized junctions between pericapillary astroglia-like cells. A belt of the glial end-feet interlocked with different types of junctions such as zonulae adherentes, maculae adherentes and gap junctions was found around all investigated capillaries. This system of specialized interendothelial and glio-glial junctions is tentatively hypothesized to be a feature of adaptation of the dolphin to the aquatic environment.

Animals↗
PubMed2025

High-Frequency Irreversible Electroporation Alters Proteomic Profiles and Tropism of Small Tumor-Derived Extracellular Vesicles to Promote Immune Cell Infiltration.

High-frequency irreversible electroporation (H-FIRE) is a nonthermal tumor ablation technique that disrupts the blood-brain barrier (BBB) in a focal and reversible manner. However, the mechanisms underlying this disruption remain poorly understood, particularly the role of small tumor-derived extracellular vesicles (sTDEVs) released from ablated tumor cells. In this study, we investigate the proteomic and functional alterations of sTDEVs released from F98 glioma and LL/2 Lewis lung carcinoma cells following H-FIRE ablation. Mass spectrometry analysis revealed 108 unique proteins in sTDEVs derived from ablative doses of H-FIRE, which are capable of disrupting the BBB in an in vitro model. Proteomic analysis of TDEVs highlights key changes in pathways related to integrin signaling, Platelet-derived growth factor receptor (PDGFR) signaling, and ubiquitination, which may underline their interactions with brain endothelial cells. These "disruptive" sTDEVs exhibit enhanced tropism for cerebral endothelial cells both in vitro and in vivo, where they persist in the brain longer than sTDEVs released after non-ablative H-FIRE doses. Notably, when introduced into a healthy Fischer rat model, disruptive sTDEVs are associated with increased recruitment of Iba1+ immune cells, suggesting a potential role in modulating post-ablation immune responses. However, despite their altered protein composition, these vesicles do not directly increase BBB permeability in vivo. This study is the first to demonstrate that electroporation-based tumor ablation significantly alters the composition and functionality of tumor-derived extracellular vesicles, potentially influencing the tumor microenvironment post-ablation. These findings have important implications for developing multimodal treatment strategies that combine H-FIRE with systemic therapies to enhance efficacy while managing the peritumoral microenvironment.

Animals↗
PubMed2006

Development of a three-dimensional multiscale agent-based tumor model: simulating gene-protein interaction profiles, cell phenotypes and multicellular patterns in brain cancer.

Experimental evidence suggests that epidermal growth factor receptor (EGFR)-mediated activation of the signaling protein phospholipase Cgamma plays a critical role in a cancer cell's phenotypic decision to either proliferate or to migrate at a given point in time. Here, we present a novel three-dimensional multiscale agent-based model to simulate this cellular decision process in the context of a virtual brain tumor. Each tumor cell is equipped with an EGFR gene-protein interaction network module that also connects to a simplified cell cycle description. The simulation results show that over time proliferative and migratory cell populations not only oscillate but also directly impact the spatio-temporal expansion patterns of the entire cancer system. The percentage change in the concentration of the sub-cellular interaction network's molecular components fluctuates, and, for the 'proliferation-to-migration' switch we find that the phenotype triggering molecular profile to some degree varies as the tumor system grows and the microenvironment changes. We discuss potential implications of these findings for experimental and clinical cancer research.

Apoptosis↗