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At least 127 records · Page 7Linked to original sources
PubMed1995

The role of trophic factors and autocrine/paracrine growth factors in brain metastasis.

The brain is a unique microenvironment enclosed by the skull, lacking lymphatic drainage and maintaining a highly regulated vascular transport barrier. To metastasize to the brain malignant tumor cells must attach to microvessel endothelial cells, respond to brain-derived invasion factors, invade the blood-brain barrier and respond to survival and growth factors. Trophic factors are important in brain invasion because they can act to stimulate this process. In responsive malignant cells trophic factors such as neurotrophins can promote invasion by enhancing the production of basement membrane-degradative enzymes (such as type IV collagenase/gelatinase and heparanase) capable of locally destroying the basement membrane and the blood-brain barrier. We examined human melanoma cell lines that exhibit varying abilities to form brain metastases. These melanoma lines express low-affinity neurotrophin receptor p75NTR in relation to their brain-metastatic potentials but the variants do not express trkA, the gene encoding a high affinity nerve growth factor (NGF) tyrosine kinase receptor p140trkA. Melanoma cells metastatic to brain also respond to paracrine factors made by brain cells. We have found that a paracrine form of transferrin is important in brain metastasis, and brain-metastatic cells respond to low levels of transferrin and express high levels of transferrin receptors. Brain-metastatic tumor cells can also produce autocrine factors and inhibitors that influence their growth, invasion and survival in the brain. We found that brain-metastatic melanoma cells synthesize transcripts for the following autocrine growth factors: TGF beta, bFGF, TGF alpha and IL-1 beta. Synthesis of these factors may influence the production of neurotrophins by adjacent brain cells, such as oligodendrocytes and astrocytes. Increased amounts of NGF were found in tumor-adjacent tissues at the invasion front of human melanoma tumors in brain biopsies. Trophic factors, autocrine growth factors, paracrine growth factors and other factors may determine whether metastatic cells can successfully invade, colonize and grow in the central nervous system.

Amino Acid Sequence↗
PubMed1998

Stimulation of the protein tyrosine kinase c-Yes but not c-Src by neurotrophins in human brain-metastatic melanoma cells.

The c-Yes proto-oncogene (pp62c-Yes) encodes a non-receptor-type protein tyrosine kinase (NRPTK) of the Src family. c-Yes activities and protein levels are elevated in human melanoma and melanocyte cell lines. Because the neurotrophins (NT) are important in the progression of melanoma to the brain-metastatic phenotype, we determined whether NT stimulate c-Yes activity in human MeWo melanoma cells and two variant sublines with opposite metastatic capabilities, 3 S 5 and 70W. The highly brain-metastatic 70W subline had an intrinsically higher c-Yes activity than parental MeWo or poorly metastatic 3 S 5 cells. c-Yes kinase was further induced by the prototypic human NT, nerve growth factor (NGF) in a dose and time-dependent manner. In contrast, c-Src activity (pp60-Src) was similar in all these cells and unaffected by NGF exposure. Additionally, human NGF and neurotrophin-3 stimulated c-Yes in brain-metastatic 70W cells. The magnitude of c-Yes activation correlated with the degree of invasion of 70 W cells following incubation of these neurotrophins. To further examine NT stimulation of c-Yes in melanoma cells, three additional cell lines were examined. Metastatic TXM-13 and TXM-18 increased c-Yes activity in response to NGF. In contrast, no increase was observed in low-metastatic TXM-40 cells. Together, these data suggest that altered c-Yes expression may play a role in the malignant progression of the human melanocyte towards the brain-metastatic phenotype and that NT enhance the activity of c-Yes in signaling penetration into the matrix of NT-rich stromal microenvironments such as the brain.

Brain Neoplasms↗
PubMed1993

Mediation of NGF-stimulated extracellular matrix invasion by the human melanoma low-affinity p75 neurotrophin receptor: melanoma p75 functions independently of trkA.

Although overexpression of the low-affinity p75 neurotrophin receptor (p75NTR) is frequently associated with advanced stages of human melanoma progression, the functional significance of this finding is unknown. We examined whether the degree of cell surface expression of p75NTR in human melanoma cell variants determines their extent of invasion stimulated by nerve growth factor (NGF). Treatment of MeWo melanoma cells or a metastatic spontaneous wheat germ agglutinin-resistant variant subline (70W) of MeWo cells with 2.5S NGF resulted in a dose-dependent enhancement of invasion through a reconstituted basement membrane. This effect was most pronounced with the 70W subline that exhibits brain-metastasizing potential in nude mice but was not found with a poorly metastatic MeWo variant subline (3S5). The expression of p75NTR as determined by Northern blotting and immunoprecipitation analysis of 125I-labeled cell surface proteins correlated with NGF-stimulated invasion. The MeWo melanoma sublines used in this study did not express p140proto-trkA mRNA or any p140proto-trkA variant transcripts including p70trkA as determined by Northern analysis and RT-PCR analysis. Thus, these melanoma cells would not be expected to form functional p75-p140 heterodimers or p140-p140 homodimers capable of transducing an NGF-generated signal to p140proto-trkA cytoplasmic substrates. These cells did express authentic p145trkC transcripts. However, NGF did not catalytically activate p145trkC receptors via increased tyrosine phosphorylation as would be expected if p145trkC participated in the signaling established by NGF. Furthermore, a NGF-stimulated purine-analogue-sensitive kinase activity was found to coimmunoprecipitate with p75NTR. This p75NTR-associated kinase may coordinate initial signaling events evoked by p75NTR ligand interaction. Addition of 2.5S NGF, at concentrations that should saturate cell surface p75NTR, to matrix-adherent cultures of human MeWo and 70W but not 3S5 melanoma cells suppressed the expression of 92-kDa type IV collagenase and stimulated the production of 72-kDa type IV collagenase in its fully active 68-kDa form. In the absence of p140proto-trkA, the matrix-dependent effects of NGF on metalloproteinase expression of brain-metastatic 70W melanoma cells suggest a signaling role for the low-affinity melanoma p75NTR receptor and its associated purine-analogue-sensitive kinase in signaling enhanced matrix penetration of NGF-rich stromal microenvironments such as the brain.

Base Sequence↗
PubMed2002

L-carnitine accelerates the in vitro regeneration of neural network from adult murine brain cells.

The development, growth and regeneration of nerve cells remain an unresolved issue. The up-to-date reported brain repair mechanisms are numerous and evidence suggests that, apart from the required trophism, tropism, microenvironment and specificity of the brain, a plethora of chemical, physiological and immunological compounds can contribute to such events. Among these compounds, we concentrated our interest on L-carnitine (L-Cn), which regulates the beta-oxidation of long chain fatty acids necessary for brain development, myelinization and growth. In contrast to fetal brain cells that grow easily in culture, adult brain cells show limited neurogenesis. Here, using adult brain cells from experimental mice, we show that although L-Cn does not improve their proliferative activity in short-term cultures, it accelerates the growth and differentiation of neurons, astrocytes, oligodendrocytes and ependymal cells from neurospheres in long-term cultures. Thus, the formation of a confluent neural network requires a 2-month period in culture. These observations provide new insights for in vivo use of L-Cn to support brain cell development in cases of injury or brain degenerative diseases.

Animals↗
PubMed1995

The relevance of cell microenvironments for the appearance of lympho-haemopoietic tissues in primitive vertebrates.

In higher vertebrates, mainly in mammals, a role for the non-lymphoid components of lymphoid organs in governing the maturation and functioning of immune system has been largely demonstrated. In contrast, such a role in the evolution of the vertebrate immune system has only been evidenced indirectly. In the present review we summarize histophysiological results which emphasize the relevance of lympho-haemopoietic stromal elements in the emergence and evolution of vertebrate lymphoid organs. The most primitive vertebrates, the Agnatha, have no true lymphoid organs and, accordingly, their immune responses seem more related to the non-anticipatory defence mechanisms of invertebrates than to the immune responses of vertebrates. So, the appearance and evolution of vertebrate lymphoid organs seems closely related with the emergence of immune capacities. Thymus, spleen and gut-associated lymphoid organs appear early in phylogeny whereas lymph nodes and bone marrow are late phylogenetical adquisitions. However, bone marrowless vertebrates contain numerous organs (i.e., gonads, kidney, brain, etc...), the cell microenvironments of which support lympho-haemopoiesis mimicking the condition of higher vertebrate bone marrow. On the other hand, the lack of germinal centres, another feature of the lymphoid organs of ectothermic vertebrates which impedes the selection of B cells raised after somatic hypermutation, presumably reflects the absence of some of the elements necessary for this organization.

Animals↗
PubMed1997

Production of neurotoxic factors by brain endothelium in Alzheimer's disease.

The cerebral vasculature is central to the maintenance of the neuronal microenvironment. We have previously demonstrated that brain microvessels in Alzheimer's disease produce high, potentially toxic, levels of nitric oxide. It is our hypothesis that neuronal injury in Alzheimer's disease occurs because an abnormal endothelium secretes factors that are toxic to neurons. In this study, we report that inhibition of protein kinase C in endothelial cells causes release of a factor that is toxic to neurons in vitro. Our results demonstrate that this endothelium-derived toxic factor is soluble, heat-labile, susceptible to proteolysis, and loses activity with repeated freeze-thawing. The molecular weight of this putative protein is between 10 and 50 kDa, and 8 hours are required after protein kinase C inhibition to detect the endothelium-derived toxic factor in the media. Finally, the endothelium-derived toxic factor kills neurons within 2 hours, suggesting that cell death occurs via necrosis, not apoptosis. These data support the notion that endothelial cells can create an injurious microenvironment for neurons by producing molecules with noxious properties. Altered/dysfunctional endothelial cells in the cerebral microcirculation could be a novel, unexplored source of neurotoxic factors in Alzheimer's disease.

Alzheimer Disease↗
PubMed1999

Astrocytoma infiltrating lymphocytes include major T cell clonal expansions confined to the CD8 subset.

Anaplastic astrocytoma and glioblastoma are frequent and malignant brain tumors that are infiltrated by T lymphocytes. Whether these cells result from non-specific inflammation following blood-brain barrier disruption or an antigen-driven specific immune response is unknown. In this study, an in-depth characterization of TCR diversity in tumor and blood RNA biopsies was performed in a series of 16 patients with malignant astrocytoma. Whilst there was no obvious restriction of the AV and BV gene segment usage, complementarity-determining region 3 size analysis and sequencing of amplified TCR transcripts revealed multiple T cell oligoclonal expansions in all astrocytomas analyzed. Unique T cell clones were present in different adjacent areas of a given tumor, but never detected in the blood. Quantification of the number of TCR clonal transcripts per microg of tumor RNA indicated that certain T cell clonal expansions may represent at least 300 cells/10(6) tumor cells. Furthermore, we demonstrated that the in vivo expanded clones were almost exclusively confined to the CD8(+) subset. Overall, these data suggest that spontaneous antigen-driven immune responses may be elicited against human astrocytoma despite the immunosuppressive microenvironment generated by the brain and the tumor itself. However, the ultimate failure of the immune system to control tumor growth could be the consequence of a deficient CD4 T(h) component of the response. This observation could have important consequences for the development of immunotherapies for astrocytoma patients.

Adult↗
PubMed2005

Does the vagus nerve inform the brain about preclinical tumours and modulate them?

The inflammatory microenvironment is thought to play a pivotal part in tumorigenesis. But, can the brain be informed about peripheral preclinical cancer cells? Can it modulate tumour development? One of the key routes for information to reach the brain from visceral regions is through the vagus nerve. Yet, patients with ulcers who have had a vagotomy have been shown to die from cancer more frequently than do those who have not had this procedure, and surgical and chemical vagotomy attenuates tumour-induced anorexia and leads to enhanced tumour progression. We therefore postulate that the vagus nerve participates in informing the brain about tumorigenesis by transmiting information to the brain about tumour-associated proinflammatory cytokines. Furthermore, activation of the vagus could slow tumorigenesis by suppression of peripheral proinflammatory cytokines.

Afferent Pathways↗
PubMed2003

Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex.

We investigated whether angiotensin II (ANG II), a peptide that plays a central role in the genesis of hypertension, alters the coupling between synaptic activity and cerebral blood flow (CBF), a critical homeostatic mechanism that assures adequate cerebral perfusion to active brain regions. The somatosensory cortex was activated by stroking the facial whiskers in anesthetized C57BL/6J mice while local CBF was recorded by laser-Doppler flowmetry. Intravenous ANG II infusion (0.25 mug.kg-1.min-1) increased mean arterial pressure (MAP) from 82 +/- 2 to 102 +/- 3 mmHg (P < 0.05) without affecting resting CBF (P > 0.05). ANG II attenuated the CBF increase produced by whisker stimulation by 65% (P < 0.05) but did not affect the response to hypercapnia or to neocortical application of the nitric oxide donor S-nitroso-N-acetyl penicillamine (P > 0.05). The effect of ANG II on functional hyperemia persisted if the elevation in MAP was offset by controlled hemorrhage or prevented by topical application of the peptide to the activated cortex. ANG II did not reduce the amplitude of the P1 wave of the field potentials evoked by whisker stimulation (P > 0.05). Infusion of phenylephrine increased MAP (P > 0.05 from ANG II) but did not alter the functional hyperemic response (P > 0.05). The data suggest that ANG II alters the coupling between CBF and neural activity. The mechanisms of the effect are not related to the elevation in MAP and/or to inhibition of the synaptic activity evoked by whisker stimulation. The imbalance between CBF and neural activity induced by ANG II may alter the homeostasis of the neuronal microenvironment and contribute to brain dysfunction during ANG II-induced hypertension.

Angiotensin II↗
PubMed2000

Local neurochemicals and site-specific immune regulation in the CNS.

Although it is often described as "immunologically privileged," the brain can display vigorous immune activity, both clinically and experimentally. The underlying control mechanisms are under active study. Here we shift attention from the brain as a whole to its diverse microenvironments. We review evidence that immune regulation in the brain is site-specific, and that local neurochemicals contribute to the site-specific control. Key points are illustrated by recent work from a rat model in which local injection of the proinflammatory cytokine, IFN-gamma, was used to modulate 2 essential aspects of the cell-mediated immune response: T cell entry from the blood, and expression of the MHC proteins that are needed to present antigen to the newly entered T cells. A growing number of neurologic disorders are known to be exacerbated by the immune/inflammatory network. Understanding the factors that influence local immune function may help explain the distribution of localized CNS damage and, more importantly, may suggest new therapeutic approaches for both desirable and unwanted responses.

Animals↗
PubMed1996

Developing brain cells produce factors capable of inducing the HT7 antigen, a blood-brain barrier-specific molecule, in chick endothelial cells.

Homeostasis of the neural microenvironment is maintained by the blood-brain barrier (BBB). To analyze the molecular mechanisms by which the BBB is induced during embryonic development, we have taken advantage of an in vivo model of BBB induction based on the expression of the HT7 cell surface protein. This protein is a transmembrane glycoprotein of the immunoglobulin superfamily. It is expressed in the chick BBB-forming endothelial cells, but not in peripheral endothelial cells. Here we show that the HT7 protein is induced in vessels which had vascularized a quail embryonic brain graft transplanted in the coelomic cavity of chick embryo. The quail brain graft was vascularized by both chick and quail-derived vessels. All chick host-derived vessels in the brain transplant were found to express HT7 while the neighboring chick vessels were negative. We conclude that the invading host endothelial cells differentiated into BBB-forming vessels under the influence of developing quail brain cells. This model reproduces the BBB induction during development. It may be useful for further approaches to study the molecular mechanisms involved in BBB induction.

Animals↗
PubMed1993

Perineuronal nets provide a polyanionic, glia-associated form of microenvironment around certain neurons in many parts of the rat brain.

The nature and function of previously described perineuronal nets are still obscure. In the present study their polyanionic components were demonstrated in the rat brain using colloidal iron hydroxide (CIH) staining. In subcortical regions, such as the red nucleus, cerebellar, and vestibular nuclei, most neurons were ensheathed by CIH-binding material. In the cerebral cortex perineuronal nets were seen around numerous nonpyramidal neurons. Biotinylated hyaluronectin revealed that hyaluronan occurs in perineuronal nets. Two plant lectins [Wisteria floribunda agglutinin (WFA) and Vicia villosa agglutinin (VVA)] with affinity for N-acetylgalactosamine visualized perineuronal nets similar to those rich in anionic components. Glutamic acid decarboxylase (GAD)-immunoreactive synaptic boutons were shown to occupy numerous meshes of perineuronal VVA-positive nets. Electron microscopically, VVA binding sites were scattered throughout perisynaptic profiles, but accumulated at membranes and in the extracellular space except not in synaptic clefts. To investigate the spatial relationship between glial cell processes and perineuronal nets, two astrocytic markers (S100-protein and glutamine synthetase) were visualized at the light and electron microscopic level. Two methods to detect microglia by the use of Griffonia simplicifolia agglutinin (GSA I-B4) and the monoclonal antibody, OX-42, were also applied. Labelled structures forming perineuronal nets were observed with both astrocytic, but not with microglial, markers. It is concluded that perineuronal nets are composed of a specialized type of glia-associated extracellular matrix rich in polyanionic groups and N-acetylgalactosamine. The net-like appearance is due to perisynaptic arrangement of the astrocytic processes and these extracellular components. Similar to the ensheathment of nodes of Ranvier, perineuronal nets may provide a special ion buffering capacity required around various, perhaps highly active, types of neurons.

Acetylgalactosamine↗
PubMed1998

Ciliary neurotrophic factor stimulates astroglial hypertrophy in vivo and in vitro.

After insult or trauma, astrocytes become activated and endeavor to restore the brain's delicately balanced microenvironment. An index of their activated state is that they become enlarged or hypertrophic. Ciliary neurotrophic factor (CNTF), a member of the alpha helical family of cytokines, is synthesized by astrocytes and is generally regarded to be an autocrine and paracrine injury signal. To determine whether CNTF might be an endogenous signal that stimulates astrocyte hypertrophy in vivo, we intracerebrally injected 200 ng of recombinant human CNTF into the adult rat neocortex. To study the astrocytes their cytosol was stained with antibodies against S100beta and their nuclei were stained with propidium iodide (PI). Fluorescent images of astrocytic nuclei and somas were acquired using a confocal laser-scanning microscope and their areas were measured using the NIH image software. Within 24 h of treatment, CNTF induced a volume increase of the somas and nuclei of protoplasmic and fibrous astrocytes in vivo, and this effect persisted for at least 48 h. To determine whether CNTF activates astrocytes directly, glial cultures were treated with CNTF (10 ng/ml) and were evaluated by measuring the area of PI stained nuclei. CNTF stimulation increased the size of both polygonal and process-bearing astroglia. Since our studies in vivo have shown that CNTF induces other key aspects of gliosis (S. W. Levison et al., 1996; Exp. Neurol. 141, 256), we conclude that CNTF is a powerful activator of astrocytes and that it is likely responsible for the persistent glial hypertrophy observed following injuries and diseases of the CNS.

Animals↗
PubMed2001

Determination of release and uptake parameters from electrically evoked dopamine dynamics measured by real-time voltammetry.

Quantifying mechanisms underlying extracellular signaling by the neurotransmitter dopamine (DA) is a difficult task, particularly in the complex extracellular microenvironment of the intact brain. In this study, two methods for evaluating release and uptake from DA dynamics monitored by real-time voltammetry are described. Both are based on a neurochemical model characterizing electrically evoked levels of DA as a balance between these opposing mechanisms. The theoretical basis of what is called here nonlinear regression and single curve analyses is given. Fitting simulated data tests the reliability of the methods. The two analyses are also compared with an experimental data set describing the effects of pharmacologically inhibiting the DA transporter in the caudate-putamen (CP) and nucleus accumbens (NAc). The results indicate that nonlinear regression and single curve analyses are suitable for quantifying release and uptake mechanisms underlying DA neurotransmission. Additionally, the most important experimental finding of this technical study was the independent confirmation of high affinity (approximately 0.2 microM) DA uptake in the intact striatum.

Action Potentials↗
PubMed1992

Blood flow and metabolic therapy in CNS injury.

A hypermetabolic state, consisting of increased resting energy expenditure, excessive protein wasting, and hyperglycemia, occurs in patients with a severe head injury. The hypermetabolism can affect survival by rapidly resulting in protein-calorie malnutrition (increased energy expenditure and protein wasting) and may adversely affect neurological recovery by altering the microenvironment of the injured brain (hyperglycemia).

Animals↗
PubMed2000

The brain and thymus have much in common: a functional analysis of their microenvironments.

Research into the neural and immune systems has begun to converge. Since the first reports that interleukins play important roles in both systems and that lymphocytes secrete neuronal factors, scientists have been surprised by the ever-increasing list of interactions. Here, Rolf Mentlein and Marion Kendall examine the major supporting cells of the brain and thymus - astrocytes and thymic epithelial cells - the similar neuroectodermal origin of which could explain such fundamental analogies.

Animals↗
PubMed2006

Trophic factors counteract elevated FGF-2-induced inhibition of adult neurogenesis.

The dentate gyrus of adult mammalian brain contains neural progenitor cells with self-renewal and multi-lineage potential. The lineage and maturation of the neural progenitors are determined by the composition and levels of the trophic factors in their microenvironment. In Alzheimer disease (AD) brain, especially the hippocampus, the level of basic fibroblast growth factor (FGF-2) is markedly elevated. Here we show that elevated FGF-2 enhances the division and nestin levels of cultured adult rat hippocampal progenitors but impairs neuronal lineage determination and maturation of these cells in culture. The trophic factors ciliary neurotrophic factor (CNTF), glial-derived neurotrophic factor (GDNF), and insulin-like growth factors-1 and -2 (IGF-1, IGF-2) as well as an Alzheimer peptidergic drug, Cerebrolysin((R)) (CL), in which we found these neurotrophic activities, counteract the effect of FGF-2 in inducing neuronal lineage (early neurogenesis). Whereas CNTF is the most active of the neurotrophic factors studied in promoting neurogenesis, CL, probably because of a combined effect of these factors, induces similar changes but without inhibiting cell proliferation. These findings suggest that CNTF, GDNF, IGF-1, and IGF-2 are promising therapeutic targets for AD and other diseases in which neurogenesis is probably inhibited.

Amino Acids↗
PubMedDate not supplied

The blood-brain barrier and its role in inflammation.

The unique microenvironment within the central nervous system (CNS) relies upon the integrity of the blood-brain barrier (BBB). This selectively permeable barrier comprises interendothelial tight junctions located at the capillaries and postcapillary venules. Cells and structures in the local environment are required to maintain normal BBB function. When inflammation is present, the BBB itself plays an integral role in the inflammatory response by either producing or expressing a variety of cytokines, adhesion molecules, metalloproteinases, serine proteases, products of arachidonic acid metabolism, and nitric oxide. Understanding the role of the BBB during inflammation is essential when creating and employing a therapeutic regime for animals with CNS disease. This review focusses on recent discoveries about the BBB and its role in inflammation, and applies this knowledge to our current understanding of inflammatory CNS disease in dogs and cats.

Animals↗