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Results for “Cellular Microenvironment”

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At least 847 records · Page 47Linked to original sources

PubMed1996

GAP-43: putting constraints on neuronal plasticity.

The brain must balance the need for synaptic precision with the ability to generate and change connectivity patterns in response to environmental stimuli. GAP-43 is a phosphoprotein associated with the cytosolic surface of the membrane, and is one of the most abundant among the small subset of total cellular proteins transported to the growth cone. It appears to play an unusual role amplifying signals from the microenvironment. One of the several ways to perform this task involves interaction of GAP-43 with the G protein transduction cascade. In mice rendered GAP-43 null by homologous recombination, some nerves manifest aberrant growth at decision points, such as the optic chiasm. Thus, GAP-43 may work via modulation of signaling cascades, rather than autonomously causing growth, and could serve to keep plasticity within constraints needed to generate and maintain accurate synaptic wiring.

Animals↗

PubMed2004

Relevance of tumor microenvironment for progression, therapy and drug development.

Tumor interstitium exhibits a microenvironment that differs from corresponding normal tissues. Tumor phenotype shows, for example, an elevated intracellular pH (pHi), a lowered extracellular pH (pHe), a low oxygen concentration and low glucose levels. These differences are caused by cell biological (so called intrinsic) factors, e.g. a higher acidification rate, as well as by more systemic (extrinsic) factors, e.g. poor tumor vascularization. They represent important factors for invasiveness, immune suppression and proliferation, and they imply possibilities for diagnosis, prognosis and therapy. We have developed an experimental data-based computer model, which has simulated the potential role of metabolic effects on tumor progression. We show an experiment on cellular metabolism demonstrating the immunosuppressive impact of low pHe on peripheral blood mononuclear cells. Finally, we review important findings on the tumor microenvironment leading to possibilities for therapy which are currently evolving and which promise higher effectiveness for cancer therapy.

Cell Hypoxia↗

PubMed1999

Requirement for membrane lymphotoxin in natural killer cell development.

Development of natural killer (NK) cells is thought to depend on interactions between NK progenitors and the bone marrow (BM) microenvironment; however, little is known about the molecular signals involved. Here we show that lymphotoxin (LT) provides an important signal for the development of both NK cells and NK/T cells. LTalpha-/- mice show marked reduction in splenic and BM NK and NK/T cell numbers and dramatically impaired NK and NK/T cell function. Mice deficient in either tumor necrosis factor receptor (TNFR)-I or TNFR-II have normal numbers of NK and NK/T cells, implying that neither of the TNFRs nor soluble LTalpha3 is required for development of these cell types. Reciprocal BM transfers between LTalpha-/- and wild-type mice suggest that close interactions between membrane LT-expressing NK cell precursors and LT-responsive radioresistant stromal cells are necessary for NK cell development. When LT-deficient BM cells are incubated with IL-15, NK cells are formed. In addition, LT-deficient BM cells produce IL-15 after activation. Thus, membrane LT appears to deliver a signal for NK cell development that is either independent of IL-15 or upstream in the IL-15 pathway. These results reveal a novel function for membrane LT in NK and NK/T cell development. They also support a cellular and molecular mechanism by which NK cell precursors themselves deliver essential signals, through the membrane ligand, that induce the microenvironment to promote further NK cell and NK/T cell development.

Animals↗

PubMed2006

Cellular mechanisms of carbachol-stimulated Cl- secretion in rat epididymal epithelium.

Neurotransmitter-controlled Cl- secretions play an important role in maintenance of the epididymal microenvironment for sperm maturation. This study was carried out to investigate the effect of carbachol (CCH) on the cultured rat epididymal epithelium and the signal transduction mechanisms of this response. In normal K-H solution, CCH added basolaterally elicited a biphasic Isc response consisting of a transient spike followed by a second sustained response. Ca2+ activated Cl- channel blocker disulfonic acid stilbene (DIDS, 300 microM) only inhibited part of the CCH-induced Isc response, while nonselective Cl- channel blocker diphenylamine-dicarboxylic acid (DPC, 1 mM) reduced all, indicating the involvement of different conductance pathways. Both peaks of the CCH-induced Isc response could be significantly inhibited by pretreatment with an adenylate cyclase inhibitor, MDL12330A (50 microM). An increase in intracellular cAMP content upon stimulation of CCH was measured. All of the initial peak and part of the second peak could be inhibited by pretreatment with Ca2+-chelating agent BAPTA/AM (50 microM) and an endoplasmic reticulum Ca2+ pump inhibitor, Thapsigagin (Tg, 1 microM). In a whole-cell patch clamp experiment, CCH induced an inward current in the single cell. Two different profiles of currents were found; the first component current exhibited an outward rectifying I-V relationship in a time and voltage-dependent manner, and the current followed showed a linear I-V relationship. The carbachol-induced current was found to be partially blockable by DIDS and could be completely blocked by DPC. The above results indicate that the CCH-induced Cl- secretion could be mediated by Ca2+ and cAMP-dependent regulatory pathways.

1-Methyl-3-isobutylxanthine↗

PubMed2004

Coupling apoptosis resistance to the cellular stress response: the IAP-Hsp90 connection in cancer.

Understanding how tumor cells manage to survive and proliferate in ever-changing and often harmful microenvironments is a daunting challenge in tumor biology, and a major cause of treatment failure in the oncology clinic. Recent data have now demonstrated a direct link between the molecular chaperone Hsp90 and survivin, a dual regulator of cell proliferation and cell death over-expressed in virtually every human tumor. While the survivin-Hsp90 association may help tumor cells elevate their anti-apoptotic threshold and promote their proliferation, it may also provide new opportunities for rational cancer therapy.

Animals↗

PubMed1991

Eclectic mechanisms of heme regulation of hematopoiesis.

Regulatory features of heme (ferroprotoporphyrin IX) on hematopoietic growth/differentiation and related processes are reviewed. It is emphasized that expressions of specific erythroid and nonerythroid heme biosynthetic and degradatory enzymes are required, and the regulatory processes whereby this occurs is considered. The specificity of heme, relationship to cellular events such as differentiation, response to growth factors, oncogene and receptor expression, and how heme counteracts toxic effects such as viral growth are all discussed. The significance of heme in the hemopoietic bone marrow microenvironment and growth factor network are considered. Finally, the third pathway for arachidonic acid metabolism via the heme-cytochrome P450 monooxygenase system, in addition to cyclooxygenase and lipoxygenase, by bone marrow adherent cells and its role in cellular differentiation is briefly reviewed.

5-Aminolevulinate Synthetase↗

PubMed1993

Developmental expression of the syndecans: possible function and regulation.

Recent work has made clear that heparan sulfate at the cell surface is essential for a wide variety of interactions of cells with their microenvironment, including the action of growth factors, extracellular matrix, proteases and protease inhibitors. A major source of this cell surface heparan sulfate is a multigene family of proteoglycans, the syndecans, that are expressed developmentally in association with changes in tissue organization and morphology and induced during wound repair. In this review, we describe mechanisms underlying the differential expression of the syndecans, focusing on syndecan-1. The induction of syndecan-1 can result from soluble extracellular factor(s) acting at multiple levels of cellular regulation. At the transcriptional level, the promoter of the murine syndecan-1 gene contains potential recognition sites for several well-known regulatory genes, including Hox and MyoD family members. Because changes in syndecan expression enable cells to become more or less responsive to their microenvironment, understanding these regulatory mechanisms can lead to an improved understanding of how cellular behavior is controlled during development and wound repair.

Animals↗

PubMed2003

Neuroendocrine differentiation in prostatic carcinoma.

Knowledge and understanding of the pathophysiology of prostate cancer remain rudimentary. However, insight into epigenetic events and cellular interactions between cancer cells and the surrounding milieu has recently opened up a broader concept of cancer development. Throughout the entire process of prostate cancer aetiology, progression and metastasis, the microenvironment of the local host tissue is an active participant, and the selective pressure exercised on the malignant cells changes with the tumour-host setting. Thus primary cancers and metastases may respond differently to biomolecules and treatment modalities. Indeed, treatment itself changes the selective pressure, and new cellular capabilities may evolve. In prostate cancer, neuroendocrine differentiation is believed to occur in response to androgen ablation, and neuroendocrine paracrine factors have been shown to stimulate growth of androgen-independent cancer cells. Review of the accumulated knowledge in this field suggests that we need to improve our understanding of neuroendocrine cells and their regulatory products and their influence in the prostate gland. Recent research shows promise however, and no doubt new protocols will soon emerge in the treatment of prostate cancer, based on neuroendocrine hormones and their intracellular pathways.

Androgens↗

PubMedDate not supplied

Three-dimensional culture and multidrug resistance: effects on immune reactivity of MCF-7 cells by monocytes.

BACKGROUND: Multicellular spheroids are known to be the most adapted model to keep the in vitro resistance properties of cells. This in vivo-like tissue-culture representation was applied to investigate the immune reactivity of MCF-7 cells by monocytes. MATERIALS AND METHODS: Human blood monocytes, obtained by elutriation, were co-cultured with multicellular tumor spheroids of drug-sensitive (MCF-7S) and doxorubicin-resistant (MCF-7DXR) MCF-7 breast cancer cells. RESULTS: Tumor cells, according to their phenotype, induced differential recruitment and behavior of the immune cells towards the two types of spheroids. The secretion of various cytokines and the expression of several adhesion molecules were analysed. The MCF-7DXR/monocytes co-culture supernatant showed higher levels of IL-6 and IL-8 than the MCF-7S/monocytes co-culture supernatant. Cells from the MCF-7DXR spheroids expressed some adhesion molecules, CD-44 and CD-54, leading to a strong cellular cohesion in comparison with the sensitive spheroids. CONCLUSION: The two spheroid phenotypes represented an excellent model system for determining the precise tumor microenvironment in which cells move, the crucial molecular requirements and the mechanisms by which immunotherapeutic strategies could be developed to eradicate chemo-resistant tumors.

Biomarkers, Tumor↗

PubMed2002

Identification of distinct protein expression patterns in bilateral matched pair breast ductal fluid specimens from women with unilateral invasive breast carcinoma. High-throughput biomarker discovery.

BACKGROUND: Analysis of the biochemical and cellular contents of breast ductal fluid has recently gained attention as a potential noninvasive method for studying the local microenvironment associated with the development and progression of breast carcinoma. METHODS: Patients with unilateral primary invasive breast carcinoma were eligible for the current prospective pilot study. Nipple aspiration fluid (NAF) was obtained from the breast with cancer and the normal contralateral breast and subjected to two-dimensional electrophoresis. Computer-assisted image analysis was used to analyze NAF protein expression profiles. RESULTS: The number of separate protein spots detected in NAF samples ranged from 1280 to 1649. Substantial qualitative differences were identified between NAF protein expression patterns in the breast with cancer compared with the breast without cancer. Protein spots detected in the breast with cancer and not in the breast without cancer from the same patient varied from 30 to 202 different proteins. In addition, the number of protein spots detected in the breast without cancer and not in the breast with cancer of the same patient varied from 14 to 73 different proteins. Conversely, in an individual without breast carcinoma, only three protein spots were detected in the left breast but not the right breast, and only two were detected in the right breast but not the left breast. CONCLUSIONS: The breast is a unique organ in that its microenvironment can be readily accessed and evaluated by aspiration of fluid from the nipple. Breast ductal fluid contains a large number of proteins. As breasts are paired organs, comparisons of ductal fluid from a breast with cancer and the same patient's normal contralateral breast may reveal significant differences in protein expression associated with breast carcinoma. Recent advances in image analysis, automated mass spectrometry, and bioinformatics have provided the tools necessary to use ductal fluids from breast carcinoma patients for high-throughput biomarker discovery.

Biomarkers, Tumor↗

PubMed2006

Gene expression profiling of human synovial sarcoma cell line (Hs701.T) in response to IL-1beta stimulation.

OBJECTIVE: Synovial sarcoma (SS) is a malignant mesenchymal tumor that accounts for 5-10% of all soft tissue sarcoma. IL-1beta, a pleiotrophic cytokine, has been found in the tumor microenvironment which plays crucial roles in the pathogenesis of tumors. METHODS: In this study, we used Hs701.T as a cellular model to study the short-term (4-h) and long-term (48-h) stimulatory effect of IL-1beta on cell proliferation and differential gene expression. RESULTS: The results showed that IL-1beta can stimulate cell proliferation through activation of NF-kappaB and AP-1 transcription factors; sequentially triggers the expression of genes related to tumor progression. The microarray data indicated that most of the up-regulated genes were related to tumor progression. Five candidate genes which are involved in the mediation of proliferation (IL-6), apoptosis (Hsp27 and Daxx), and angiogenesis (PlGF and SPARC) were further validated by RT-PCR. CONCLUSION: These findings may be useful for understanding the pathogenesis of synovial sarcoma.

Cell Line, Tumor↗

PubMed1995

Expression and regulation of aromatase and 17 beta-hydroxysteroid dehydrogenase type 4 in human THP 1 leukemia cells.

Estradiol is active in proliferation and differentiation of sex-related tissues like ovary and breast. Glandular steroid metabolism was for a long time believed to dominate the estrogenic milieu around any cell of the organism. Recent reports verified the expression of estrogen receptors in "non-target" tissues as well as the extraglandular expression of steroid metabolizing enzymes. Extraglandular steroid metabolism proved to be important in the brain, skin and in stromal cells of hormone responsive tumors. Aromatase converts testosterone into estradiol and androstenedione into estrone, thereby activating estrogen precursors. The group of 17 beta-hydroxysteroid dehydrogenases catalyzes the oxidation and/or reduction of the forementioned compounds, e.g. estradiol/estrone, thereby either activating or inactivating estradiol. Aromatase is expressed and regulated in the human THP 1 myeloid leukemia cell line after vitamin D/GMCSF-propagated differentiation. Aromatase expression is stimulated by dexamethasone, phorbolesters and granulocyte/macrophage stimulating factor (GMCSF). Exons I.2 and I.4 are expressed in PMA-stimulated cells only, exon I.3 in both PMA- and dexamethasone-stimulated cells. Vitamin D-differentiated THP 1 cells produce a net excess of estradiol in culture supernatants, if testosterone is given as aromatase substrate. In contrast, the 17 beta-hydroxysteroid dehydrogenase type 4 (17 beta-HSD 4) is abundantly expressed in unstimulated THP 1 cells and is further stimulated by glucocorticoids (2-fold). The expression is unchanged after vitamin D/GMCSF-propagated differentiation. 17 beta-HSD 4 expression is not altered by phorbolester treatment in undifferentiated cells but is abolished after vitamin D-propagated differentiation along with downregulation of beta-actin. Protein kinase C activation therefore appears to dissociate the expression of aromatase and 17 beta-HSD 4 in this differentiation stage along the monocyte/phagocyte pathway of THP 1 myeloid cells. The expression of steroid metabolizing enzymes in myeloid cells is able to create a microenvironment which is uncoupled from dominating systemic estrogens. These findings may be relevant in the autocrine, paracrine or iuxtacrine cellular crosstalk of myeloid cells in their respective states of terminal differentiation, e.g. in bone metabolism and inflammation.

Actins↗

PubMed2005

Redox regulation of protein-tyrosine phosphatases.

The protein-tyrosine phosphatases (PTPs) form a large family of signaling proteins with essential functions in embryonic development and adult physiology. The PTPs are characterized by an absolutely conserved catalytic site cysteine with a low pK(a) due to its microenvironment, making it vulnerable to oxidation. PTPs are differentially oxidized and inactivated in vitro and in living cells. Many cellular stimuli induce a shift in the cellular redox state towards oxidation and evidence is accumulating that at least part of the cellular responses to these stimuli are due to specific, transient inactivation of PTPs, indicating that PTPs are important sensors of the cellular redox state.

Catalytic Domain↗

PubMed2004

Nuclear factor-kappaB: the enemy within.

Numerous lines of investigation suggest that nuclear factor NF-kappaB, a proinflammatory transcription factor, could promote tumorigenesis. Various inflammatory agents, carcinogens, tumor promoters, and the tumor microenvironment activate NF-kappaB. NF-kappaB proteins themselves and proteins regulated by it have been linked to cellular transformation, proliferation, apoptosis suppression, invasion, angiogenesis, and metastasis. Constitutively activated NF-kappaB is common in wide variety of tumors. Furthermore, there exists genetic evidence that NF-kappaB mediates tumorigenesis. Thus, suppression of NF-kappaB activation should be effective in the prevention and treatment of cancer.

Apoptosis↗

PubMed2004

The immunoregulatory effects of homocysteine and its intermediates on T-lymphocyte function.

Elevated levels of homocysteine (Hcy) have been identified as independent risk identifiers for cardiovascular disease, cerebrovascular disease as well as for all-cause mortality. Despite the potential importance of these observations, a definitive pathological role for Hcy or its various metabolites in any of these conditions has not been established. Particularly deficient is a description of the effects of elevated levels of homocysteine on immune function. Folic acid and vitamin B12 deficiency have been independently associated with decreased immune function, the apoptosis of bone marrow hematopoietic progenitor cells and the appearance of leukocytes with hypomethylated DNA in the peripheral circulation. A specific role for Hcy or its metabolites in these processes has not been described. We have examined the effects of Hcy and its various derivatives on T cell activation, differentiation and cell viability. Our results have demonstrated that Hcy is a potent concentration-dependent T cell activator promoting cellular activation and differentiation as well as potentiating activation-induced cell death (AICD) and cellular apoptosis. Overall, Hcy appears to exert diverse effects on immune function in the circulation and within the tissue microenvironment possibly contributing to age-related immune dysfunction and disease pathology.

Aged↗

PubMed2026

Enhancing pan-cancer spatial transcriptomics at single-cell resolution with stPainter.

Subcellular spatial transcriptomics can resolve tissue architecture at cellular scale, but sparse gene panels and limited detection sensitivity constrain downstream analysis. Existing enhancement methods often require tissue-matched single-cell RNA sequencing (scRNA-seq) references and dataset-specific retraining. Here we show that stPainter, a conditional generative model pretrained on a pan-cancer scRNA-seq atlas, can enhance spatial transcriptomics data without matched references or retraining. Using a latent diffusion architecture guided by Stochastic Differential Equations (SDE), stPainter reconstructs expanded expression profiles from sparse measurements and produces latent representations for clustering and cell-state analysis. When we apply stPainter upon 6 spatial transcriptomics datasets of different cancer types, we demonstrate that our model empowers downstream biological analyses, including fine-grained subpopulation clustering and pathway enrichment. Comparison with spatially resolved proteomics (CODEX) provided independent support for regional agreement between imputed cellular compositions and protein-level tissue organization. These results establish stPainter as a scalable approach for analyzing tumor microenvironments without auxiliary sequencing data.

Spatial Transcriptomics↗

PubMed2002

Maintenance of ATP favours apoptosis over necrosis triggered by benzamide riboside.

A new synthetic drug, benzamide riboside (BR) exhibited strong oncolytic activity against leukemic cells in the 5-10 microM range. Higher BR-concentrations (20 microM) predominantly induced necrosis which correlated with DNA strand breaks and subsequent depletion of ATP- and dATP levels. Replenishment of the ATP pool by addition of adenosine prevented necrosis and favoured apoptosis. This effect was not a pecularity of BR-treatment, but was reproduced with high concentrations of all trans-retinoic acid (120 microM) and cyanide (20 mM). Glucose was also capable to suppress necrosis and to favour apoptosis of HL-60 cells, which had been treated with necrotic doses of BR and cyanide. Apoptosis eliminates unwanted cells without affecting the microenvironment, whereas necrosis causes severe inflammation of surrounding tissues due to spillage of cell fluids into the peri-cellular space. Thus, the monitoring and maintenance of cellular energy pools during therapeutic drug treatment may help to minimize nonspecific side effects and to improve attempted drug effects.

Adenosine↗

PubMed2005

How do follicular dendritic cells interact intimately with B cells in the germinal centre?

The germinal centre is a dynamic microenvironment where antigen-activated B cells rapidly expand and differentiate, generating plasma cells and memory B cells. These cellular events are accompanied by dramatic changes in the antibody molecules that undergo somatic hypermutation and isotype switching. Follicular dendritic cells (FDCs) are the stromal cells located in the germinal centre. Although the capacity of FDCs to present antigen to B cells through antigen-antibody complexes has been recognized for many years, additional critical functions of FDCs have only recently been recognized. FDCs prevent apoptosis of germinal centre B cells and stimulate cellular interaction and proliferation. Here, we review the FDC signalling molecules that have recently been identified, some of which offer potential therapeutic targets for autoimmune diseases and B-cell lymphomas.

B-Lymphocytes↗