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At least 667 records · Page 37Linked to original sources
PubMed2006

Occurrence of thymosin beta4 in human breast cancer cells and in other cell types of the tumor microenvironment.

Previous studies have shown that the G-actin sequestering polypeptide thymosin beta4 frequently is overexpressed in cancers and that such overexpression correlates to malignant progression. However, the localization of thymosin beta4 in human cancers has not been determined. We now demonstrate that there is a considerable heterogeneity in the cellular distribution of thymosin beta4 in breast cancer. In most tumors examined, cancer cells showed low or intermediate reactivity for thymosin beta4, whereas leukocytes and macrophages showed intense reactivity. In addition, endothelial cells showed variable reactivity to thymosin beta4, whereas myofibroblasts were negative. There was no correlation between the intensity of tumor cell staining and histological grade, whereas there was a tendency toward a correlation between endothelial cell staining and grade. These results demonstrate that multiple cell types within the tumor microenvironment produce thymosin beta4 and that such expression varies from tumor to tumor. Such heterogeneity of expression should be taken into account when the role of thymosin beta4 in tumor biology is assessed.

Breast Neoplasms↗
PubMed2006

Thymus-homing precursors and the thymic microenvironment.

T cells develop in the thymus from precursors that are generated in the bone marrow and continuously seed the thymus through the blood. During evolution, 'outsourcing' the development of one blood lineage, namely the T-cell lineage, to an anatomically distinct hematopoietic organ required the generation of migratory precursors in the bone marrow, their homing to specialized, precursor-retaining thymic niches and their subsequent differentiation. Niche building and precursor homing are therefore intricately linked and should be viewed in context. In this review, we discuss recent findings on the developmental and genetic events that prepare the thymic epithelial microenvironment for its complex tasks, and highlight recent progress in the definition of the thymus-settling cells and the homing process that leads them into the thymus.

Animals↗
PubMed2005

Thermo-responsive behavior and microenvironments of poly(N-isopropylacrylamide) microgel particles as studied by fluorescent label method.

Poly(N-isopropylacrylamide) (PNIPAM) microgel particles labeled with a fluorescent monomer 4-N-(2-acryloyloxyethyl)-N-methylamino-7-N,N-dimethylaminosulfonyl-2,1,3-benzoxadiazole (DBD-AE) were prepared by emulsion polymerization under various crosslinker concentrations. The thermo-responsive behavior and the microenvironment of the microgel particles were studied in water by turbidimetric and fluorescence analyses. For the microgel particles prepared under the crosslinker concentration of 1 mM, the turbidity began to increase at ca. 32.5 degrees C, but the relative fluorescence intensity dramatically increased and the wavelength at the maximum fluorescence intensity (lambda(max)) was dramatically blue-shifted both at ca. 31.5 degrees C with increasing the temperature, suggesting the hydrophobicity around the DBD-AE unit was dramatically increased and the subsequent shrinking of the microgel particles occurred. As the crosslinker concentration increased from 0.5 to 20 mM, the transition temperature determined by turbidimetric analysis was constant upto 2 mM, rose between 2 and 10 mM, leveled off above 10 mM, and was ca. 34 degrees C at 20 mM. The temperature-induced microenvironmental change inside the microgel particles was also reduced at high crosslinker concentrations. The results obtained from the fluorescence of the DBD-AE unit and another fluorescent monomer unit 3-(2-propenyl)-9-(4-N,N-dimethylaminophenyl)phenanthrene (VDP) suggested that the heterogeneity inside the microgel particles prepared under the crosslinker concentration of 20 mM became high.

Journal Article↗
PubMed2006

Role of microenvironment in the mixed Langmuir-Blodgett films.

This paper reports the pi-A isotherms and spectroscopic characteristics of mixed Langmuir and Langmuir-Blodgett (LB) films of nonamphiphilic carbazole (CA) molecules mixed with polymethyl methacrylate (PMMA) and stearic acid (SA). pi-A isotherm studies of mixed monolayer as well as the remarkable change in collapse pressure of the mixed monolayer isotherms definitely show that CA is incorporated into PMMA and SA matrices. However, CA is stacked in the PMMA/SA chains and forms microcrystalline aggregates, as is evidenced from the scanning electron micrograph picture. The nature of these aggregated species in the mixed LB films has been revealed by UV-vis absorption and fluorescence spectroscopic studies. The presence of two different kinds of band systems in the fluorescence spectra of the mixed LB films have been observed. This may be due to the formation of low-dimensional aggregates in the mixed LB films. Intensity distribution of different band systems is highly sensitive to the microenvironment of two different matrices as well as also on the film thickness.

Journal Article↗
PubMed2006

Gene stage-specific expression in the microenvironment of pediatric myelodysplastic syndromes.

Using cDNA microarray assays we have observed a clear difference in the gene expression pattern between bone marrow stromal cells obtained from healthy children (CT) and from pediatric patients with either myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) associated with MDS (MDS-AML). The global gene function profiling analysis indicated that in the pediatric MDS microenvironment the disease stages may be characterized mainly by underexpression of genes associated with biological processes such as transport. Furthermore, a subset of downregulated genes related to endocytosis and protein secretion was able to discriminate MDS from MDS-AML.

Bone Marrow↗
PubMed2005

Quantitative fluorescence microscopy to probe intracellular microenvironments.

Some intracellular pathogens avoid killing within phagosomes--which are specialized microbicidal organelles in cells of the innate immune system--by altering phagosomal maturation or by entering a different subcellular compartment. The fate of the microorganisms is ultimately dictated by the composition of the surrounding environment. The unique problems associated with in situ measurements of intracellular microenvironments within intact cells and the advantages of quantitative fluorescence microscopy have recently been investigated. Of particular interest are the various techniques and reagents used in analysis of the pH and reactive oxygen intermediates in phagosomes and invasion vacuoles.

Humans↗
PubMed2026

CD36 Influences Leukemia Progression in MLL-AF9-Driven AML by Modulating the Leukemia Immune Microenvironment.

CD36, a fatty-acid translocase, is increasingly implicated in acute myeloid leukemia biology and treatment resistance, yet its contribution to leukemogenesis is still unclear. Using the MLL-AF9 model, we transduced hematopoietic stem/progenitor cells (HSPCs) from Cd36-knockout (KO) or wild-type (WT) mice and assessed leukemic potential with in vitro assays, transplants, and transcriptomic, metabolomic, and immune profiling. Both Cd36KO- and Cd36WT-HSPCs underwent efficient MA9-driven transformation, with comparable colony formation and Hox/Meis1 pathway activation, indicating Cd36 is dispensable for leukemic initiation. However, Cd36 deletion markedly attenuated disease progression, reducing leukemic burden and extending survival in irradiated mice (median 22 vs. 15 days, P = 0.001). Effects were strikingly amplified in immunocompetent, non-irradiated recipients (median 63 vs. 22 days, P = 0.002), revealing immune-dependent suppression. Immune profiling showed enhanced CD4⁺ and CD8⁺ T cell infiltration, reduced CD4⁺CD25⁺ regulatory-like cells, and lower Tim-3 expression in Cd36KO-MA9 spleens, consistent with a less exhausted, more effective anti-leukemic T cell response. Despite enhanced T cell infiltration, TCR repertoires remained conserved, indicating functional reprogramming rather than clonal selection. Consistent with a suppressive leukemia immune microenvironment, RNA-seq gene set enrichment analysis identified upregulation of inflammatory (TNFα/NF-κB) and hypoxic pathways in Cd36WT-MA9 cells. Untargeted metabolomics revealed metabolic shifts in Cd36KO cells, involving a reduction in three key metabolites, UDP-GlcNAc, UDP-Galactose/UDP-Glucose, and O-Phospho-L-Serine, that likely support an immune evasion mechanism. These findings demonstrate that while Cd36 is not essential for MLL-AF9-mediated transformation, its cell-intrinsic expression in leukemic cells suppresses anti-leukemic immunity and accelerates progression. This positions CD36 as a promising target to enhance immune surveillance and limit AML aggressiveness.

Acute Myeloid Leukemia (AML)↗
PubMedDate not supplied

Electrochemical effect on denitrification in different microenvironments around anodes and cathodes.

A bio-anode reactor and a bio-cathode reactor were developed to investigate the microenvironments around anodes and cathodes and their effects on denitrification. With an applied current of 40 mA, the oxidation-reduction potentials (ORPs) in the bio-cathode and bio-anode reactors were 100-200 mV lower and 50 mV higher, respectively, than that in the control reactor (a normal bio-reactor). The cathode reaction enhanced denitrification and the anode reaction inhibited denitrification. At 40 mA, the denitrification rate in the bio-cathode reactor was 55.1% higher than that in the control reactor. At 75 mA, the denitrification rate in the bio-anode reactor was just 33.5% of that in control reactor. Electric current of less than 20 mA had no effect on the most probable number (MPN) of denitrifiers, but at 75 mA, the MPN of denitrifiers decreased by 90% in the bio-anode reactor. In the bio-cathode reactor, the MPN of denitrifiers increased more than 100% for the lower ORP environment produced by a cathode reaction at 75 mA.

Bacteria↗
PubMed2005

Stromagenesis: the changing face of fibroblastic microenvironments during tumor progression.

During tumorigenesis, reciprocal changes in stromal fibroblasts and tumor cells induce changes to the neoplastic microenvironmental landscape. In stromagenesis, both the complex network of bi-directional stromal fibroblastic signaling pathways and the stromal extracellular matrix are modified. The presence of a 'primed' stroma during the early, reversible stage of tumorigenesis is optimal for stromal-directed therapeutic intervention. Three-dimensional (3D) cell culture systems have been developed that mimic the in vivo microenvironment. These systems provide unique experimental tools to identify early alterations in stromagenesis that are supportive of tumor progression with the ultimate goal of blocking neoplastic permissiveness and restoring normal phenotypes.

Cell Adhesion↗
PubMed2005

Selective evolutionary pressure from the tissue microenvironment drives tumor progression.

Cells grow within defined environmental niches and are subject to microenvironmental control. Outside of their niche, the environment is hostile, the normal cells lack appropriate survival signals which leads to anoikis. During tumor development and progression, malignant cells must escape the local tissue control and resist anoikis. The inherent genetic instability of tumor cells makes their phenotype very plastic, which changes under continuous environmental selection pressure. In this way the microenvironment drives the somatic evolution of the tumor. In the current review, we assess how this environmental selection pressure fits into the classical scheme of tumor progression.

Animals↗
PubMed2004

The hypoxic tumor microenvironment and gene expression.

Solid tumors are not static entities but are constantly responding to environmental signals as they grow and develop. One mechanism by which they respond to the adverse conditions of the tumor microenvironment is through coordinated changes in gene expression. The synchronized turning of genes on and off leads to biologic adaption to the adverse oxygen-poor environment. Because tumor hypoxia can be found in almost every solid tumor, it represents one of the most pervasive microenvironmental stresses that can impact malignant progression and therapeutic response. Interestingly, tumors that exhibit robust induction of hypoxia-responsive gene expression networks show a clinically more aggressive natural history. The contribution of hypoxia-responsive gene networks to malignant response is currently under investigation. An understanding of the coordinated functions of hypoxia induced and repressed genes can lead to a better understanding of the clinical significance of the hypoxic tumor phenotype.

Apoptosis↗
PubMed2006

Understanding hematopoietic stem-cell microenvironments.

The hematopoietic system is the paradigm for adult mammalian stem-cell research. Recent advances have improved our understanding of the cellular and molecular components of the microenvironment - or niche - that regulates hematopoietic stem cells (HSCs). Here, we summarize the molecular and cellular properties of two types of niche, namely the osteoblastic and the vascular niche, in homeostatic regulation of HSC behavior, including its maintenance, proliferation, differentiation, mobilization and homing. We highlight the most recent findings and point to an important trend to the study of niche activity in cancers. Knowledge of the basic features of the HSC niches, including physical location, cell type and various signaling pathways, should provide insights into other stem-cell systems and benefit clinical applications.

Animals↗
PubMed2006

Promotion of haematopoietic activity in embryonic stem cells by the aorta-gonad-mesonephros microenvironment.

We investigated whether the in vitro differentiation of ES cells into haematopoietic progenitors could be enhanced by exposure to the aorta-gonadal-mesonephros (AGM) microenvironment that is involved in the generation of haematopoietic stem cells (HSC) during embryonic development. We established a co-culture system that combines the requirements for primary organ culture and differentiating ES cells and showed that exposure of differentiating ES cells to the primary AGM region results in a significant increase in the number of ES-derived haematopoietic progenitors. Co-culture of ES cells on the AM20-1B4 stromal cell line derived from the AGM region also increases haematopoietic activity. We conclude that factors promoting the haematopoietic activity of differentiating ES cells present in primary AGM explants are partially retained in the AM20.1B4 stromal cell line and that these factors are likely to be different to those required for adult HSC maintenance.

Animals↗
PubMed2003

Hepatic microenvironment affects oval cell localization in albumin-urokinase-type plasminogen activator transgenic mice.

Mice carrying an albumin-urokinase type plasminogen activator transgene (AL-uPA) develop liver disease secondary to uPA expression in hepatocytes. Transgene-expressing parenchyma is replaced gradually by clones of cells that have deleted transgene DNA and therefore are not subject to uPA-mediated damage. Diseased liver displays several abnormalities, including hepatocyte vacuolation and changes in nonparenchymal tissue. The latter includes increases in laminin protein within parenchyma and the appearance of cytokeratin 19-positive bile ductule-like cells (oval cells) both in portal regions and extending into the hepatic parenchyma. In this study, we subjected AL-uPA mice to two-thirds partial hepatectomy to identify the response of these livers to additional growth stimulation. We observed several changes in hepatic morphology. First, the oval cells increased in number and often formed ductules in the parenchyma. Second, this cellular change was accompanied by a further increase in laminin associated with single or clusters of oval cells. Third, desmin-positive Ito cells increased in number and maintained close association with oval cells. Fourth, these changes were localized precisely to uPA-expressing areas of liver. Regenerating clones of uPA-deficient cells appeared to be unaffected both by stromal and cellular alterations. Thus, additional growth stimulation of diseased uPA-expressing liver induces an oval cell-like response, as observed in other models of severe hepatic injury, but the localization of this response seems to be highly regulated by the hepatic microenvironment.

Animals↗
PubMed2001

Protective function of p27(KIP1) against apoptosis in small cell lung cancer cells in unfavorable microenvironments.

A previous study of ours unexpectedly found that in contrast to frequent reductions in non-small cell lung cancer, high expression of the p27(KIP1) cyclin-dependent kinase (CDK) inhibitor was retained in virtually all small cell lung cancers (SCLCs), suggesting the possibility of high expression of nonfunctional p27(KIP1) in this virulent tumor. The study presented here, however, shows that p27(KIP1) in SCLC biochemically functions as a CDK inhibitor, clearly showing induction apparently associated with G(1)/G(0) arrest and efficient binding to and inhibition of the cyclin E-CDK2 complex. Interestingly, induction of p27(KIP1) seems to confer on SCLC cells the ability to survive under culture conditions unfavorable for cell growth such as a lack of nutrients and hypoxia. Subsequent experiments manipulating p27(KIP1) levels by using a sense p27(KIP1) expression construct or an antisense oligonucleotide supported this notion. These observations suggest that high expression of p27(KIP1) in vivo may favor the survival of SCLC by preventing apoptosis in a microenvironment unfavorable for cell proliferation.

Animals↗
PubMed2003

Ca2+ regulation in the near-membrane microenvironment in smooth muscle cells.

The microenvironment between the plasma membrane and the near-membrane sarcoplasmic reticulum (SR) may play an important role in Ca(2+) regulation in smooth muscle cells. We used a three-dimensional mathematical model of Ca(2+) diffusion and regulation and experimental measurements of SR Ca(2+) uptake and the distribution of the SR in isolated smooth muscle cells to predict the extent that the near-membrane SR could load Ca(2+) after the opening of single plasma membrane Ca(2+) channels. We also modeled the effect of SR uptake on 1), single-channel Ca(2+) transients in the near-membrane space; 2), the association of Ca(2+) with Ca(2+) buffers in this space; and 3), the amount of Ca(2+) reaching the central cytoplasm of the cell. Our results indicate that, although single-channel Ca(2+) transients could increase SR Ca(2+) to a certain extent, SR Ca(2+) uptake is not rapid enough to greatly affect the magnitude of these transients or their spread to the central cytoplasm unless the Ca(2+) uptake rate of the peripheral SR is an order-of-magnitude higher than the mean rate derived from our experiments. Immunofluorescence imaging, however, did not reveal obvious differences in the density of SR Ca(2+) pumps or phospholamban between the peripheral and central SR in smooth muscle cells.

Algorithms↗
PubMed1993

Hindered diffusion of high molecular weight compounds in brain extracellular microenvironment measured with integrative optical imaging.

This paper describes the theory of an integrative optical imaging system and its application to the analysis of the diffusion of 3-, 10-, 40-, and 70-kDa fluorescent dextran molecules in agarose gel and brain extracellular microenvironment. The method uses a precisely defined source of fluorescent molecules pressure ejected from a micropipette, and a detailed theory of the intensity contributions from out-of-focus molecules in a three-dimensional medium to a two-dimensional image. Dextrans tagged with either tetramethylrhodamine or Texas Red were ejected into 0.3% agarose gel or rat cortical slices maintained in a perfused chamber at 34 degrees C and imaged using a compound epifluorescent microscope with a 10 x water-immersion objective. About 20 images were taken at 2-10-s intervals, recorded with a cooled CCD camera, then transferred to a 486 PC for quantitative analysis. The diffusion coefficient in agarose gel, D, and the apparent diffusion coefficient, D*, in brain tissue were determined by fitting an integral expression relating the measured two-dimensional image intensity to the theoretical three-dimensional dextran concentration. The measurements in dilute agarose gel provided a reference value of D and validated the method. Values of the tortuosity, lambda = (D/D*)1/2, for the 3- and 10-kDa dextrans were 1.70 and 1.63, respectively, which were consistent with previous values derived from tetramethylammonium measurements in cortex. Tortuosities for the 40- and 70-kDa dextrans had significantly larger values of 2.16 and 2.25, respectively. This suggests that the extracellular space may have local constrictions that hinder the diffusion of molecules above a critical size that lies in the range of many neurotrophic compounds.

Animals↗
PubMed2002

Doppel and PrP(C) do not share the same membrane microenvironment.

Doppel is a paralog of the normal prion protein, PrP(C). It has been suggested that Doppel can compensate for the absence of PrP(C) in PrP(0/0) mice. In this work, we tested whether Doppel and PrP(C) share the same cell location, thereby sharing the same neighboring cell components, probably required to share the same cell function. Our results show that, at detergent conditions in which membrane rafts were intact, neither PrP(C) and Doppel co-immunoprecipitate with the appropriate antibodies, nor was Doppel retained by a Cu(2+)IMAC resin, as PrP(C) does. This indicates that, although Doppel is a raft-associated protein as is PrP(C), both proteins are not present in the same membrane microenvironment, and they probably do not perform the same function.

Animals↗