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At least 1,153 records · Page 64Linked to original sources
PubMed1994

RHAMM, a receptor for hyaluronan-mediated motility, on normal human lymphocytes, thymocytes and malignant B cells: a mediator in B cell malignancy?

RHAMM (Receptor for HA Mediated Motility) is a novel HA receptor that has been linked to regulating cell locomotion and density dependent contact inhibition of fibroblasts, smooth muscle cells, macrophages, lymphocytes, astrocytes and sperm. The ubiquitous expression of RHAMM suggests the existence of multiple isoforms, and indeed, RHAMM is found in various cellular compartments, namely nuclear, cytosolic, membrane-bound and extracellular. In this review, we emphasize the evolving role of RHAMM in B cell malignancies, and examine the function of RHAMM in T cell development in the thymic microenvironment. Both the motile behaviour of progenitor thymocytes (CD3-CD4-CD8-) and malignant B cells from multiple myeloma (MM), plasma cell leukemia, and hairy cell leukemia was blocked by monoclonal antibodies to RHAMM, suggesting that motility may correlate with increased expression of RHAMM at the cell surface. Interestingly, the soluble form of RHAMM is able to inhibit fibroblast locomotion, and it is likely that a balance between expression of both forms determines, in part the motility of cells. RHAMM appears to play a fundamental role in the immune system and the ability of RHAMM to function as a motility receptor is likely to be due to complex variables including the extent to which soluble RHAMM is secreted. RHAMM expression characterizes circulating monoclonal B cells as abnormal. potentially invasive and/or metastatic components of myeloma and may underlie the malignant behavior of these cells.

B-Lymphocytes↗
PubMed1999

The role of interleukin-1 in interactive senescence and age-related human endometrial cancer.

The causes of the age-related increase in cancer rates are poorly understood. One cause could be age-related changes in the stromal/epithelial cell interactions that facilitate tumorigenesis. We tested the hypothesis that aging of human endometrial stromal fibroblasts (ESF) alters their influence over endometrial epithelial cells. ESF from adults were found to inhibit anchorage-independent proliferation, to restrain colony outgrowth, and to induce formation of normal tissue architecture by human endometrial cancer cells. As ESF age, these inhibitory influences on malignant-like behaviors by epithelial cells are altered, becoming stimulatory. Age-related change in interleukin-1alpha (IL-1alpha) expression is a molecular determinant of ESF/epithelial cell interactions. Levels of IL-1alpha and IL-1-induced mRNAs increase in ESF with age. Treatment with IL-1 accelerates age-related changes in mRNA abundance and loss of ESF restraint over malignancy-associated behaviors by epithelial cells. Transfection of ESF with the intracellular IL-1 receptor antagonist preserved the young phenotype with respect to interactions with epithelial cells and prevented age-associated increases in groalpha and IL-8 mRNA levels. Our results indicate that aging of ESF is accompanied by an interactive senescence that alters ESF signaling to cancer cells and could contribute to increased cancer rates by providing a microenvironment that is more conducive to tumorigenesis.

Adenocarcinoma↗
PubMed1997

Effects of essential fatty acid deficiency on prostaglandin E2 production and cell-mediated immunity in a mouse model of leprosy.

Results from animal and in vitro studies suggest that essential fatty acid (EFA) deficiency enhances cell-mediated immunity by reducing production of prostaglandins with immunosuppressive actions. However, direct experimental evidence that EFA deficiency enhances T-lymphocyte function in vivo has not been obtained. In this study, athymic (nu/nu) mice were infected in the footpads with Mycobacterium leprae and fed a linoleic acid-free diet. These mice, and infected nu/nu mice on control diets, were given an adoptive transfer of M. leprae-primed, T-cell-enriched lymphocytes. After 2 weeks, M. leprae bacilli were harvested from the recipient mice and bacterial viability was determined by the BACTEC system. M. leprae recovered from recipient mice fed control diets displayed little reduction in metabolic activity. In contrast, M. leprae from recipient mice fed the EFA-deficient (EFAD) diet exhibited markedly reduced viability. In vitro, donor cells from M. leprae-primed mice secreted elevated levels of gamma interferon upon exposure to the bacilli. These cells also exhibited an enhanced proliferative response, which was reduced by exogenous prostaglandin E2 (PGE2). In addition, M. leprae-infected granuloma macrophages (Mphi) from EFAD recipient nu/nu mice secreted significantly less PGE2 than granuloma Mphi from mice on control diets. These data suggest that enhanced levels of Mphi-generated PGE2, induced by M. leprae or its constituents, could act as an endogenous negative modulator of the immune response occurring in the microenvironment of the lepromatous granuloma.

Animals↗
PubMed2004

Hypoxia and the regulation of mitogen-activated protein kinases: gene transcription and the assessment of potential pharmacologic therapeutic interventions.

Oxygen is an environmental/developmental signal that regulates cellular energetics, growth, and differentiation processes. Despite its central role in nearly all higher life processes, the molecular mechanisms for sensing oxygen levels and the pathways involved in transducing this information are still being elucidated. Altering gene expression is the most fundamental and effective way for a cell to respond to extracellular signals and/or changes in its microenvironment. During development, the expression of specific sets of genes is regulated spatially (by position/morphogenetic gradients) and temporally, presumably via the sensing of molecular oxygen available within the microenvironment. Regulation of signaling responses is governed by transcription factors that bind to control regions (consensus sequences) of target genes and alter their expression in response to specific signals. Complex signal transduction during hypoxia (deficiency of oxygen in inspired gases or in arterial blood and/or in tissues) involves the coupling of ligand-receptor interactions to many intracellular events. These events basically include phosphorylations by tyrosine kinases and/or serine/threonine kinases, such as those of mitogen-activated protein kinases (MAPKs), a superfamily of kinases responsive to stress nonhomeostatic conditions. Protein phosphorylations imposed during hypoxia change enzyme activities and protein conformations, and the eventual outcome is rather complex, comprising of an alteration in cellular activity and changes in the programming of genes expressed within the responding cells. These molecular changes serve as signals that are crucial for cell survival under contingent conditions imposed during hypoxia. This review correlates current concepts of hypoxic sensing pathways with hypoxia-related phosphorylation mechanisms mediated by MAPKs via the genetic and pharmacologic regulation/manipulation of specific transcription factors and related cofactors.

Gene Expression Regulation, Enzymologic↗
PubMed1994

Interleukin-11: a multifunctional growth factor derived from the hematopoietic microenvironment.

IL-11 is a unique growth factor derived from cells making up the HM. Although cloned based on IL-6-like bioactivity, IL-11 and IL-6 have distinct biologic profiles (Table 1). IL-11, like many recently cloned growth factors, has pleiotropic effects on hematopoietic cells presumably depending on the cytokine and cellular environment into which it is introduced. However, some general findings are consistent (Table 2). In addition, IL-11 has significant effects, either primary or secondary, on nonhematopoietic cells, including neurons, small intestine crypt progenitor/stem cells, and preadipocytes. The institution of human trials with IL-11 will provide important information on the pharmacologic effects of IL-11 on human hematopoietic cells in the context of frequently used chemotherapy protocols. The physiologic role(s) of IL-11 are unknown but will become clear (at least in the mouse) with gene targeting experiments underway in several laboratories.

Acute-Phase Proteins↗
PubMed1998

Dendritic cells, but not macrophages, produce IL-12 immediately following Leishmania donovani infection.

Infection with Leishmania, an obligate intracellular parasite of mononuclear phagocytes, stimulates the production of IFN-gamma from NK cells, via a pathway which is dependent upon IL-12 and IL-2. IL-12 is also essential for the development of host protective T cell responses to this parasite. However, previous in vitro studies have indicated that macrophages fail to make IL-12 following infection with Leishmania, and that subsequent to infection, macrophages become refractory to normal IL-12-inducing stimuli. We have used an in situ approach to attempt to resolve this apparent paradox, and by immunostaining for IL-12 p40 protein, we now demonstrate for the first time, that dendritic cells (DC) are the critical source of early IL-12 production following Leishmania infection. IL-12 production by DC is transient, peaking at 1 day post infection and returning to the levels seen in uninfected mice by day 3. Although resident tissue macrophages fail to produce IL-12 after Leishmania infection, these cells are not totally refractory to cytokine inducing stimuli, as TNF-alpha production is induced by day 3 post infection. Not only do these data satisfactorily explain the differences between in vivo and in vitro data by identifying the cellular source of IL-12, but they also suggest a novel model for NK cell activation; namely that in response to pathogens which fail to trigger IL-12 production by macrophages, DC-T cell clusters provide the microenvironment for initial NK cell activation.

Animals↗
PubMed2001

Proteomic profiling of the cancer microenvironment by antibody arrays.

Critical changes in protein expression that enable tumors to initiate and progress originate in the local tissue microenvironment, and there are increasing indications that these microenvironmental alterations in protein expression play critical roles in shaping and directing this process. As a model to better understand how patterns of protein expression shape the tissue microenvironment, we analyzed protein expression in tissue derived from squamous cell carcinoma of the oral cavity through an antibody microarray approach for high-throughput proteomic analysis. Utilizing laser capture microdissection to procure total protein from specific microscopic cellular populations, we demonstrate that quantitative, and potentially qualitative, differences in expression patterns of multiple proteins within epithelial cells reproducibly correlate with oral cavity tumor progression. Furthermore, differential expression of multiple proteins was also found in stromal cells surrounding and adjacent to regions of diseased epithelium that directly correlated with tumor progression of the epithelium. Most of the proteins identified in both cell types are involved in signal transduction pathways, thus we hypothesize that extensive molecular communication involving complex cellular signaling between epithelium and stroma play a key role in driving oral cavity cancer progression.

Antibodies, Neoplasm↗
PubMed1978

Recent developments in understanding the pathogenesis of aplastic anemia.

Bone marrow failure in aplastic anemia (AA) could result from abnormalities of hematopoietic stem cells, abnormal control of hematopoiesis, or abnormalities of the hematopoietic environment. Bone marrow transplantation, in vitro marrow culture techniques, and studies in animal models of marrow failure have provided insights on the possible pathogenetic mechanisms underlying AA. Studies in man and in murine models suggest that most often AA results from injuries to hematopoietic stem cells. Despite the intriguing report of abnormal regulatory cells in congenitally anemic mice, instances of marrow failure due to defective humoral or cellular control of hematopoiesis have not been identified in man. In vitro studies employing allogeneic marrow targets have suggested that immune suppression of hematopoiesis may occasionally mediate AA in man. Marrow failure due to abnormalities of the hematopoietic microenvironment has been suggested by experience with bone marrow transplantation, but no direct study of this possibility has been reported. Based on available evidence, it seems likely that AA will prove to be many diseases that share common clinical and morphologic features.

Anemia, Aplastic↗
PubMed2026

Pan-cancer analysis identifies APOC1 as a TAM-derived modulator of adaptive immune resistance and predictor of therapeutic response.

BACKGROUND: Apolipoprotein C1 (APOC1) has been implicated in several malignancies, yet its expression patterns, clinical significance, and immunomodulatory roles across cancer types remain poorly characterized. METHODS: We performed a comprehensive multi-omic analysis of APOC1 across 33 cancer types integrating transcriptomic, proteomic, genomic, epigenomic, and pharmacogenomic data from TCGA, GTEx, CPTAC, and multiple independent external cohorts. Immune infiltration was assessed using seven complementary algorithms. Spatial transcriptomics and single-cell RNA sequencing were employed to determine the cellular source of APOC1 expression. RESULTS: APOC1 upregulation in most cancers was associated with cancer type-specific prognosis. After adjustment for clinical covariates and macrophage infiltration, high APOC1 remained an independent adverse factor in KIRC, LGG, and STAD. APOC1 expression positively correlated with genomic instability hallmarks, including homologous recombination deficiency and aneuploidy, with these associations largely independent of immune infiltration; in contrast, associations with tumor mutational burden were substantially confounded by macrophage abundance. Immune infiltration analysis revealed a pattern consistent with adaptive immune resistance: APOC1 correlated positively with immune-activating signatures (STAT1, MHC-II, TCR signaling) and immunosuppressive M2 macrophages and Tregs, yet negatively with anti-tumor effectors (activated NK cells, dendritic cells). Spatial transcriptomics and single-cell RNA sequencing identified tumor-associated macrophages (TAMs) as the primary cellular source of APOC1, with transcripts co-localizing with CD68 in tissue sections. APOC1 expression correlated with multiple immune checkpoint molecules and was elevated in responders to immune checkpoint blockade, consistent with an inflamed yet regulated tumor microenvironment. Pharmacogenomic analyses revealed that APOC1-high tumors display distinct drug response profiles, characterized by resistance to MAPK pathway inhibitors and potential sensitivity to the HDAC inhibitor Entinostat. CONCLUSION: This pan-cancer analysis establishes APOC1 as a context-dependent biomarker and a TAM-derived modulator of adaptive immune resistance, with prognostic and therapeutic implications across malignancies. APOC1-expressing TAMs represent a potential target for combination immunotherapy strategies.

APOC1↗
PubMed1993

Ion-selective microelectrodes and diffusion measurements as tools to explore the brain cell microenvironment.

The construction and application of liquid-membrane ion-selective microelectrodes (ISM) are described. Recommendations are provided for the selection of appropriate cocktails containing neutral carriers to form the liquid membrane to sense K+, Ca2+, H+ and Na+. The use of charged carriers to sense Cl- and the cation tetramethylammonium (TMA+) is discussed. A detailed protocol is given for constructing double-barreled electrodes (ion-sensor and reference barrel) with tips of 1 micron diameter or more for extracellular ion measurements. The primary results obtained with ISMs in the brain cell microenvironment are briefly surveyed. The theoretical basis for measuring diffusion properties of extracellular space is described. Such measurements enable the estimation of volume fraction (proportion of tissue that is extracellular space) and tortuosity (hindrance of diffusion due to cellular obstructions). A method is given for using TMA+ ISMs in combination with iontophoresis or pressure ejection of TMA+ from a nearby micropipette to measure diffusion properties.

Animals↗
PubMed2000

The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages.

The cellular response to hypoxia includes the hypoxia-inducible factor-1 (HIF-1)-induced transcription of genes involved in diverse processes such as glycolysis and angiogenesis. Induction of the HIF-regulated genes, as a consequence of the microenvironment or genetic changes, is known to have an important role in the growth of experimental tumors. Hypoxia-inducible factors 1alpha and 2alpha (HIF-1alpha and HIF-2alpha) are known to dimerize with the aryl hydrocarbon receptor nuclear translocator in mediating this response. Because regulation of the alpha chain protein level is a primary determinant of HIF activity, our aim was to investigate the distribution of HIF-1alpha and HIF-2alpha by immunohistochemistry in normal and pathological tissues using monoclonal antibodies (mAb). We raised a new mAb to detect HIF-1alpha, designated 122, and used our previously validated mAb 190b to HIF-2alpha. In the majority of solid tumors examined, including bladder, brain, breast, colon, ovarian, pancreatic, prostate, and renal carcinomas, nuclear expression of HIF-1alpha and -2alpha was observed in varying subsets of the tumor cells. HIF-2alpha was also strongly expressed by subsets of tumor-associated macrophages, sometimes in the absence of any tumor cell expression. Less frequently staining was observed in other stromal cells within the tumors and in normal tissue adjacent to tumor margins. In contrast, in normal tissue neither molecule was detectable except within subsets of bone marrow macrophages, where HIF-2alpha was strongly expressed.

Animals↗
PubMed2003

B1 and related SINEs in mammalian genomes.

Although B1 and Alu were the first discovered Short Interspersed Elements (SINEs), the studies of these genomic repeats were mostly limited to mice and humans and little data on their presence in other animals were available. Here we report the presence of these SINEs in a wide range of rodents (in all 15 tested families) as well as primates and tree-shrews and their absence in other mammals. Distribution pattern of these SINEs in mammals supports close relationship between rodents and primates as well as tree-shrews. Sequence analysis of these elements, apparently descending from cellular 7SL RNA indicates their rearrangements such as dimerization (Alu), quasi-dimerization (B1), acquiring a tRNA-related unit (B1-dID), extended deletions, etc., preceding their active expansion in the genomes. The revealed common pattern of microenvironment of some rearrangement hot spots in SINEs (internal duplications and deletions) suggests involvement of short direct repeats in the mechanism of such rearrangements. This hypothesis allows us to explain short rearrangements in these and other short retroposons.

Animals↗
PubMed2000

Visualization of carbohydrate-binding molecules expressed by myelomono- and erythropoietic cells derived from human bone marrow: an immunoenzymatic double-staining study.

Interactions between human haematopoietic and bone marrow stromal cells are governed by complex carbohydrate-mediated adhesion processes. In order to evaluate corresponding carbohydrate-binding sites on human myelo- and erythropoietic cells which were able to react with mono- or oligosaccharides, we established an immunocytochemical double-staining assay. In a first step, cell lineages were visualized using Lewis(x) (CD15) or glycophorin C-specific monoclonal antibodies. The second step included polyacrylamide-conjugated carbohydrate structures. According to our results, the carbohydrate-binding potential of granulopoietic cells increased during the process of maturation, contrasting a reduction of carbohydrate-binding sites on erythroid precursor cells during differentiation. With respect to previous in vitro studies, these findings shed some light on certain aspects of bone marrow homing as well as on the trafficking of mature cellular elements into circulation. It is tempting to speculate that carbohydrate-mediated adhesion mechanisms may be involved in the various functional defects of progenitor cells in chronic myelogenic leukaemia, especially regarding their complex interactions with the marrow microenvironment.

Binding Sites↗
PubMed2004

Cultured embryonic retina systems as a model for the study of underlying mechanisms of Toxoplasma gondii infection.

PURPOSE: Toxoplasma gondii, the most common cause of retinochoroiditis in humans, is an obligate intracellular protozoan parasite that depends on te host cell's microenvironment to proliferate. Because congenital infection is associated with a higher risk of ocular involvement than a postnatally acquired infection, this study was conducted to investigate the ability of Toxoplasma gondii to infect retinal tissue during development, when cellular environmental changes normally occur. METHODS: Retinas from 5- to 9-day-old chick embryos were used. Stationary cultures were prepared in 24-well cell culture dishes and maintained at 37 degrees C in DMEM plus 5% fetal bovine serum for 2 to 6 days. Then the wells were infected with 4 x 10(5) tachyzoites. Retina explants and aggregate cell cultures were maintained in DMEM under rotation at 37 degrees C. T. gondii proliferation was measured using [(3)H]-thymidine incorporation after 72 hours. Ornithine and arginine decarboxylase (ODC and ADC) activities were determined by measuring CO(2) production from [1-(14)C]-ornithine and [1-(14)C]-arginine, respectively. RESULTS: The proliferation of tachyzoites was high in dense, stationary cultures expressing elevated ODC and ADC activity. The addition of ODC or ADC inhibitors reduced T. gondii proliferation by approximately 20% to 40%. As for cultured retina cells, retina explants also allowed T. gondii proliferation whenever ODC activity was high. CONCLUSIONS: The data suggest a direct correlation between retinal polyamine biosynthesis and the proliferation of T. gondii, in agreement with the observation that individuals infected congenitally have a greater risk of development of toxoplasmic retinochoroiditis.

Animals↗
PubMed2002

Transplanted hematopoietic cells seed in clusters in recipient bone marrow in vivo.

The process of hematopoietic stem and progenitor cell (HSPC) seeding in recipient bone marrow (BM) early after transplantation is not fully characterized. In vivo tracking of HSPCs, labeled with PKH dyes, through an optical window surgically implanted on the mouse femur revealed that transplanted cells cluster in the recipient BM. Within the first day after intravenous injection, 86 +/- 6% of the cells seeded in clusters (p < 0.001 versus scattered cells) in the endosteal surfaces of the epiphyses. The primary clusters were formed by concomitant seeding of 6-10 cells over an area of approximately 70 microm, and secondarily injected cells did not join the already existing clusters but formed new clusters. Major antigen-disparate HSPCs participated in formation of the primary clusters, and T lymphocytes were also incorporated. After 4 to 5 days, some cellular clusters were observed in the more central regions of the BM, where the brightness of PKH fluorescence decreased, indicating cellular division. These later clusters were classified as secondary, assuming that the mechanisms of migration in the BM might be different from those of primary seeding. Some clusters remained in the periphery of the BM and retained bright fluorescence, indicating cellular quiescence. The number of brightly fluorescent cells in the clusters decreased exponentially to two to three cells after 24 days (p < 0.001). The data suggest that the hematopoietic niche is a functional unit of the BM stromal microenvironment that hosts seeding of a number of transplanted cells, which form a cluster. This may be the site where auxiliary non-HSPC cells, such as T lymphocytes, act in support of HSPC engraftment.

Animals↗
PubMed1999

Phosphorylase phosphatase: new horizons for an old enzyme.

Protein phosphatase-1, originally studied as phosphorylase phosphatase, is one of the major ser/thr protein phosphatases. It has a long history and a complex enzymology. It consists of a catalytic subunit of 37 kDa, which is bound to a number of different regulatory or targeting subunits. These are believed to restrict its activity to its immediate microenvironment and thus define its specificity, as well as acting to regulate phosphatase activity. The existence of multiple protein phosphatase-1 binding proteins provides the mechanism whereby phosphatase-1 activity can be involved in a diverse range of cellular functions, and reflects a novel strategy for its evolutionary development.

Amino Acid Sequence↗
PubMed2003

Therapeutic vaccine to control stromal tumor-induced immunosuppression in human uterine cervixc cancer.

Cancer cells may escape immune surveillance by secreting in their microenvironment soluble factors that may locally paralyze the stromal effector immune cells. In the human uterine cervix cancer, HPV-16 E7 protein, released in the stroma, should contribute to cancer cells immune escape since this protein inhibits the cellular immune response to recall antigens or alloantigens and strongly enhances the release of immunosuppressive cytokines by APCs. This prompted us to prepare a therapeutic vaccine triggering anti-E7 neutralizing Abs to antagonize the E7-induced stromal immunosuppressive effects and allow cellular immune reaction towards cancer cells including specific CTLs, induced by conventional vaccine, to be effective. Since HPV-16 is a mucosotropic virus, this therapeutic vaccine has been prepared to generate systemic as well as mucosal immunity.

Animals↗