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At least 361 records · Page 20Linked to original sources
PubMed2004

Proteomic characterization of the interstitial fluid perfusing the breast tumor microenvironment: a novel resource for biomarker and therapeutic target discovery.

Clinical cancer proteomics aims at the identification of markers for early detection and predictive purposes, as well as to provide novel targets for drug discovery and therapeutic intervention. Proteomics-based analysis of traditional sources of biomarkers, such as serum, plasma, or tissue lyzates, has resulted in a wealth of information and the finding of several potential tumor biomarkers. However, many of these markers have shown limited usefulness in a clinical setting, underscoring the need for new clinically relevant sources. Here we present a novel and highly promising source of biomarkers, the tumor interstitial fluid (TIF) that perfuses the breast tumor microenvironment. We collected TIFs from small pieces of freshly dissected invasive breast carcinomas and analyzed them by two-dimensional polyacrylamide gel electrophoresis in combination with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, Western immunoblotting, as well as by cytokine-specific antibody arrays. This approach provided for the first time a snapshot of the protein components of the TIF, which we show consists of more than one thousand proteins--either secreted, shed by membrane vesicles, or externalized due to cell death--produced by the complex network of cell types that make up the tumor microenvironment. So far, we have identified 267 primary translation products including, but not limited to, proteins involved in cell proliferation, invasion, angiogenesis, metastasis, inflammation, protein synthesis, energy metabolism, oxidative stress, the actin cytoskeleton assembly, protein folding, and transport. As expected, the TIF contained several classical serum proteins. Considering that the protein composition of the TIF reflects the physiological and pathological state of the tissue, it should provide a new and potentially rich resource for diagnostic biomarker discovery and for identifying more selective targets for therapeutic intervention.

Adult↗
PubMed2006

The dynamic conduct of bone marrow-derived cells in the choroidal neovascularization microenvironment.

PURPOSE: Choroidal neovascularization (CNV) is one of the most frequent causes of severe and progressive vision loss. Prior studies have shown that bone marrow-derived cells (BMCs) play an important role in CNV, indicating that BMCs can be a potential target for inhibiting the development of CNV. It could be helpful for our understanding of CNV to study the dynamic conduct of BMCs in the CNV microenvironment. METHODS: Green fluorescent protein (gfp) chimeric mice were developed by transplanting bone marrow cells from gfp+/+ transgenic mice to adult C57BL/6J mice. The chimeric mice underwent laser rupture of Bruch's membrane to induce CNV and were killed at 1, 2, 3, and 4 weeks after laser injury. The eyes were enucleated and processed for immunofluorescence to detect markers for vascular smooth muscle cells (alpha smooth muscle actin, alpha SMA), endothelial cells (CD31), or macrophages (F4/80) on gfp+ cells. All sections were qualitatively and quantitatively assessed by confocal microscopy. RESULTS: Large number of gfp-labeled cells appeared in the lesions and integrated into CNV. Gfp+ cells, which were immunoreactive for alpha SMA, CD31, or F4/80, can be detected through the whole study. The constituent ratio of those three cell-types in total gfp+ cells in CNV altered as CNV developed. The maximal ratios of CD31-labeled cells and F4/80-labeled cells presented at 2 week, while the ratio of alpha SMA-labeled cells upgraded continuously. CONCLUSIONS: BMCs underwent a serial of changes in position and expression during the progression of CNV. Those changes may result from the interaction between BMCs and the CNV microenvironment.

Actins↗
PubMed2006

More than structural cells, fibroblasts create and orchestrate the tumor microenvironment.

The tumor microenvironment comprises many cell types including infiltrating immune cells such as lymphocytes, endothelial cells and a complex stroma consisting mainly of fibroblasts. Fibroblasts are heterogeneous and consist of Thy-1+ and Thy-1- subsets that define different biosynthetic and differentiation potential. They produce mediators linked to carcinogenesis and metastasis, including Cox-2 and PGE2, both of which are also increased in most cancers. This review will highlight the emerging role of the complex fibroblastic stroma in establishing a microenvironment supporting malignant transformation, tumor growth and attenuation of host anti-tumor immune responses.

Animals↗
PubMed2006

Effects of the tumor microenvironment on the efficacy of tumor immunotherapy.

Cancer immunotherapy utilizes vaccines targeting tumor antigens or tumor endothelium to prevent or regress tumors. Many cancer vaccines are designed to induce antigen-specific effector T cells that migrate to the tumor site. In an optimal situation, the effector T cells penetrate the tumor, release their effector molecules, induce tumor cell death and tumor regression. However, the tumor microenvironment is frequently immunosuppressive and contributes to a state of immune ignorance, impacting on the vaccine's ability to break tolerance to tumor antigen/s. This review discusses the factors in the tumor microenvironment that can affect the efficacy of cancer vaccines. In particular, the review focuses on pathways leading to effector T cell penetration of tumors or the inhibition of this process.

Animals↗
PubMed2006

Memory T cells in human tumor and chronic inflammatory microenvironments: sleeping beauties re-awakened by a cytokine kiss.

Human tumors often progress and spread in spite of the presence of large numbers of CD4+ and CD8+ T cells with activated or memory cell phenotypes. The T cells in the microenvironment of human lung tumors fail to be activated in response to stimulation via the T cell receptor and CD28 under conditions that fully activate T cells derived from the peripheral blood of the cancer patients. A combination of regulatory mechanisms which are also observed in a variety of different chronic inflammatory conditions may contribute to the T cell unresponsiveness, and to their inability to respond to and kill tumor cells. The non-responsiveness of memory T cells isolated from human lung tumors and non-malignant chronic inflammatory tissues can be reversed in vitro by a brief pulse with IL-12, and the local and sustained release of exogenous IL-12 into the microenvironment of human tumor xenografts in SCID mice re-activates the tumor-associated T cells in situ. In the later case, the T cells proliferate, secrete interferon-gamma and initiate a cascade of events that culminate in the eradication of tumor cells from the xenograft. In transplantable and spontaneously developing tumors of mice the injection of a single tumor nodule with IL-12 loaded biodegradable microspheres activates tumor-associated T cells to kill tumor cells in situ, and provokes a systemic anti-tumor response that results in the eradication of distant metastatic tumor nodules that are not treated with the cytokine. These mice exhibit a systemic tumor specific immunity as they resist a second challenge with the same (but not a different) tumor. These findings suggest that it will be possible to provoke a systemic anti-tumor immunity in cancer patients by the direct injection of IL-12 loaded biodegradable microspheres or liposomes to locally deliver very low but sustained doses of IL-12 into a single tumor site. This strategy which is based upon the ability of IL-12 to re-activate tumor-associated T cells is termed in situ tumor vaccination.

Animals↗
PubMed2006

Dendritic cells and tumor microenvironment: a dangerous liaison.

The fact that the immune response to cancer is compromised has been convincingly demonstrated in murine tumor models as well as in cancer patients. The unresponsiveness of the host immune system is one of the major mechanisms of tumor escape as well as an important factor that limits the success of cancer immunotherapy. Inadequate function of professional antigen presenting cells dendritic cells (DC) in cancer is one of the major elements of compromised anti-tumor immune response. Despite substantial progress in recent years, the mechanism of inadequate DC function in cancer still remains unclear. The tumor microenvironment has emerged as an important component contributing to DC malfunction. In this review we will discuss the potential role of tumor microenvironment in DC dysfunction.

Animals↗
PubMed2007

The role of death receptor ligands in shaping tumor microenvironment.

Death receptor ligands (FasL, TRAIL) activate apoptosis in cells expressing the cognate receptors. Evidence suggests that these ligands also deliver pro-inflammatory signals. In the tumor microenvironment, "Fas counterattack" mounted by tumors against immune cells is mediated by tumor-associated FasL. But death ligands crosslinking their receptors also induce inhibition of apoptosis and activation of the transcription factor, NFkappaB, with a subsequent burst of pro-inflammatory cytokine production and tumor growth promotion. NFkappaB, a key link between inflammation and cancer, regulates dual activities of death ligands, depending on molecular signals in the tumor microenvironment. This paper focuses on death ligands as an example of the extensive repertoire of strategies devised by tumors for escape from immune control.

Antineoplastic Agents↗
PubMed2002

Speciation and bioavailability of EDTA complexed copper in the microenvironment of fish gills.

Carp were exposed to a synthetic solution with varied concentrations of Cu-EDTA and constant levels of other copper species and the amount of copper accumulated in the fish gills was measured. The distributions of copper species in both the bulk solution and the fish gill microenvironment were modeled using MINTEQA2. Under experimental conditions without EDTA, Cu(OH)2 was the most dominant species in the bulk solution while Cu-mucus dominated the gill microenvironment. When Cu-EDTA was added to the solution, copper accumulation in the fish gills increased significantly, suggesting a change in copper speciation. The amount of copper accumulated in the fish gills correlated positively to the concentration of Cu-mucus, rather than to free copper.

Animals↗
PubMed1993

Tenascin is a cytoadhesive extracellular matrix component of the human hematopoietic microenvironment.

Tenascin is a large extracellular matrix (ECM) glycoprotein found in restricted tissue locations in the adult organism. It is copiously synthesized in regenerative organs or regenerating tissues and by certain tumors. We have analyzed the expression of tenascin in human long term bone marrow cultures as well as in cryostat sections of native bone marrow and found it strongly expressed by the stromal cells of the microenvironment. Two different protein subunits of 280 and 220 kD were detected by immunoblotting. These two forms are derived most likely from two different mRNA splice variants of 6 and 8 kb detected by Northern blotting. The in vivo analysis of cryostat sections showed a codistribution with other ECM molecules such as fibronectin and collagen type III in the microenvironment surrounding the maturing hematopoietic cells. Using two independent cell adhesion assays tenascin could be shown to function as a cytoadhesive molecule for hematopoietic cells. These data suggest a direct involvement of tenascin in the retention of hematopoietic progenitor cells in the stroma.

Blotting, Northern↗
PubMed1997

Vascular bed-specific expression of an endothelial cell gene is programmed by the tissue microenvironment.

The endothelium is morphologically and functionally adapted to meet the unique demands of the underlying tissue. At the present time, little is known about the molecular basis of endothelial cell diversity. As one approach to this problem, we have chosen to study the mechanisms that govern differential expression of the endothelial cell-restricted von Willebrand factor (vWF) gene. Transgenic mice were generated with a fragment of the vWF gene containing 2,182 bp of 5' flanking sequence, the first exon and first intron coupled to the LacZ reporter gene. In multiple independent lines of mice, beta-galactosidase expression was detected within endothelial cells in the brain, heart, and skeletal muscle. In isogeneic transplantation models, LacZ expression in host-derived auricular blood vessels was specifically induced by the microenvironment of the heart. In in vitro coculture assays, expression of both the transgene and the endogenous vWF gene in cardiac microvascular endothelial cells (CMEC) was upregulated in the presence of cardiac myocytes. In contrast, endothelial cell levels of thrombomodulin protein and mRNA were unchanged by the addition of ventricular myocytes. Moreover, CMEC expression of vWF was not influenced by the addition of 3T3 fibroblasts or mouse hepatocytes. Taken together, the results suggest that the vWF gene is regulated by vascular bed-specific pathways in response to signals derived from the local microenvironment.

Animals↗
PubMed1984

Phenotypic characterization and ontogeny of mesodermal-derived and endocrine epithelial components of the human thymic microenvironment.

Using murine monoclonal antibodies TE-4 and TE-7 raised against human thymic stroma, we identified two distinct and mutually exclusive thymic microenvironment components: the thymic endocrine epithelium (TE-4+) and mesodermal-derived fibrous stroma (TE-7+). TE-4-reactive epithelium did not react with antibody TE-7, contained thymosin alpha 1 and keratin, and expressed other known markers of thymic endocrine epithelium (A2B5 and p19). Moreover, TE-4+ thymic epithelial cells strongly expressed class I (HLA-A, -B and -C) and class II (Ia-like) major histocompatibility complex (MHC) antigens. In contrast, TE-7+ thymic fibrous stroma did not react with antibody TE-4, did not contain thymosin alpha 1 nor keratin, and did not express the thymic endocrine epithelium markers A2B5 and p19. TE-7+ thymic stromal cells weakly expressed class I and did not express class II MHC antigens. Both TE-4+ and TE-7+ thymic microenvironment compartments were identifiable in thymus from 7 wk gestation through adult life. At 7 wk fetal gestation, TE-7+ stroma surrounded a cylindrical TE-4+, A2B5+ thymic epithelial rudiment. Between 10 and 15 wk fetal gestation, TE-7+ thymic stroma surrounded early thymic lobules. By 15 wk fetal gestation, antibody TE-4 defined subcapsular cortical and medullary zones of endocrine thymic epithelium, while antibody TE-7 bound to interlobular fibrous septae, vessels, and thymic fibrous capsule. While otherwise specific for endocrine thymic epithelium, antibody TE-4 reacted with the basal layer of squamous epithelium in skin, tonsil, conjunctiva, and upper esophagus.

Adolescent↗
PubMed1987

Seeding of thymic microenvironments defined by distinct thymocyte-stromal cell interactions is developmentally controlled.

Seeding of distinct intrathymic microenvironments defined by direct thymocyte-stromal cell interactions was correlated with T cell development in situ using radiation and nonradiation chimeras of Thy-1.1/1.2 congenic mice. The results identify associations of thymocytes with I-A- macrophages in the cortex as the earliest discernible cell-cell interactions during thymopoiesis. After a significant delay, this recognition stage is followed by concomitant interactions of T cells with I-A+ epithelial cells in the cortex and bone marrow-derived I-A+ dendritic cells in the medulla. All three types of T cell-stromal cell interactions occur after seeding of the intrathymic precursor cell subset and before development of mature medullary-type T cells. The seeding kinetics imply that recognition of cortical epithelial cells by thymocytes in situ represents a relatively late stage of cortical T cell development, whereas thymocyte-dendritic cell interactions denote a very early stage of T cell development in the medulla. The relative positioning of these cell-cell recognition stages during the course of T cell maturation pertains to a putative role of these microenvironments in selection and tolerization of the T cell repertoire.

Animals↗
PubMed1993

Human immunodeficiency virus infection of the human thymus and disruption of the thymic microenvironment in the SCID-hu mouse.

Infection with the human immunodeficiency virus (HIV) results in immunosuppression and depletion of circulating CD4+ T cells. Since the thymus is the primary organ in which T cells mature it is of interest to examine the effects of HIV infection in this tissue. HIV infection has been demonstrated in the thymuses of infected individuals and thymocytes have been previously demonstrated to be susceptible to HIV infection both in vivo, using the SCID-hu mouse, and in vitro. The present study sought to determine which subsets of thymocytes were infected in the SCID-hu mouse model and to evaluate HIV-related alterations in the thymic microenvironment. Using two different primary HIV isolates, infection was found in CD4+/CD8+ double positive thymocytes as well as in both the CD4+ and CD8+ single positive subsets of thymocytes. The kinetics of infection and resulting viral burden differed among the three thymocyte subsets and depended on which HIV isolate was used for infection. Thymic epithelial (TE) cells were also shown to endocytose virus and to often contain copious amounts of viral RNA in the cytoplasm by in situ hybridization, although productive infection of these cells could not be definitively shown. Furthermore, degenerating TE cells were observed even without detection of HIV in the degenerating cells. Two striking morphologic patterns of infection were seen, involving either predominantly thymocyte infection and depletion, or TE cell involvement with detectable cytoplasmic viral RNA and/or TE cell toxicity. Thus, a variety of cells in the human thymus is susceptible to HIV infection, and infection with HIV results in a marked disruption of the thymic microenvironment leading to depletion of thymocytes and degeneration of TE cells.

Animals↗
PubMed2005

A configurable three-dimensional microenvironment in a microfluidic channel for primary hepatocyte culture.

We have developed a technique for the in situ three-dimensional (3D) immobilization of primary rat hepatocytes within a localized matrix in a microfluidic channel that provides a 3D microenvironment incorporating both a configurable 3D matrix and fluid perfusion. This is based on the laminar flow complex coacervation of a pair of oppositely charged polyelectrolytes, i.e., methylated collagen and a terpolymer of HEMA-MMA-MAA. 3D collagen matrices were formed with minimal gelation times (<8 min), were able to entrap cells under aqueous noncytotoxic conditions, and permitted culture media to be perfused in the microchannel by virtue of the spatial confinement of the 3D matrix on one side of the channel. The architecture and stability of the collagen matrix could be configured by the use of different material combinations and changes in the polyelectrolyte flow rates and retention time. Primary rat hepatocytes cultured for 24 h in the 3D matrix within the microchannel showed comparable or enhanced cytochrome P450 7-ethoxyresorufin-O-deethylation activity with static controls. The configurable 3D microenvironment in the microfluidic channel may be a potential 3D culture model of primary hepatocytes for drug testing applications.

Animals↗
PubMed2006

Impact craters as biospheric microenvironments, Lawn Hill Structure, Northern Australia.

Impact craters on Mars act as traps for eolian sediment and in the past may have provided suitable microenvironments that could have supported and preserved a stressed biosphere. If this is so, terrestrial impact structures such as the 18-km-diameter Lawn Hill Structure, in northern Australia, may prove useful as martian analogs. We sampled outcrop and drill core from the carbonate fill of the Lawn Hill Structure and recorded its gamma-log signature. Facies data along with whole rock geochemistry and stable isotope signatures show that the crater fill is an outlier of the Georgina Basin and was formed by impact at, or shortly before, approximately 509-506 million years ago. Subsequently, it was rapidly engulfed by the Middle Cambrian marine transgression, which filled it with shallow marine carbonates and evaporites. The crater formed a protected but restricted microenvironment in which sediments four times the thickness of the nearby basinal succession accumulated. Similar structures, common on the martian surface, may well have acted as biospheric refuges as the planet's water resources declined. Low-pH aqueous environments on Earth similar to those on Mars, while extreme, support diverse ecologies. The architecture of the eolian crater fill would have been defined by long-term ground water cycles resulting from intermittent precipitation in an extremely arid climate. Nutrient recycling, critical to a closed lacustrine sub-ice biosphere, could be provided by eolian transport onto the frozen water surface.

Ecosystem↗
PubMed1994

Presentation and intercellular transfer of self antigen within the thymic microenvironment: expression of the E alpha peptide-I-Ab complex by isolated thymic stromal cells.

Expression of a self peptide derived from the alpha chain of MHC class II (I-Ed) in association with I-Ab was studied in the murine thymic microenvironment. Previous work using the mAb Y-Ae which specifically recognizes the E alpha-I-Ab complex had reported differential expression between the thymic medulla and the cortex of this peptide-MHC complex: MHC class II-positive stromal cells in the medulla were strongly positive, whereas this complex was barely detectable on cortical epithelial cells (cEpC) in situ. This difference in presentation of an abundant self peptide is intriguing, since the self protein from which this peptide is derived and the presenting MHC molecule are strongly expressed in both compartments. In this report we show by cell surface phenotype and functional assays that isolated cEpC express the E alpha-I-Ab complex at significant although lower levels than medullary dendritic cells (DC), when examined ex vivo. These results support the notion that cEpC and bone marrow-derived stromal cells present a similar set of self peptide-MHC complexes in situ. In addition, we detect intercellular transfer in situ of the E alpha determinant from radioresistant stromal cells to thymic DC, a mechanism which may enhance the efficacy of tolerance induction by spreading self antigens with the thymic microenvironment.

Animals↗
PubMed2006

Platelet derived growth factor receptor alpha is essential for establishing a microenvironment that supports definitive erythropoiesis.

The hematopoietic system undergoes a qualitative change during the embryogenesis of most vertebrates. It is designated as the shift of primitive to definitive hematopoiesis and suitable microenvironment must be established to support this shift. While studying the role of platelet derived growth factor receptor alpha (PDGFR alpha) in embryonic hematopoiesis, we found that it was expressed in a stromal cell component of liver, a major site of this shift, but not in the yolk sac, the site of primitive hematopoiesis. Thus, we considered that development of PDGFRalpha positive stromal cells is an essential requirement for this shift. Without PDFGRalpha positive cell component, erythropoiesis was suppressed in the culture of fetal liver. Moreover, injection of an antagonistic anti-PDGFRalpha monoclonal antibody during embryogenesis suppressed the production of definitive erythrocytes. These indicated that PDGF exerts its effect on a subset of stromal components to prepare a microenvironment that can support the definitive erythropoiesis.

Animals↗
PubMed1988

Modulation of cholesterol microenvironment with apolipoproteins induced by the presence of cholesteryl ester in lipid microemulsion.

In order to investigate the effect of cholesteryl ester (CE) accumulation in plasma lipoprotein on its metabolism, change of the cholesterol (CHOL) microenvironment was studied by using a lipid microemulsion model system (J. Biol. Chem. 258, 10073-10082, 1983 and 260, 16375-16382, 1985) in the presence of CE and apolipoproteins. Solubility of CHOL in the triolein (TG) core of the emulsion was limited (0.4 weight percent), so that most of the CHOL in the emulsion was found to be associated with the phosphatidylcholine (PC) surface membrane. CE was associated almost exclusively with the TG core without any significant effect on the partitioning of cholesterol between the core and the surface. However, membrane-associated CHOL seems to be present in the TG core adjacent to the surface membrane in the microemulsion without CE, and it is likely to be shifted into the membrane by the presence of CE in the core according to the compositional analysis. Binding parameters of apolipoproteins (apo) A-I, A-II, C-III1, and E were not significantly different among the emulsions with and without CHOL and/or CE at CHOL/PC ratios up to 0.17 (w/w). Susceptibility of CHOL to cholesterol oxidase was observed as an enzymatic probe for CHOL microenvironment. In the absence of apolipoproteins, CHOL reacted similarly to the enzyme regardless of its shift by CE. When apolipoproteins bound to the emulsion containing only CHOL, the rate of CHOL oxidation was decreased by 40% with apoE but not with the others.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoproteins↗