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PubMed2004

Functional plasticity of macrophages: reversible adaptation to changing microenvironments.

There has been substantial research activity in the past decade directed at phenotyping macrophage lineages and defining macrophage functional subsets or patterns of activity. The emphasis over the past 2-3 years has been to divide macrophage functional patterns into type 1 (Th1-driven) or type 2 (Th2-driven) functions. However, a huge array of environmental factors (including cytokines, chemokines, pattern recognition receptors, hormones) differentially regulates macrophage response patterns, resulting in the display of numerous distinct, functional phenotypes. Upon stimulation, a macrophage does not display just a single set of functions but rather displays a progression of functional changes in response to the progressive changes in its microenvironment. The remarkable ability of monocytes and tissue macrophages to adapt to changes in their microenvironment challenges the thesis that macrophages displaying unique tissue-specific or response-specific, functional patterns represent distinct lineages. With the exception of mature osteoclasts and mature dendritic cells, evidence supporting stable differentiation as the basis for macrophage functional heterogeneity is equivocal. The concept of whether macrophages develop into functional subsets as opposed to continuously adapting their functional pattern in response to the changing environment of a progressive inflammatory response is important to resolve from the perspectives of therapeutic targeting and understanding the role of macrophages in disease pathogenesis.

Adaptation, Physiological↗
PubMed1995

Cerebral microenvironment influences expression of the vitronectin gene in astrocytic tumors.

Expression of the vitronectin gene was detected in advanced human astrocytoma by in situ hybridization, whereas vitronectin mRNA was undetectable in low grade tumors or in normal adult brain, indicating that vitronectin is a marker of malignant astrocytoma. We established a model of human astrocytoma by transplanting U-251MG human astrocytoma cells intracerebrally into acid mice (C.B.17 severe combined immunodeficient mice). In this model, tumors progressed rapidly and vitronectin mRNA was preferentially detected at the invading tumor margins, i.e. where tumor cells were adjacent to the normal brain tissue. Surprisingly, when U-251MG cells were injected subcutaneously into scid mice, vitronectin mRNA was undetectable throughout the tumor. Moreover, vitronectin mRNA or protein could not be detected among these cells in culture under a wide variety of growth conditions. These findings demonstrate that the cerebral microenvironment influences the expression of the vitronectin gene in malignant astrocytoma. Importantly, the vitronectin binding integrins alpha v beta 3 and alpha v beta 5 localized to distinct sites within these tumors, with beta 3 mRNA synthesized among invading cells, and alpha v and beta 5 mRNAs detected throughout the tumor. In vitro, both of these receptors were capable of promoting adhesion and invasion of astrocytoma cells on a vitronectin substratum. These findings implicate the expression of the vitronectin gene as a contributing factor to the biological behavior of astrocytomas within the cerebral microenvironment.

Animals↗
PubMed1991

Endothelial cells create a hematopoietic inductive microenvironment preferential to erythropoiesis in the mouse spleen.

The spleen is an erythropoietic organ in mouse. To reconstruct a microenvironment essential for erythropoiesis in vitro, the stroma (MSS31) cell line had been established from a newborn mouse spleens. MSS31 cells exhibited properties of endothelial cells: (a) the cells showed the activity to uptake acetylated low-density lipoprotein (Ac-LDL) and (b) the cells can form a capillarylike structure by a phenotypic modulation in collagen matrices. MSS31 cells selectively supported the proliferation and differentiation of the erythroid progenitor cells by direct cell-to-cell contact in a semisolid medium in the presence of erythropoietin. These layers also supported erythrocyte maturation and enucleation of erythroblasts. This suggests that spleen endothelial cells are a new type of stromal cell with erythropoietic stimulation activity and may have a critical function in the hemopoietic inductive microenvironment of the mouse spleen.

Animals↗
PubMed1997

Effect of N-B transition on the microenvironment surrounding 34Cys in human serum albumin.

The effect of pH on the microenvironment surrounding 34Cys in human serum albumin (HSA) has been studied using acrylodan, a Cys-specific fluorescence probe. The reactivity of 34Cys with 5,5'-dithiobis(2-nitro benzoic acid) (DTNB) followed a pseudo-first-order reaction, and the increase in reactivity was dependent on pH and oleate content. Compared with the N-form of HSA-acrylodan conjugate (pH 6.2), the B-form (pH 8.4) has a blue-shifted Emmax and enhanced fluorescence intensity derived from acrylodan covalently attached to 34Cys suggesting that the exposure around 34Cys in the B-form was less than that in the N-form. The conformational change induced by fatty acid increased the exposure around 34Cys, while that induced by an increase in pH decreased it. Further, since the effect of oleate on the fluorescence of acrylodan was nearly the same for both conformers, the effects of pH and oleate on the microenvironment surrounding 34Cys should be independent and additive. We concluded that the increase of reactivity of 34Cys as a function in increasing pH may well be related to an increase in mercaptide ion content.

2-Naphthylamine↗
PubMed2004

A comparison of a forced-air warming system to traditional thermal support for rodent microenvironments.

Thermal homeostasis is important for the well-being of laboratory rodents during experimental investigations involving chemical restraint. Anaesthesia-induced hypothermia may alter physiological processes, prolong recovery times, or result in death. Therefore, active warming may be needed to prevent excess heat loss from the rodent to the environment. Three methods of active warming were evaluated in typical rodent procedural areas and recovery cages: a forced-air warming system, infra-red heat emitter and circulating-water blanket. The first experiment involved recording the temperature of the immediate environment of the three devices, with and/or without the accompanying plastic drape, to simulate a surgical situation. In the second experiment, temperatures were recorded within cages that simulated a recovery situation with the same modalities. Forced-air warmer blankets (FAWB) were either wrapped around or placed underneath standard polycarbonate rodent cages and the results were compared with cage temperatures warmed by the heat emitter and circulating-water blanket. Temperatures were recorded at 0, 20, 40, and 60 min for each warming treatment, to determine mean temperature (+/- SEM) and the magnitude of increase (+/- SEM) between 0 and 60 min. All three devices showed an increase in temperature, but the FAWB with a plastic drape heated the procedural area microenvironment (Experiment 1) quickly and to a final temperature of 38.6 degrees C (101.5 degrees F) at 60 min, compared with 25 degrees C (77 degrees F) for the heat emitter and 28 degrees C (82.4 degrees F) for the circulating-water blanket. The magnitude of increase was significantly different for each treatment, but the FAWB with a plastic drape climbed 16.3 degrees C (29.3 degrees F) in 60 min. In Experiment 2, the FAWB wrapped around a cage, covered with a plastic drape, heated recovery cages to 32.5 degrees C (90.5 degrees F) compared to the heat emitter 26.4 degrees C (79.5 degrees F) and circulating-water blanket with drape 26.3 degrees C (79.3 degrees F). The magnitude of increase in the microenvironmental temperature was significantly higher for the FAWB, with the plastic drape wrapped around the recovery cage, compared to the other treatments. In both experiments, forced-air warming proved superior to the more traditional thermal support treatments in heating the microenvironments quickly and to an optimum ambient temperature. Forced-air warming devices should be considered when thermal support is required for rodent procedural areas and recovery cages.

Anesthesia↗
PubMed2003

Trabecular bone response to mechanical and parathyroid hormone stimulation: the role of mechanical microenvironment.

UNLABELLED: Bone response under combined mechanical and PTH stimuli is important in osteoporosis. A rat tail animal model with computer modeling was used to examine bone response to loading and PTH. PTH enhances and sustains increased bone formation rate, which directly correlates to mechanical microenvironment, suggesting beneficial effects of combined PTH treatment and exercise in preventing osteoporosis. INTRODUCTION: Using an in vivo rat tail vertebra model combined with a specimen-specific, high-resolution microcomputed tomography (microCT)-based finite element analysis (FEA) technique, trabecular bone response to combined dynamic compressive loading and parathyroid hormone (PTH) stimulation was characterized. MATERIALS AND METHODS: Two hundred twenty-four male Sprague-Dawley rats were randomly divided into seven treatment groups: (1) Control, (2) vehicle + 0N, (3) PTH + 0N, (4) vehicle + 50N, (5) PTH + 50N, (6) vehicle + 100N, and (7) PTH + 100N, with three treatment durations (1, 2, or 4 weeks). Rat PTH(1-34) was administered daily in the PTH-stimulated groups approximately 3 h before daily mechanical stimulation with 0, 50, or 100N dynamic compressive loading. microCT-based FEA was performed for each loaded vertebra after death. Bone histomorphometry was performed on trabecular bone with double fluorochrome labeling to assess bone formation. RESULTS: Daily mechanical loading or PTH administration significantly increased bone formation rate (BFR) compared with control or V + 0N with significant increases in both mineral apposition rate (MAR) and labeled bone surface (LS/BS). PTH, when combined with mechanical loading, enhanced BFR mainly through a significant increase in MAR after the first week and through a significant increase in LS/BS after 2 and 4 weeks. Synergistic effects in BFR were present when PTH was combined with mechanical loading, especially after 2 and 4 weeks, where the increase in BFR was sustained. However, when either PTH or mechanical loading was the only stimulus, the bone formation response diminished to the level of Control animals after 4 weeks. Furthermore, significant correlations were observed between the bone formation indices and trabecular bone tissue mechanical microenvironments at 1 and 2 weeks, with PTH administration enhancing and sustaining these correlations into 4 weeks. CONCLUSIONS: The synergistic effects of combined PTH and mechanical stimulation on trabecular bone formation rate suggest a potential benefit for combined PTH administration and exercise in the treatment of osteoporosis.

Animals↗
PubMed2003

Use of laser scanning cytometry to study tumor microenvironment.

The study of phenomena occurring in the tumor microenvironment is a challenging task because of technical difficulties, particularly when dealing with hypocellular specimens. Laser scanning cytometry (LSC) is a new laboratory technology that has been recently introduced to overcome the limitations of other traditional technologies. By combining the properties and the advantages of flow cytometry (FC) and immunohistochemistry (IHC), LSC allows the investigator to obtain objective information on DNA content, protein expression and cellular localization is combination with morphological features. It has been already shown that LSC results are reliable compared to more traditional technologies, and its implementation in the clinical routine is under way. Its use in oncology, which is rapidly expanding, spans from apoptosis analysis to DNA content quantitation and tumor cell phenotyping. Here we describe the technology underlying this novel fluorescence-based device, review its use in oncology by dissecting the phenomena occurring in the tumor microenvironment and propose its application for the immunological follow-up of malignant lesions undergoing immunotherapeutic manipulation.

Animals↗
PubMed2006

The tumour microenvironment and implications for cancer immunotherapy.

Tumour cells exist in a complex milieu of cellular and non-cellular components comprising fibroblasts, endothelial cells, immune cells and metabolites of cellular respiration. An elaborate interplay between these components and tumour cells exists with implications for immunological recognition of tumour cells. Tumours have been shown to alter their antigen and cytokine profiles, desensitise and impair immune defences, signal fibroblasts to facilitate metastasis, and take advantage of acidic and hypoxic conditions that impede normal cells. This paper aims to review the roles of the stroma, extracellular matrix and chemistry of the microenvironment on tumour growth, with particular emphasis on interactions with the immune system, and to highlight some of the novel therapeutic strategies that target the tumour microenvironment.

Antineoplastic Agents↗
PubMed2006

Microenvironment and effect of energy depletion in the nucleus analyzed by mobility of multiple oligomeric EGFPs.

Four different tandem EGFPs were constructed to elucidate the nuclear microenvironment by quantifying its diffusional properties in both aqueous solution and the nuclei of living cells. Diffusion of tandem EGFP was dependent on the length of the protein as a rod-like molecule or molecular ruler in solution. On the other hand, we found two kinds of mobility, fast diffusional mobility and much slower diffusional mobility depending on cellular compartments in living cells. Diffusion in the cytoplasm and the nucleoplasm was mainly measured as fast diffusional mobility. In contrast, diffusion in the nucleolus was complex and mainly much slower diffusional mobility, although both the fast and the slow diffusional mobilities were dependent on the protein length. Interestingly, we found that diffusion in the nucleolus was clearly changed by energy depletion, even though the diffusion in the cytoplasm and the nucleoplasm was not changed. Our results suggest that the nucleolar microenvironment is sensitive to energy depletion and very different from the nucleoplasm.

Cell Line↗
PubMed2005

Treatment of mantle cell lymphoma: targeting the microenvironment.

Mantle cell lymphoma is a distinct entity among the non-Hodgkin's lymphomas characterized by a specific chromosomal translocation, the t(11;14)(q13;q32), overexpression of cyclin-D1 and frequent disease manifestations at extranodal sites. Mantle cell lymphoma remains difficult to treat and belongs to the lymphomas with the poorest long-term outcome. Recent advances in our understanding of lymphoma biology suggest that both alterations of the lymphoma cells themselves and interactions with the microenvironment are important for the growth and survival of the malignant B-cell clone. This novel approach to therapy is being exploited by evaluating drugs such as bortezomib and thalidomide that target interactions between tumor cells and cells of the microenvironment. Thus, with the use of novel therapeutic interventions, it is hoped that clinicians will be able to improve the outcome of patients with mantle cell lymphoma.

Antibodies, Monoclonal↗
PubMed2005

Bone microenvironment modulates expression and activity of cathepsin B in prostate cancer.

Prostate cancers metastasize to bone leading to osteolysis. Here we assessed proteolysis of DQ-collagen I (a bone matrix protein) and, for comparison, DQ-collagen IV, by living human prostate carcinoma cells in vitro. Both collagens were degraded, and this degradation was reduced by inhibitors of matrix metallo, serine, and cysteine proteases. Because secretion of the cysteine protease cathepsin B is increased in human breast fibroblasts grown on collagen I gels, we analyzed cathepsin B levels and secretion in prostate cells grown on collagen I gels. Levels and secretion were increased only in DU145 cells--cells that expressed the highest baseline levels of cathepsin B. Secretion of cathepsin B was also elevated in DU145 cells grown in vitro on human bone fragments. We further investigated the effect of the bone microenvironment on cathepsin B expression and activity in vivo in a SCID-human model of prostate bone metastasis. High levels of cathepsin B protein and activity were found in DU145, PC3, and LNCaP bone tumors, although the PC3 and LNCaP cells had exhibited low cathepsin B expression in vitro. Our results suggest that tumor-stromal interactions in the context of the bone microenvironment can modulate the expression of the cysteine protease cathepsin B.

Animals↗
PubMed2005

Rac2-deficient hematopoietic stem cells show defective interaction with the hematopoietic microenvironment and long-term engraftment failure.

The hematopoietic-specific Rho GTPase, Rac2, regulates a variety of cellular functions including cell shape changes, motility, integrin-dependent adhesion, and apoptosis. In the study reported here, we demonstrate that wild-type (WT) hematopoietic stem cells/progenitors (HSC/P) preferentially engraft in nonablated Rac2(-/-) bone marrow. In addition, primitive Rac2(-/-) HSC/P transplanted into lethally irradiated WT recipients showed a significant competitive defect compared with WT cells. These defects appeared to be related to HSC/P-intrinsic defective microenvironment interactions, since Rac2(-/-) cells showed less adhesion to the femur bone marrow density 1 (FBMD-1) stromal cell line, a lower frequency of cobblestone area-forming cells, and lower performance in long-term marrow cultures in vitro when compared with WT cells. In contrast, primitive Rac2(-/-) hematopoietic cells exhibited normal progenitor colony formation in semisolid medium in vitro and normal proliferation in the steady state in vivo when compared with WT cells. Taken together, these data suggest that Rac2(-/-) stem/progenitor cells exhibit abnormal interaction with the hematopoietic microenvironment, which leads to defective long-term engraftment.

Animals↗
PubMed2003

Reconstruction of cartilage, bone, and hematopoietic microenvironment with demineralized bone matrix and bone marrow cells.

Highly specialized hard tissues, such as cartilage, bone, and stromal microenvironment supporting hematopoiesis, originate from a common type of mesenchymal progenitor cell (MPC). We hypothesized that MPCs present in bone marrow cell suspension and demineralized bone matrix (DBM) that possess natural conductive and inductive features might constitute a unit containing all the essential elements for purposive bone and cartilage induction. Using a rodent preclinical model, we found that implantation of a composite comprising DBM and MPCs into A) a damaged area of a joint; B) an ablated bone marrow cavity, and C) a calvarial defect resulted in the generation of A) a new osteochondral complex comprising articular cartilage and subchondral bone; B) trabecular bone and stromal microenvironment supporting hematopoiesis, and C) flat bone, respectively. The new tissue formation followed differentiation pathways controlled by site-specific physiological conditions, thus developing tissues that precisely met local demands.

Animals↗
PubMed1984

Ultrastructural identification of the hemopoietic inductive microenvironment in the human embryonic liver.

Reciprocal interaction between the hemopoietic organ stromal cells and the cells of the granulocytic, megakaryocytic and erythrocytic series in the human liver obtained from 109 embryos 28 to 49 days after ovulation and 76 fetuses from 8 to 22 weeks of gestation were investigated by light and electron microscopy. The close association of stromal cells with immature cells of the three series was confirmed under the electron microscope and a presumptive HIM (hemopoietic inductive microenvironment) was visualized. A majority of immature erythroblasts intruded into the cytoplasm of the hepatocytes, so the presumptive hemopoietic stem cell types II and IV are undoubtedly differentiated into cells of the erythroid line by contact with hepatocytes at a certain stage of maturation. Granulopoiesis developed among the reticular cells around the ductus venosus--or large arteries in hepatic parenchyma--and the cells of the granulocytic series were enclosed by thin cytoplasmic projections of mesenchymal cells. Neither erythropoiesis nor megakaryopoiesis was noted here. Therefore the compartments composed of one or more reticular cells around the ductus venosus or large arteries seem to have a capacity to regulate the differentiation of the presumptive hemopoietic stem cells type IV into cells of the granulocytic series. This differentiation of presumptive hemopoietic stem cell types II and IV into the megakaryocytic series is belived to be induced by the presence of the microenvironments that consist of foci of a few reticular cells in the hepatic parenchyma, as immature cells of megakaryocytic lineage were encircled by the cytoplasmic projection of one or more reticular cells among hepatocytes. Erythroblastic islets are concluded to be a kind of HIM, where erythroblasts loosely adhere to the central macrophages and undergo mitoses and maturation.

Erythrocytes↗
PubMed2005

Histological observations on the microenvironment of osteolytic bone metastasis by breast carcinoma cell line.

Bone tissue, with its dynamic microenvironment featuring osteoclastic bone resorption, angiogenesis and matrix degradation, appears to facilitate proliferation of tumor cells after the onset of bone metastasis. In this study, we examined metastatic lesions in the femora of BALB/c nu/nu mice two weeks after intracardiac injection with human breast carcinoma MDA-231 cells. Histopathological observations showed the metastatic lesions close to the chondro-osseous junction, and revealed MDA-231 cells loosely intermingled with different cell types such as osteoblasts, fibroblastic stromal cells, osteoclasts and endothelial cells. In the metastatic nest, many tartrate resistant acid phosphatase (TRAPase)-positive osteoclasts accumulated in direct contact with or were close to alkaline phosphatase (ALPase)- or receptor activator of NF-kappaB ligand (RANKL)-positive osteoblastic cells. It seems likely that osteoclastogenesis is mediated through cell-to-cell contacts with ALPase- and RANKL-expressing osteoblastic cells. Formation of many capillaries lacking complete basal membranes and pericytes ratified the results of in situ hybridization, which revealed intense expression of VEGF in tumor nests, and therefore, indicated ongoing tumor-induced angiogenesis. The tumor cells possessed matrix metallo-proteinases (MMPs)-1 and -9, and frequently extended their stout cytoplasmic processes into fragmented fibrillar components of the growth plate cartilage, implicating degradation of cartilaginous matrix. Thus, osteolytic bone metastasis has demonstrated pathological features as tumor-induced angiogenesis and degradation of extracellular matrix, in addition to osteoclastogenesis. This complex interplay between tumor cells and host tissues may enable and nourish the establishment of a microenvironment that facilitates tumor progression.

Animals↗
PubMed2006

Tumor cell plasticity in uveal melanoma: microenvironment directed dampening of the invasive and metastatic genotype and phenotype accompanies the generation of vasculogenic mimicry patterns.

The histological detection of laminin-rich vasculogenic mimicry patterns in human primary uveal melanomas is associated with death from metastases. We therefore hypothesized that highly invasive uveal melanoma cells forming vasculogenic mimicry patterns after exposure to a laminin-rich three-dimensional microenvironment would differentially express genes associated with invasive and metastatic behavior. However, we discovered that genes associated with differentiation (GDF15 and ATF3) and suppression of proliferation (CDKNa1/p21) were up-regulated in highly invasive uveal melanoma cells forming vasculogenic mimicry patterns, and genes associated with promotion of invasive and metastatic behavior such as CD44, CCNE2 (cyclin E2), THBS1 (thrombospondin 1), and CSPG2 (chondroitin sulfate proteoglycan; versican) were down-regulated. After forming vasculogenic mimicry patterns, uveal melanoma cells invaded only short distances, failed to replicate, and changed morphologically from the invasive epithelioid to the indolent spindle A phenotype. In human tissue samples, uveal melanoma cells within vasculogenic mimicry patterns assumed the spindle A morphology, and the expression of Ki67 was significantly reduced in adjacent melanoma cells. Thus, the generation of vasculogenic mimicry patterns is accompanied by dampening of the invasive and metastatic uveal melanoma genotype and phenotype and underscores the plasticity of these cells in response to cues from the microenvironment.

Biomarkers, Tumor↗
PubMed2003

Quantitation of house dust mites and house dust mite allergens in the microenvironment of dogs.

OBJECTIVE: To quantitate the density of Dermatophagoides farinae and D pteronyssinus and concentrations of house dust mite (HDM) allergens (Der f 1, Der p 1, and Group 2 allergens) in the indoor microenvironment of dogs. Sample Population-50 homes in Columbus, Ohio. PROCEDURES: n each home, samples of dust were collected from 3 locations in which dogs spent most time. Whenever possible, the species of mites collected was identified. Mite density (mites/g of dust) was assessed, and allergen concentrations were assayed by standardized ELISAs. Relative humidity and temperature in each home were monitored during a 5-day period. Characteristics of homes and sample sources were evaluated. RESULTS: Dust samples from all 50 homes contained > or = 1 HDM allergen; Der f 1 and Der p 1 were detected in 100 and 74% of homes, respectively. Fifteen homes had HDMs; compared with D pteronyssinus, D farinae was found more commonly (14/15 homes) and at a higher density. Basements, homes without central air-conditioning, and dog beds that were > or = 1 year old had high HDM allergen concentrations. Homes with > or = 2 microg of Der f 1 or Group 2 allergens/g of dust or > or = 100 mites/g of dust were significantly more likely to have a maximum relative humidity > or = 75%. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate the presence of HDMs and HDM allergens in the specific microenvironment of dogs in homes. Factors associated with high levels of exposure were identified, which may be associated with increased risk for sensitization and development of atopic diseases.

Allergens↗
PubMed2003

Quantitation of house dust mites and house dust mite allergens in the microenvironment of dogs.

OBJECTIVE: To quantitate the density of Dermatophagoides farinae and D pteronyssinus and concentrations of house dust mite (HDM) allergens (Der f 1, Der p 1, and Group 2 allergens) in the indoor microenvironment of dogs. SAMPLE POPULATION: 50 homes in Columbus, Ohio. PROCEDURES: In each home, samples of dust were collected from 3 locations in which dogs spent most time. Whenever possible, the species of mites collected was identified. Mite density (mites/g of dust) was assessed, and allergen concentrations were assayed by standardized ELISAs. Relative humidity and temperature in each home were monitored during a 5-day period. Characteristics of homes and sample sources were evaluated. RESULTS: Dust samples from all 50 homes contained > or = 1 HDM allergen; Der f 1 and Der p 1 were detected in 100 and 74% of homes, respectively. Fifteen homes had HDMs; compared with D pteronyssinus, D farinae was found more commonly (14/15 homes) and at a higher density. Basements, homes without central air-conditioning, and dog beds that were > or = 1 year old had high HDM allergen concentrations. Homes with > or = 2 microg of Der f 1 or Group 2 allergens/g of dust or > or = 100 mites/g of dust were significantly more likely to have a maximum relative humidity > or = 75%. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated the presence of HDMs and HDM allergens in the specific microenvironment of dogs in homes. Factors associated with high levels of exposure were identified, which may be associated with increased risk for sensitization and development of atopic diseases.

Allergens↗