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Results for “tissue microenvironment”

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PubMed2005

Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: the role of extracellular matrix and its degrading enzymes.

It is now widely accepted that elements of the cellular and tissue microenvironment are crucial regulators of cell behavior in culture and homeostasis in vivo, and that many of the same factors influence the course of tumor progression. Less well established is the extent to which extracellular factors actually cause cancer, and the circumstances under which this may occur. Using physiologically relevant three-dimensional culture assays and transgenic animals, we have explored how the environmental and architectural context of cells, tissues, and organs controls mammary-specific gene expression, growth regulation, apoptosis, and drug resistance and have found that loss of tissue structure is a prerequisite for cancer progression. Here we summarize this evidence and highlight two of our recent studies. Using mouse mammary epithelial cells, we show that exposure to matrix metalloproteinase-3 (MMP-3) stimulates production of reactive oxygen species (ROS) that destabilize the genome and induce epithelial-mesenchymal transition, causing malignant transformation. Using a human breast cancer progression series, we find that ADAM-dependent growth factor shedding plays a crucial role in acquisition of the malignant phenotype. These findings illustrate how normal tissue structure controls the response to extracellular signals so as to preserve tissue specificity and growth status.

Animals↗

PubMed2004

Potential role of ABCA7 in cellular lipid efflux to apoA-I.

ABCA7 is homologous to ABCA1 and has recently been shown in cell culture to bind apolipoprotein A-I (apoA-I) and to promote the efflux of phospholipids. However, it is not known if ABCA7 promotes lipid efflux in vivo. When expressed in HEK293 cells, both human and mouse ABCA7 promoted phospholipid efflux to apoA-I but no detectable cholesterol efflux. However, genetic knockdown of ABCA7 in mouse peritoneal macrophages did not affect phospholipid or cholesterol efflux to apoA-I. Moreover, in ABCA1-knockout macrophages, there was no detectable apoA-I-stimulated phospholipid efflux, inconsistent with a residual role of ABCA7. In contrast to plasma membrane localization of ABCA7 in transfected embryonic kidney cells, immunofluorescence microscopy of endogenous ABCA7 in macrophages showed a predominantly intracellular localization of the protein. Strikingly, immunofluorescence studies of adult mouse kidney revealed an apical brush border membrane localization of ABCA7 in the proximal tubule, suggesting that ABCA7 may come in contact with apoA-I in the glomerular filtrate. Although ABCA7 does not contribute to apolipoprotein-mediated lipid efflux in resting macrophages, its cell surface location in the kidney suggests that it could serve such a role in tissue microenvironments.

ATP-Binding Cassette Transporters↗

PubMed2005

Inhibition of HIV-1 replication in human lymphoid tissues ex vivo by measles virus.

Human immunodeficiency virus (HIV) type 1 replication and disease progression are enhanced by various pathogens in coinfected individuals. However, acute infection with measles virus (MV) has been found to suppress HIV-1 replication in coinfected children. We investigated the mechanisms of this phenomenon using human lymphoid tissues coinfected ex vivo with HIV-1 and MV. MV inhibited both CXCR4-tropic (X4) and CCR5-tropic (R5) HIV-1, but the inhibitory effect was particularly profound for R5 virus, which transmits infection and dominates the early stages of HIV-1 disease. MV inhibits the replication of R5 HIV-1 in coinfected tissues by up-regulation of the CC chemokine RANTES, a well-known inhibitor of R5 HIV-1 infection, and this up-regulation is augmented in tissues coinfected with R5 HIV-1. Deciphering the molecular mechanisms by which MV and other pathogens alter local cytokine/chemokine networks and cause tissue microenvironments to become detrimental to HIV-1 may significantly contribute to the development of effective anti-HIV therapies.

Chemokine CCL4↗

PubMed2006

Endogenous factors enhance HIV infection of tissue naive CD4 T cells by stimulating high molecular mass APOBEC3G complex formation.

Human immunodeficiency virus (HIV) can infect resting CD4 T cells residing in lymphoid tissues but not those circulating in peripheral blood. The molecular mechanisms producing this difference remain unknown. We explored the potential role of the tissue microenvironment and its influence on the action of the antiviral factor APOBEC3G (A3G) in regulating permissivity to HIV infection. We found that endogenous IL-2 and -15 play a key role in rendering resident naive CD4 T cells susceptible to HIV infection. Infection of memory CD4 T cells also requires endogenous soluble factors, but not IL-2 or -15. A3G is found in a high molecular mass complex in HIV infection-permissive, tissue-resident naive CD4 T cells but resides in a low molecular mass form in nonpermissive, blood-derived naive CD4 T cells. Upon treatment with endogenous soluble factors, these cells become permissive for HIV infection, as low molecular mass A3G is induced to assemble into high molecular mass complexes. These findings suggest that in lymphoid tissues, endogenous soluble factors, likely including IL-2 and -15 and others, stimulate the formation of high molecular mass A3G complexes in tissue-resident naive CD4 T cells, thereby relieving the potent postentry restriction block for HIV infection conferred by low molecular mass A3G.

APOBEC-3G Deaminase↗

PubMed2025

Intrinsic changes in cell differentiation and identity drive impaired wound healing in aged female murine skin.

Cellular and molecular mechanisms that drive a perturbed wound microenvironment and impaired healing in aged skin have not been fully delineated. To obtain a comprehensive understanding of cell-intrinsic changes acquired during ageing that impact early responses to injury, we performed single-cell RNA sequencing in young and aged intact female murine skin and wounds 3 days post-injury. We observed that substantial changes in the mean proportional distribution and transcriptomic state of skin resident subpopulations in aged, but not young, tissues accompany a global increase in basal inflammation. This is driven by an altered signalling environment leading to impaired keratinocyte differentiation, loss of fibroblast identity and defective macrophage function. Further, we show that ageing-induced changes in skin resident cells persist after injury, resulting in increased expression of senescence-related genes in wound fibroblasts and aberrant monocyte-to-macrophage transitioning coupled to an enhanced inflammatory signature and defective intercellular signalling in comparison to wounds in young mice. In summary, our data highlights a contribution of both cell-intrinsic changes and an altered tissue microenvironment to poor wound healing responses in aged mice.

Animals↗

PubMed2003

Metalloproteinases, inflammation, and rheumatoid arthritis.

Ideally, the inflammatory response occurs rapidly to terminate infection. It also must halt in a timely manner to stop this reaction from inflicting self damage. Such a highly regulated process results from altering balances in pro- and anti-inflammatory signals orchestrated by multiple cell types and factors within the tissue microenvironment. The discovery of new substrates of metalloproteinases within this microenvironment has disclosed a new function in inflammation. The role of these proteases now extends beyond extracellular matrix remodelling enzymes to that of mediators of inflammatory signals involving various chemokines and cytokines. As natural inhibitors of these metalloproteinases, TIMPs have the potential of regulating the inflammatory response and affecting diseases such as rheumatoid arthritis. TIMP-3, in particular, stands out as an important regulator of inflammation with its ability to specifically inhibit proinflammatory cytokines and tissue destruction in the joint.

Arthritis, Rheumatoid↗

PubMed1987

Ontogeny of in vitro-differentiated mouse mast cells.

Rat and mouse heparin-containing connective tissue mast cells (CTMC) are stained by both alcian blue and safranin, whereas the chondroitin sulfate-containing mucosal mast cells (MMC) are stained by alcian blue but not by safranin. Mouse bone marrow-derived mast cells (BMMC) (the presumptive in vitro counterpart of the in vivo-differentiated MMC) were derived by culture of progenitors in the presence of 50% WEHI-3-conditioned medium and 10% fetal calf serum and were then cultured for up to 14 days with confluent skin-derived mouse 3T3 fibroblasts in the same culture medium. Although the BMMC adhered to the fibroblast monolayer, they continued to divide, probably because of the presence of interleukin 3 in the conditioned medium. After 14 days of coculture, their cellular histamine content increased approximately 15-fold, and greater than 50% of the BMMC changed histochemically from safranin negative to safranin positive. At this time 30-50% of the glycosaminoglycans of the proteoglycans synthesized by these cocultured mast cells were heparin, whereas the initial BMMC synthesized proteoglycans containing chondroitin sulfate E. When activated immunologically, the cocultured mast cells generated approximately fivefold more prostaglandin D2 than did the activated starting BMMC. Thus, interleukin 3-dependent mouse BMMC can be induced to undergo phenotypic changes in staining characteristics, histamine content, glycosaminoglycan structure, and metabolism of arachidonic acid to resemble heparin-containing CTMC. These findings suggest that the tissue microenvironment determines the phenotypic characteristics of mast cells. This demonstration of the functional diversity of different populations of mast cells adds an important dimension to the understanding of the role of mast cells in biological processes.

Animals↗

PubMed1995

Tissue-regulated differentiation and maturation of a v-abl-immortalized mast cell-committed progenitor.

An immature v-abl-transformed mast cell line (V3-MC) was derived from a mouse that developed systemic mastocytosis after transplantation of v-abl-infected bone marrow cells. V3-MCs injected intravenously into adult BALB/c mice infiltrated the liver, spleen, and intestine by day 6 and underwent progressive differentiation and maturation, eventually resembling indigenous mast cells. In terms of their protease content, the V3-MCs that localized in the liver and spleen differed from those in the intestine, and both differed from the cultured V3-MCs. The acquired expression of certain proteases and the loss of expression of other proteases in these tissue V3-MCs defines particular phenotypes and indicates that the differentiation and maturation of mast cell-committed progenitor cells are primarily regulated by factors in the different tissue microenvironments.

Animals↗

PubMed2005

HIF-1alpha expression regulates the bactericidal capacity of phagocytes.

Hypoxia is a characteristic feature of the tissue microenvironment during bacterial infection. Here we report on our use of conditional gene targeting to examine the contribution of hypoxia-inducible factor 1, alpha subunit (HIF-1alpha) to myeloid cell innate immune function. HIF-1alpha was induced by bacterial infection, even under normoxia, and regulated the production of key immune effector molecules, including granule proteases, antimicrobial peptides, nitric oxide, and TNF-alpha. Mice lacking HIF-1alpha in their myeloid cell lineage showed decreased bactericidal activity and failed to restrict systemic spread of infection from an initial tissue focus. Conversely, activation of the HIF-1alpha pathway through deletion of von Hippel-Lindau tumor-suppressor protein or pharmacologic inducers supported myeloid cell production of defense factors and improved bactericidal capacity. HIF-1alpha control of myeloid cell activity in infected tissues could represent a novel therapeutic target for enhancing host defense.

Animals↗

PubMed2026

RAS Pathway Activation and Microenvironmental Adaptation as Hallmarks of Myeloid Sarcoma.

UNLABELLED: Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in approximately 20% of patients and remains strikingly understudied in large-scale genomic and multiomic investigations. The key drivers of its tumor evolution are largely unknown; timely detection in asymptomatic patients poses a clinical challenge, and effective treatment options are limited, as patients are often excluded from clinical trials, rendering it a largely neglected disease entity. In this study, we demonstrate that myeloid sarcoma evolves from medullary AML but exhibits distinct site-specific clonal evolution. This is supported by unique transcriptional signatures of myeloid sarcoma, reflecting adaptation to the extramedullary microenvironment. We establish a proof of concept that circulating tumor DNA (ctDNA) sequencing captures the molecular composition of myeloid sarcoma, offering a potential noninvasive approach for molecular profiling of extramedullary AML. Our findings highlight marked differences between medullary AML and myeloid sarcoma, including universal molecular evolution and RAS pathway activation as disease hallmarks. SIGNIFICANCE: We provide a comprehensive multiomic characterization of myeloid sarcoma, identifying key molecular pathways that contribute to its development, and suggest ctDNA as a noninvasive method of detection. We identify RAS pathway activation and transcriptional adaptation to the solid tissue microenvironment as cardinal features of myeloid sarcoma, suggesting novel therapeutic avenues.

Sarcoma, Myeloid↗

PubMed1995

Prostaglandins and gangliosides of tumor microenvironment: their role in angiogenesis.

In the solid tumor the microenvironment is the space limited by the basement membrane of the microvessels and the neoplastic cells membrane. It includes the stroma and a liquid phase, the tumor interstitial fluid (TIF). We developed a method to sample TIF in vivo and found it rich in prostaglandins. In the rabbit cornea PGE1 induces neovascularization and acts as an angiogenesis factor. Before angiogenesis appears the ganglioside content of the cornea doubles with sharp reduction of the GM3/GD3 ratio. These gangliosides are not angiogenic but they influence the endothelial cell behavior. In particular when the PGE1 dose is insufficient to induce angiogenesis, enrichment of corneal tissue with GD3 or GM1 stimulates angiogenesis. However, when the corneal tissue is enriched with GM3, doses of PGE1, normally angiogenic fail to do so. The same was observed when bFGF substituted PGE1 as an angiogenesis trigger. The gangliosides tested acted as modulators of the angiogenic response by promoting the angiogenic capacity of molecules, such as PGE1 or bFGF, normally present in the tissue microenvironment. Several neoplastic cells, especially melanomas, shed gangliosides in the microenvironment. Their modulatory effect on angiogenesis may influence metastatic and/or primary tumor growth.

Alprostadil↗

PubMed1993

Dermatitis characterized by mastocytosis at immunization sites in mast-cell-deficient W/Wv mice.

W/Wv mice have been extensively used as an important model to study the maturation/differentiation and pathophysiology of mast cells. These albino mice have been shown to have less than 1% of the mast cells found in the skin of their +/+ controls or other normal mice. Moreover, no mast cells are detected in other organs even though they apparently have an adequate number of mast cell precursors. Presumably, these precursors do not respond appropriately to microenvironmental growth factors, while 'normal' precursors from the +/+ controls of S1/S1d-deficient mice mature appropriately in the tissue microenvironment of the W/Wv mice. Female W/Wv mice and +/+ controls were immunized with allogeneic spinal cord homogenate in complete Freund's adjuvant and Mycobacterium tuberculosis in order to induce experimental allergic encephalomyelitis. All W/Wv mice developed extensive dermatitis with mastocytosis at the injection sites about 4 months after inoculation. Mast cells were identified by light microscopy following staining with toluidine blue and berberine sulfate as well as electron microscopy. They were also found to be functional since they secreted serotonin and histamine in response to either compound 48/80 or carbachol. The majority of these mast cells were, therefore, considered to be mature, connective tissue like, but many of them were in different stages of granule maturation as seen with electron microscopy. These findings imply that W/Wv mice may not always be appropriate as models of mast cell deficiency. Moreover, these results suggest that the 'defect' in W/Wv mast cell precursors can be overcome by factors produced during immunization and/or development of dermatitis. These findings may, therefore, help elucidate what regulates mast cell maturation/differentiation as well as their pathophysiology.

Animals↗

PubMed1996

Regulation of T-cell activation in the lung: isolated lung T cells exhibit surface phenotypic characteristics of recent activation including down-modulated T-cell receptors, but are locked into the G0/G1 phase of the cell cycle.

Peripheral lung tissue contains large numbers of T cells, strategically located for immune surveillance at the blood-air interface. Given the intensity of antigenic exposure at this site, it is clear that local T-cell activation events require strict control, in order to maintain tissue homeostasis. How this control is achieved in this unique tissue microenvironment is unknown, and the present study sought to elucidate the process via detailed analysis of the surface phenotypic characteristics of freshly isolated lung T cells. We report below that these cells display typical characteristic of 'postactivation', notably elevated basal Ca2+ concentrations, down-modulated T-cell receptors, expression of Ia and 'late' activation antigens and concomitant CD4/CD8. However, levels of interleukin-2 receptor and CD2 expression were below those expected of 'activated' T-cell populations, and virtually all of the cells were found to be in the G0/G1 phases of the cell cycle. These properties bear a remarkable similarity to those of T cells activated in the presence of endogenous tissue (alveolar) macrophages from the lung (see accompanying paper). We hypothesize that they reflect the in vivo operation of an endogenous macrophage-mediated T-cell anergy-induction process, the function of which is to limit the local clonal expansion of T cells in peripheral lung tissue after in situ activation.

Animals↗

PubMed2003

The not-so innocent bystander: the microenvironment as a therapeutic target in cancer.

The microenvironment in which cancer arises is often regarded as a bystander to the clonal expansion and acquisition of malignant characteristics of the tumour. However, a major function of the microenvironment is to suppress cancer, and its disruption is required for the establishment of cancer. In addition, tumour cells can further distort the microenvironment to promote growth, recruit non-malignant cells that provide physiological resources, and facilitate invasion. In this review, the authors discuss the contribution of the microenvironment, i.e., the stroma and its resident vasculature, inflammatory cells, growth factors and the extracellular matrix (ECM), in the development of cancer, and focus on two components as potential therapeutic targets in breast cancer. First, the ECM, which imparts crucial signalling via integrins and other receptors, is a first-line barrier to invasion, modulates aggressive behaviour and may be manipulated to provide novel impediments to tumour growth. Second, the authors discuss the involvement of TGF-beta1 as an example of one of many growth factors that can regulate ECM composition and degradation and that play complex roles in cancer. Compared to the variable routes taken by cells to become cancers, the response of tissues to cancer is relatively consistent. Therefore, controlling and eliminating cancer may be more readily achieved indirectly via the tissue microenvironment.

Breast Neoplasms↗

PubMed1990

Stromal hemopoietic microenvironment in aging.

The bone marrow content, proliferative potential and proliferative activity of precursor cells for stromal fibroblast colony forming cells (CFC-F) were investigated in young and old CBA mice. The relationship between CFC-F and the number of bone marrow nucleated cells and granulocytic-macrophagal precursors (GM-CFC) was studied as well. The results obtained showed increased CFC-F contents in old animals. The proliferative potential of old mice CFC-F did not appear to differ from that of young animals. The proliferative activity of bone marrow CFC-F and hemopoietic stem cells--spleen colony forming cells (CFC-S) was studied by determining the sensitivity to hydroxyurea administration. The responses were almost the same in young and old mice. A direct correlation between CFC-F and nucleated cells and GM-CFC precursors was found in young mice, but not in the old animals. The results of the present study have pointed to the reorganisation of the stromal tissue microenvironment in bone marrow in old age.

Aging↗

PubMed1995

Phenotypic analysis of donor cells infiltrating the small intestinal epithelium and spleen during graft-versus-host disease.

One of the principal target organs during graft-versus-host disease (GvHD) is the intestinal epithelium, although the reasons for the preferential involvement of particular organs in this disease are not known. This study analyzed the subset distribution of donor and host lymphocytes in the small intestinal epithelium and the spleen during GvHD in a parent (C57BL/6J) into F1 (C57BL/6JxDBA2/J F1) model. While the donor cell population in the spleen consisted of B and T cells, the donor cell population in the intestine contained only T cells during the course of GvHD. These infiltrating donor cells resembled the host intraepithelial lymphocytes (IELs), which are predominantly CD8+ T cells. This subset distribution of donor cells in the intestinal epithelium was remarkable since they originated from a donor splenocyte population containing few CD8+ lymphocytes. In addition, although the injected donor splenic T cells were virtually all alpha/beta TCR+, several months after GvHD induction more than 30% of the donor cells in the intestine were gamma/delta TCR+, thereby resembling the host IELs not only in their expression of CD4 and CD8, but also in their TCR expression. In contrast, no gamma/delta TCR+ donor cells were detectable in the spleen of GvHD mice. The subset distribution of donor and host IELs remained constant throughout the disease, while in the spleen a decrease of both donor and host B cells and a temporary increase of both donor and host CD8+ cells was observed. These findings demonstrate that in a given target organ during GvHD the disease process affects both donor and host lymphoid populations. In addition the different tissue microenvironments eventually lead to donor cell repopulation with a subset distribution similar to the host natural lymphoid population of the particular target organ.

Animals↗

PubMed2002

Presence of host ICAM-1 in laboratory and clinical strains of human immunodeficiency virus type 1 increases virus infectivity and CD4(+)-T-cell depletion in human lymphoid tissue, a major site of replication in vivo.

Human immunodeficiency virus type 1 (HIV-1) incorporates several host proteins. Earlier studies have indicated that such foreign constituents can modulate the virus life cycle, although the potential roles that these proteins might play in the viral pathology in vivo remain unclear. In an attempt to shed light on this issue, we first exposed explants of human lymphoid tissue to isogenic viruses except for the presence or absence of host-derived ICAM-1. Incorporation of ICAM-1 alone increased HIV-1 infectivity for human tonsillar tissue cultured ex vivo. This observation was made for viruses bearing distinct coreceptor utilization profiles. Conversion of LFA-1 to a high-affinity-high-avidity state for ICAM-1 further augmented the susceptibility of human tonsillar histocultures to infection by ICAM-1-bearing virions. A more massive depletion of CD4(+) T lymphocytes was seen with X4 ICAM-1/POS viruses than with isogenic ICAM-1/NEG virions. Exposure of X4 and R5 primary isolates of HIV-1 to a blocking anti-ICAM-1 antibody resulted in a decrease of virus infection. Finally, X4 and R5 virions derived from a natural human lymphoid tissue microenvironment incorporated high levels of ICAM-1. Altogether, these results indicate that the incorporation of host ICAM-1 can significantly modulate the biology of HIV-1 in a cellular milieu recognized as the major site of replication in vivo and suggest that host proteins found in HIV-1 particles may participate in the pathogenesis of this disease.

CD4-Positive T-Lymphocytes↗

PubMed2006

A postmigrational switch among skin-derived dendritic cells to a macrophage-like phenotype is predetermined by the intracutaneous cytokine balance.

Migration of dendritic cells (DC) to secondary lymphoid organs under proinflammatory conditions coincides with their maturation and acquisition of T cell stimulatory abilities. In contrast, impaired activation of DC, e.g., in tumor-conditioned environments, may hamper their activation and possibly their subsequent migration to lymph nodes, leading to either immunological tolerance or ignorance, respectively. In this study, the influence of cytokines in the peripheral skin microenvironment on the activation state of migrating cutaneous DC was assessed using an ex vivo human skin explant model. We observed a phenotypic shift from mature CD83(+) DC to immature CD14(+) macrophage-like cells within 7 days subsequent to migration from unconditioned skin. These macrophage-like cells displayed a poor T cell stimulatory ability and lacked expression of CCR7, thus precluding their migration to paracortical T cell areas in the lymph nodes. The balance of suppressive and stimulatory cytokines during the initiation of migration decided the postmigrational fate of DC with IL-10 accelerating and GM-CSF and IL-4 preventing the phenotypic switch, which proved irreversible once established. These observations indicate that, in immunosuppressed environments, a postmigrational DC-to-macrophage shift may hinder T cell activation, but also that it may be prevented by prior conditioning of the tissue microenvironment by GM-CSF and/or IL-4.

Biomarkers↗