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Results for “tissue microenvironment”

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At least 37 records · Page 2Linked to original sources
PubMed1998

Structural cues from the tissue microenvironment are essential determinants of the human mammary epithelial cell phenotype.

Historically, the study of normal human breast function and breast disorders has been significantly impaired by limitations inherent to available model systems. Recent improvements in human breast epithelial cell lines and three-dimensional (3-D)3 culture systems have contributed to the development of in vitro model systems that recapitulate differentiated epithelial cell phenotypes with remarkable fidelity. Molecular characterization of these human breast cell models has demonstrated that normal breast epithelial cell behavior is determined in part by the precise interplay that exists between a cell and its surrounding microenvironment. Recent functional studies of integrins in a human model system provide evidence to support the idea that the structural stability afforded by integrin-mediated cell-extracellular matrix interactions is an important determinant of normal cellular behavior, and that alterations in tissue structure can give rise to tumorigenic progression.

Breast↗
PubMed2005

Susceptibility to colon carcinogenesis in C3H<-->C57BL/6 chimeric mice reflects both tissue microenvironment and genotype.

Considerable rodent strain differences have been documented with regard to susceptibility to colon carcinogens. To clarify mechanisms, chimeras of susceptible strain C3H and relatively resistant strain C57BL/6N (B6) mice were exposed to a colonotropic carcinogen, 1,2-dimethylhydrazine (DMH) and tumor incidence and multiplicity were assessed. In the chimeras, incidence was as high as the C3H level. Multiplicity of lesions of B6 cells was also increased (P<0.001), but maintenance of the strain difference. When tumor localization was analyzed, tumors of B6 genotype in chimeras demonstrated a greater spread of distribution than in the parental case. The chimeric environment may thus stimulate tumor initiation but cell autonomous suppressive factors may be retained.

Animals↗
PubMed2006

A novel experimental platform for investigating cancer growth and anti-cancer therapy in a human tissue microenvironment derived from human embryonic stem cells.

There is no available experimental system wherein human cancer cells can be grown in the context of a mixed population of normal differentiated human cells for testing biological aspects of cancer cell growth (tumor cell invasion, angiogenesis) or response to anti-cancer therapies. Human embryonic stem cells when implanted into immunocompromised mice develop teratomas containing complex structures, comprising differentiated cell types representing the major germline-derived lineages. We sought to determine whether human cancer cells would grow within such teratomas and display properties associated with malignancy such as invasiveness and recruitment of blood vessels. Ovarian cancer cells (HEY), stably expressing an H2A-GFP fusion protein, which allows tracking of tumor cells, were injected into mature teratomas and developed into tumors. The growth, proliferation capacity, invasion, and induction of blood vessel formation were examined. We propose using the novel experimental platform we have described, consisting of human tumor cells growing within a human cellular microenvironment derived from human embryonic stem cells, to develop a preclinical model for investigating and manipulating the stromal response in tumor cell growth, as an additional tool in cancer research.

Animals↗
PubMed2002

Why does inflammation persist: a dominant role for the stromal microenvironment?

Inflammatory responses occur within tissue microenvironments, with functional contributions from both haematopoietic (lymphocytic) cells and stromal cells (including macrophages and fibroblasts). These environments are complex--a compound of many different cell types at different stages of activation and differentiation. Traditional models of inflammatory disease highlight the role of antigen-specific lymphocyte responses and attempt to identify causative agents. However, recent studies have indicated the importance of tissue microenvironments and the innate immune response in perpetuating the inflammatory process. The prominent role of stromal cells in the generation and maintenance of these environments has begun to challenge the primacy of the lymphocyte in regulating chronic inflammatory processes. Sensible enquiries into factors regulating the persistence of inflammatory disease necessitate an understanding of the mechanisms regulating tissue homeostasis and remodelling during inflammation. This article highlights recent insights into the factors regulating dynamic aspects of inflammation, focusing particularly on mononuclear cell infiltrates, their interactions with stromal cells in tissues and the relevance of these interactions to existing and possible future therapies. A key feature of current research has been a growing appreciation that disordered spatial and temporal interactions between infiltrating immune cells and resident stromal cells lie at the heart of disease persistence.

Arthritis, Rheumatoid↗
PubMed2001

Adult-derived stem cells from the liver become myocytes in the heart in vivo.

Recent evidence suggests that adult-derived stem cells, like their embryonic counterparts, are pluripotent. These simple, undifferentiated and uncommitted cells are able to respond to signals from their host tissue microenvironment and differentiate, producing progeny that display a phenotype characteristic of the mature cells of that tissue. We used a clonal stem cell line (termed WB-F344) that was derived from an adult male rat liver to investigate the possibility that uncommitted stem cells from a nonmyogenic tissue source would respond to the tissue microenvironment of the heart in vivo and differentiate into cardiac myocytes. Male WB-F344 cells that carry the Escherichia coli beta-galactosidase gene were identified in the left ventricular myocardium of adult female nude mice 6 weeks after transplantation. We confirmed the presence of a rat Y-chromosome-specific repetitive DNA sequence exclusively in the beta-galactosidase-positive myocytes by polymerase chain reaction and fluorescence in situ hybridization. Immunohistochemistry, using a cardiac troponin T-specific monoclonal antibody, and ultrastructural analysis confirmed a cardiac myocyte phenotype of the stem cell-derived myocytes. The beta-galactosidase-positive myocytes ranged from < 20 microm to 110 microm in length. The longer of these cells contained well-organized sarcomeres and myofibrils, and formed intercalated disks and gap junctions with endogenous (host-derived) myocytes, suggesting that WB-F344-derived myocytes participate in the function of the cardiac syncytium. These results demonstrate that adult liver-derived stem cells respond to the tissue microenvironment of the adult heart in vivo and differentiate into mature cardiac myocytes.

Animals↗
PubMed2000

Role of chemokines in trafficking of lymphocytes and dendritic cells.

Lymphocytes continuously recirculate between the vascular system and tissues. Furthermore, different lineages and subsets are capable of migrating to different tissues and tissue microenvironments. Upon proinflammatory stimulation or antigen loading, immature dendritic cells in the skin and mucosa migrate into the T-cell zones of regional lymph nodes, where they become fully differentiated dendritic cells capable of activating naive T cells. These migratory properties of lymphocytes and dendritic cells, which are essential for the homeostasis and function of the immune system, are regulated by various cell-adhesion molecules and by a group of chemokines collectively called "immune chemokines." These chemokines are expressed constitutively in specific tissue microenvironments within the primary and secondary lymphoid organs, act via highly specific G protein-coupled receptors, and regulate the migration of lymphocytes and dendritic cells to specific tissue microenvironments. Immune chemokines are thus key elements in the genesis, maintenance, and function of the immune system.

Cell Movement↗
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↗
PubMed2006

Progesterone metabolites in breast cancer.

In the 70 years since progesterone (P) was identified in corpus luteum extracts, its metabolism has been examined extensively in many tissues and cell lines from numerous species. In addition to the reproductive tissues and adrenals, every other tissue that has been investigated appears to have one or more P-metabolizing enzyme, each of which is specific for a particular site on the P molecule. In the past, the actions of the P metabolizing enzymes generally have been equated to a means of reducing the P concentration in the tissue microenvironment, and the products have been dismissed as inactive waste metabolites. In human breast tissues and cell lines, the following P-metabolizing enzymes have been identified: 5alpha-reductase, 3alpha-hydroxysteroid oxidoreductase (3alpha-HSO), 3beta-HSO, 20alpha-HSO, and 6alpha-hydroxylase. Rather than providing diverse pathways for inactivating and controlling the concentration of P in breast tissue microenvironments, it is proposed that the enzymes act directly on P to produce two types of autocrines/paracrines with opposing regulatory roles in breast cancer. Evidence is reviewed which shows that P is directly converted to the 4-pregnenes, 3alpha-hydroxy-4-pregnen-20-one (3alpha-dihydroprogesterone; 3alphaHP) and 20alpha-dihydroprogesterone (20alphaHP), by the actions of 3alpha-HSO and 20alpha-HSO respectively and to the 5alpha-pregnane, 5alpha-pregnane-3,20-dione(5alpha-dihydroprogesterone; 5alphaP), by the irreversible action of 5alpha-reductase. In vitro studies on a number of breast cell lines indicate that 3alphaHP promotes normalcy by downregulating cell proliferation and detachment, whereas 5alphaP promotes mitogenesis and metastasis by stimulating cell proliferation and detachment. The hormones bind to novel, separate, and specific plasma membrane-based receptors and influence opposing actions on mitosis, apoptosis, and cytoskeletal and adhesion plaque molecules via cell signaling pathways. In normal tissue, the ratio of 4-pregnenes:5alpha-pregnanes is high because of high P 3alpha- and 20alpha-HSO activities/expression and low P 5alpha-reductase activity/expression. In breast tumor tissue and tumorigenic cell lines, the ratio is reversed in favor of the 5alpha-pregnanes because of altered P-metabolizing enzyme activities/expression. The evidence suggests that the promotion of breast cancer is related to changes in in situ concentrations of cancer-inhibiting and -promoting P metabolites. Current estrogen-based theories and therapies apply to only a fraction of all breast cancers; the majority (about two-thirds) of breast cancer cases are estrogen-insensitive and have lacked endocrine explanations. As the P metabolites, 5alphaP and 3alphaHP, have been shown to act with equal efficacy on all breast cell lines tested, regardless of their tumorigenicity, estrogen sensitivity, and estrogen receptor/progesterone receptor status, it is proposed that they offer a new hormonal basis for all forms of breast cancer. New diagnostic and therapeutic possibilities for breast cancer progression, control, regression, and prevention are suggested.

Apoptosis↗
PubMed2007

TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation.

Dendritic cells (DCs) are professional antigen-presenting cells that have the ability to sense infection and tissue stress, sample and present antigen to T lymphocytes, and induce different forms of immunity and tolerance. The functional versatility of DCs depends on their remarkable ability to translate collectively the information from both the invading microbes and their resident tissue microenvironments and then make an appropriate immune response. Recent progress in understanding TLR biology has illuminated the mechanisms by which DCs link innate and adaptive antimicrobial immune responses. However, how tissue microenvironments shape the function of DCs has remained elusive. Recent studies of TSLP (thymic stromal lymphopoietin), an epithelial cell-derived cytokine that strongly activates DCs, provide evidence at a molecular level that epithelial cells/tissue microenvironments directly communicate with DCs. We review recent progress on how TSLP expressed within thymus and peripheral lymphoid and nonlymphoid tissues regulates DC-mediated central tolerance, peripheral T cell homeostasis, and inflammatory Th2 responses.

Animals↗
PubMed2004

Short-term human prostate primary xenografts: an in vivo model of human prostate cancer vasculature and angiogenesis.

Transgenic spontaneously occurring and transplantable xenograft models of adenocarcinoma of the prostate (CaP) are established tools for the study of CaP progression and metastasis. However, no animal model of CaP has been characterized that recapitulates the response of the human prostate vascular compartment to the evolving tumor microenvironment during CaP progression. We report that primary xenografts of human CaP and of noninvolved areas of the human prostate peripheral zone transplanted to athymic nude mice provide a unique model of human angiogenesis occurring in an intact human prostate tissue microenvironment. Angiogenesis in human kidney primary xenografts established from human renal cell carcinoma and noninvolved kidney tissue, a highly vascular organ and cancer, was compared with angiogenesis in xenografts from the relatively less vascularized prostate. Immunohistochemical identification of the human versus mouse host origin of the endothelial cells and of human endothelial cell proliferation in the human prostate and human kidney xenografts demonstrated that: (a) the majority of the vessels in primary xenografts of benign and malignant tissue of both organs were lined with human endothelial cells through the 30-day study period; (b) the mean vessel density was increased in both the CaP and benign prostate xenografts relative to the initial tissue, whereas there was no significant difference in mean vessel density in the renal cell carcinoma and benign kidney xenografts compared with the initial tissue; and (c) the number of vessels with proliferating endothelial cells in primary xenografts of CaP and benign prostate increased compared with their respective initial tissue specimens, whereas the number of vessels with proliferating endothelial cells decreased in the benign kidney xenografts. Short-term primary human prostate xenografts, therefore, represent a valuable in vivo model for the study of human angiogenesis within a human tissue microenvironment and for comparison of angiogenesis in CaP versus benign prostate.

Animals↗
PubMed2006

Effects of oestrogen on gene expression in epithelium and stroma of normal human breast tissue.

Oestrogen (E) is essential for normal and cancer development in the breast, while anti-oestrogens have been shown to reduce the risk of the disease. However, little is known about the effect of E on gene expression in the normal human breast, particularly when the epithelium and stroma are intact. Previous expression profiles of the response to E have been performed on tumour cell lines, in the absence of stroma. We investigated gene expression in normal human breast tissue transplanted into 9-10-week-old female athymic nude (Balb/c nu/nu) mice. After 2 weeks, when epithelial proliferation is minimal, one-third of the mice were treated with 17beta-oestradiol (E2) to give human luteal-phase levels in the mouse, which we have previously shown to induce maximal epithelial cell proliferation. RNA was isolated from treated and untreated mice, labelled and hybridized to Affymetrix HG-U133A (human) GeneChips. Gene expression levels were generated using BioConductor implementations of the RMA and MAS5 algorithms. E2 treatment was found to represent the largest source of variation in gene expression and cross-species hybridization of mouse RNA from xenograft samples was demonstrated to be negligible. Known E2-responsive genes (such as TFF1 and AREG), and genes thought to be involved in breast cancer metastasis (including mammoglobin, KRT19 and AGR2), were upregulated in response to E treatment. Genes known to be co-expressed with E receptor alpha in breast cancer cell lines and tumours were both upregulated (XBP-1 and GREB1) and downregulated (RARRES1 and GATA3). In addition, genes that are normally expressed in the myoepithelium and extracellular matrix that maintain the tissue microenvironment were also differentially expressed. This suggests that the response to oestrogen in normal breast is highly dependent upon epithelial-stromal/myoepithelial interactions which maintain the tissue microenvironment during epithelial cell proliferation.

Adult↗
PubMed2006

Novel concepts in hepatocellular carcinoma: from molecular research to clinical practice.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, burdened by a constantly increasing frequency. Therapy is currently restricted to invasive techniques but prognosis and survival are still unsatisfactory, mainly because of HCC recurrence and metastasis diffusion. This review will focus on the problem of tumor recurrence and/or metastasis, pointing out the role of the tissue microenvironment in affecting HCC behavior; new experimental findings will also be discussed in the light of their implications in medical care. Finally, new therapeutic approaches will be considered, paying particular attention to the tissue microenvironment as a potential target. In conclusion, this review will attempt to stimulate debate on translational research into HCC biology, in the field of clinical applications.

Antineoplastic Agents↗
PubMedDate not supplied

Cancer, aging and cellular senescence.

Normal cells do not divide indefinitely due to a process termed cellular or replicative senescence. Several lines of evidence suggest that replicative senescence evolved to protect higher eukaryotes, particularly mammals, from developing cancer. Senescent cells differ from their presenescent counterparts in three way: 1) they arrest growth and cannot be stimulated to reenter the cell cycle by physiological mitogens; 2) they become resistant to apoptotic cell death; 3) they acquire altered differentiated functions. Replicative senescence occurs because, owing to the biochemistry of DNA replication, cells acquire one or more critically short telomere. The mechanism by which a short telomere induces the senescent phenotype is unknown. Recent findings suggest that certain types of DNA damage and inappropriate mitogenic signals can also cause cells to adopt a senescent phenotype. Thus, cells respond to a number of potentially oncogenic stimuli by adopting a senescent phenotype. These findings suggest that the senescence response is a fail-safe mechanism that protects cells from tumorigenic transformation. Despite the protection from cancer conveyed by cellular senescence and other mechanisms that suppress tumorigenesis, the development of cancer is almost inevitable as mammalian organisms age. Why is this the case? Certainly, aging predisposes cells to accumulate mutations, several of which are necessary before malignant transformation occurs, particularly in humans. However, many benign or relatively well-controlled tumors may also harbor many potentially oncogenic mutations, suggesting that the tissue microenvironment can suppress the expression of many malignant phenotypes. Although the idea remains controversial, cellular senescence has also been proposed to contribute to organismal aging. Senescent cells have recently been shown to accumulate with age in human tissues. One possibility is that the tissue microenvironment is disrupted by the accumulation of dysfunctional senescent cells. Thus, mutation accumulation may synergize with the accumulation of senescent cells, leading to increasing risk for developing cancer that is a hallmark of mammalian aging.

Aging↗
PubMed2005

Characterization of CD8+ T cells and microenvironment in oral lesions of human immunodeficiency virus-infected persons with oropharyngeal candidiasis.

Oropharyngeal candidiasis (OPC), the most common oral infection in human immunodeficiency virus-positive persons, correlates with reduced blood CD4+ T cells. In those with OPC, CD8+ T cells accumulate at the lamina propria-epithelium interface at a distance from the organism at the outer epithelium. The present study aimed to characterize the tissue-associated CD8+ T cells and tissue microenvironment in both OPC+ and OPC- persons. The results show that the majority of CD8+ T cells possess the alphabeta T-cell receptor, the thymus-derived alphabeta CD8 antigen heterodimer, and similar levels of the alpha(4)beta(7), alpha(4)beta(1), and alpha(e)beta(7) homing receptors. Studies to evaluate the tissue microenvironment showed that in OPC+ persons, the adhesion molecule for T cells to enter mucosa, mucosal addressin cell adhesion molecule, is significantly increased, whereas E-cadherin, which allows T cells to migrate through mucosa, is significantly decreased compared to OPC- persons. These results continue to support a role for CD8+ T cells against OPC under conditions of reduced numbers of CD4+T cells, with susceptibility to infection potentially associated with a dysfunction in mucosal CD8+ T-cell migration by reduced tissue-associated E-cadherin.

CD8-Positive T-Lymphocytes↗