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Results for “Cellular Microenvironment”

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PubMed2001

The concept of cellular "fight-or-flight" reaction to stress.

As animals respond to environmental stress with a set of default reactions described as the "fight-or-flight" response, so do epithelial and endothelial cells when they are confronting stressors in their microenvironment. This review will summarize a growing body of data suggesting the existence of a set of stereotypical cellular reactions to stress, provide some examples of diseases that are characterized by excessive flight reactions, describe the cellular mechanisms whereby the fight-or-flight reaction is accomplished, as well as cellular mechanisms triggering either fight or flight. It is proposed that cell-matrix adhesion is a sensitive indicator of the severity of stress. This indicator is interfaced with several default programs for cellular survival or death, thus dictating the fate of the cell. Some diagnostic and therapeutic applications of the concept, presently used and potentially useful, are outlined. The essential feature of this concept is its ability to categorize cellular events in terms of either type of default reaction, predict the details of each, and potentially exploit them clinically.

Animals↗

PubMed1991

Stromal cell-associated hematopoiesis: immortalization and characterization of a primate bone marrow-derived stromal cell line.

An elucidation of the interaction between the bone marrow microenvironment and hematopoietic stem cells is critical to the understanding of the molecular basis of stem cell self renewal and differentiation. This interaction is dependent, at least in part, on direct cell to cell contact or cellular adhesion to extracellular matrix proteins. Long-term bone marrow cultures (LTMC) provide an appropriate microenvironment for maintenance of primitive hematopoietic stem cells and a means of analyzing this stem cell-stromal cell interaction in vitro. Although LTMC have been successfully generated from murine and human bone marrow, only limited success has been reported in a primate system. In addition, few permanent stromal cell lines are available from nonmurine bone marrow. Because the primate has become a useful model for large animal bone marrow transplant studies and, more specifically, retroviral-mediated gene transfer analysis, we have generated immortalized bone marrow stromal cell lines from primate bone marrow using gene transfer of the Simian virus large T (SV40 LT) antigen. At least one stromal cell line has demonstrated the capacity to maintain early hematopoietic cells in long-term cultures for up to 4 weeks as measured by in vitro progenitor assays. Studies were undertaken to characterize the products of extracellular matrix biosynthesis and growth factor synthesis of this cell line, designated PU-34. In contrast to most murine bone marrow-derived stromal cell lines capable of supporting hematopoiesis in vitro that have been examined, the extracellular matrix produced by this primate cell line includes collagen types I, laminin. Growth factor production analyzed through RNA blot analysis, bone marrow cell culture data, and factor-dependent cell line proliferation assays includes interleukin-6 (IL-6), IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, leukemia inhibitory factor, and a novel cytokine designated IL-11. This immortalized primate bone marrow stromal cell line may be useful in maintaining early progenitor cells for experimental manipulation without the loss of reconstituting capacity and as a potential source of novel hematopoietic growth factors.

Animals↗

PubMed1994

Integrins and adhesive receptors in normal and leukemic CD34+ progenitor cells: potential regulatory checkpoints for cellular traffic.

Multiple adhesion receptors are involved in the interaction of hematopoietic cells with the marrow microenvironment. This work characterizes the expression of various adhesive receptors on normal early hematopoietic precursors and reviews how they might be altered in leukemic states. Early hematopoietic CD34+ cells express CD18, CD11a, CD49d, CD49e, CD44, ICAM-1, and ICAM-3. Likewise, most AML samples express CD49d, CD49e, and CD44. In addition to mediating the adherence of progenitors to the marrow, these multiple receptors and their respective ligands may serve to regulate in vivo leukemic cell agrees from marrow and the ability of certain leukemic phenotypes to selectively seek extramedullary sanctuary sites such as the skin and the central nervous system.

Antigens, CD↗

PubMed1982

Effect of subarachnoid hemorrhage on the extracellular microenvironment.

Local experimental subarachnoid hemorrhage (SAH) was produced over the cerebral cortex in 15 cats. The cellular response was monitored using ion-specific electrodes for extracellular potassium (K+) and calcium (Ca++) activity, DC cortical potential, and electrocorticogram. The response was characterized by a profound cellular depolarization and extracellular calcium (Ca++) depletion which accompanied extracellular potassium (K+) accumulation. The prehemorrhage baseline calcium levels measured 1.14 +/- 0.11 mM, and were lowered to 0.4 to 0.7 mM/liter in different experiments. The K+ accumulation reached levels between 16 and 31 mM from a baseline of 3.17 +/- 0.52 mM and were cleared to normal or nearly normal within 5 minutes. The Ca++ levels also returned to normal within 5 minutes, but remained depressed for the duration of the experiment in two animals. These results confirm that blood extravasated into the subarachnoid space had a direct effect on parenchymal elements. The combination of transient K+ elevations and calcium depression may play an important role in the development of vascular spasm by inducing or facilitating a contraction in the muscular layer in the wall of major intracranial vessels.

Animals↗

PubMed1993

The kit-ligand (steel factor) and its receptor c-kit/W: pleiotropic roles in gametogenesis and melanogenesis.

The c-kit receptor tyrosine kinase belongs to the PDGF/CSF-1/c-kit receptor subfamily. The kit-ligand, KL, also called steel factor, is synthesized from two alternatively spliced mRNAs as transmembrane proteins that can either be proteolytically cleaved to produce soluble forms of KL or can function as cell-associated molecules. The c-kit receptor kinase and KL are encoded at the white spotting (W) and steel (Sl) loci of the mouse, respectively. Mutations at both the W and the Sl locus cause deficiencies in gametogenesis, melanogenesis and hematopoiesis. The c-kit receptor is expressed in the cellular targets of W and Sl mutations, while KL is expressed in their microenvironment. In melanogenesis, c-kit is expressed in melanoblasts from the time they leave the neural crest and expression continues during embryonic development and in the melanocytes of postnatal animals. In gametogenesis c-kit is expressed in primordial germ cells, in spermatogonia, and in primordial and growing oocytes, implying a role at three distinct stages of gametogenesis. Many mutant alleles are known at W and Sl loci and their phenotypes vary in the degree of severity in the different cellular targets of the mutations. While many W and Sl alleles severely affect primordial germ cells (PGC), several mild Sl alleles have weak effects on PGCs and exhibit differential male or female sterility. Steel Panda (Sl(pan)) is a KL expression mutation in which KL RNA transcript levels are reduced in most tissues analyzed. In female Sl(pan)/Sl(pan) mice, ovarian follicle development is arrested at the one layered cuboidal stage as a result of reduced KL expression in follicle cells, indicating a role for c-kit in oocyte growth. Wsh is a c-kit expression mutation, which affects mast cells and melanogenesis. While the mast cell defect results from lack of c-kit expression, the pigmentation deficiency appears to stem from ectopic c-kit receptor expression in the somitic dermatome at the time of migration of melanoblasts from the neural crest to the periphery. It is proposed that the ectopic c-kit expression in Wsh mice affects early melanogenesis in a dominant fashion. The "sash" or white belt of Wsh/+ animals and some other mutant mice is explained by the varying density of melanoblasts along the body axis of wild-type embryos.

Animals↗

PubMed1994

The role of cellular and extracellular matrix adhesion proteins in organ transplantation.

The specific adhesion of cells to other cells or to particular tissue microenvironments is a basic function of cell migration and recognition, and underlines many biologic processes including embryogenesis, repair and immunity. Leukocytes express an array of surface receptors broadly known as "accessory adhesion molecules." which mediate most cell-cell interactions, direct lymphocyte traffic between anatomical compartments, and facilitate cellular adhesion to the inflammation or alloantigenic sites (Springer 1990). In addition, adhesion molecules are involved in the process of antigen recognition, and may costimulate cell activation and transformation. These proteins are thought to affect the very early antigen independent events between host leukocytes and vascular endothelium. Because of these activities, the subject of adhesion molecules is gaining interest in the field of organ transplantation, in both conceptualization and development of novel therapeutic strategies (de Sousa et al. 1991, Kupiec-Weglinski et al. 1993a, Heemann et al. 1993).

Animals↗

PubMed2006

15-deoxy-Delta12,14-prostaglandin J2 as a potential endogenous regulator of redox-sensitive transcription factors.

15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) has been known to display multifaceted cellular functions, including anti-inflammatory and cytoprotective effects. However, depending on the concentrations and intracellular microenvironment, this cyclopentenone prostaglandin can exert opposite effects. Because of the alpha,beta-unsaturated carbonyl moiety present in its cyclopentenone ring structure, 15d-PGJ(2) can act as a Michael reaction acceptor and readily interacts with critical cellular nucleophiles, such as cysteine thiol groups in proteins. Many of the biological effects induced by 15d-PGJ(2) involve redox-transcription factors as the potential targets. Thus, 15d-PGJ(2) can modulate the transcriptional activities of nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), nuclear factor-erythroid 2p45 (NF-E2)-related factors (Nrf2), hypoxia inducible factor (HIF), etc. 15d-PGJ(2) is also well known as an endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARgamma). However, the regulation of the aforementioned redox-sensitive transcription factors by 15d-PGJ(2) is not necessarily mediated via PPARgamma activation, but rather involves covalent modification or oxidation of their critical cysteine residues acting as a redox-sensor. This commentary describes the biological and physiological functions of 15d-PGJ(2) and underlying biochemical and molecular mechanisms with emphasis on the modulation of redox-sensitive transcription factors and their regulators.

Animals↗

PubMed2026

TFPI-high myofibroblast states and a meta-program-related five-gene prognostic signature in breast cancer.

Intratumoral heterogeneity and tumor-microenvironment interactions limit prognostic stratification in breast cancer, but the prognostic relevance and cellular context of recurrent transcriptional meta-programs remain unclear. We aimed to derive a meta-program-related prognostic signature and characterize its component transcripts at single-cell resolution. Six paired institutional tumors and adjacent non-tumor tissues served as a proof-of-concept comparison. Univariable Cox screening and least absolute shrinkage and selection operator Cox regression were used to derive a five-gene score from a prespecified meta-program-related candidate set in The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) training cohort; the score was tested internally and assessed in GSE20685 using fixed coefficients and cohort-specific median cutoffs. GSE161529 single-cell transcriptomic data were used to map signature transcripts across 136,526 quality-controlled cells, while donor-aware pseudobulk analysis compared upper- and lower-quartile TFPI expression states in annotated myofibroblasts. The score comprised TCN1, FOXJ1, PIGR, SLAIN1, and TFPI and was associated with overall survival in the training, testing, and external cohorts, with concordance indices of 0.782, 0.756, and 0.721, respectively. TFPI transcripts were detected across endothelial, fibroblast, and myofibroblast compartments. TFPI-high myofibroblasts showed transcriptional enrichment of extracellular matrix and collagen fibril organization, transforming growth factor beta signaling, epithelial-mesenchymal transition, and myogenesis, together with lower oxidative phosphorylation and fatty acid metabolism programs. In bulk TCGA-BRCA tissue, TFPI expression correlated positively with stromal (r = 0.48), immune (r = 0.25), and composite microenvironment scores (r = 0.40; all p < 0.001). These findings identify a hypothesis-generating five-gene bulk-tissue prognostic signature and an expression-associated TFPI-high myofibroblast state but do not establish a discrete lineage, the cellular source of bulk TFPI, a TFPI-dependent mechanism, or clinical utility. Independent prospective cohorts, spatial and protein-level validation, and functional perturbation studies are required.

Journal Article↗

PubMed2005

Biology of normal and acute myeloid leukemia stem cells.

The substantial understanding that has been gained over the past 5 decades of the biology of blood formation is largely due to the development of functional quantitative assays for cells at all stages of differentiation, from multipotential stem cells to mature cells. The majority of studies have involved the mouse because the ease with which repopulation studies can be carried out with this animal model allows the assay of complete lineage development from stem cells. In the past decade, advances in repopulation assays for human stem cells using xenotransplantation have greatly enhanced our understanding of human stem cell biology. Importantly, the xenotransplantation methodology has also been used to identify the cancer stem cell that initiates and sustains leukemic proliferation, providing key evidence for the cancer stem cell hypothesis. This hypothesis argues that cancer cells are functionally heterogeneous and hierarchically organized such that only specific cells are capable of sustaining tumor growth and continuously producing the cells that make up the bulk of the tumor. Recent studies have also brought into focus the importance of the intimate relationship between the stem cell (normal or leukemic) and its microenvironment. Coming into view are the molecular players involved in stem cell homing, migration, and adhesion, as well as the cellular components of the microenvironmental niche. Here we review recent studies that have begun, to elucidate the interplay between normal and leukemic human stem cells and their microenvironment.

Animals↗

PubMed1981

An in vitro investigation of the hematopoietic microenvironment in young and aged mice.

Dexter-type cultures derived from the bone marrow of young and aged mice were established as in vitro correlates to the hematopoietic microenvironment and inoculated two weeks later with fresh bone marrow-derived stem cells (colony-forming units, CFUs) from young, syngeneic mice. Such cultures allowed the observation, quantitation and evaluation of interactions between aged or young microenvironments and the young stem cells. The hematopoietic microenvironments derived from aged marrow were found to support a greater total nucleated cellularity and a significantly greater number of CFUs. Also, the production of CFUs on aged monolayers occurred at an elevated rate. Though cyclic variations in total cellularity were noted in all cultures, the granulocyte--macrophage lineage always predominated. Lymphocyte populations in all cultures were seen to decline rapidly with time as other cell types became more abundant. The number of megakaryocytes in the aged marrow-derived cultures was significantly elevated in the early time periods post-refeeding. Differences in the adherent cell population densities were noted with the aged monolayers being somewhat less dense. However, there were no differences in morphologically identifiable cell types comprising the adherent layers derived from marrow of young and old mice. From these results, we conclude that there are differences in the ability of aged versus young hematopoietic microenvironments to support normal young stem cells in vitro and that the microenvironmental influences present in the in vitro system are reflective of those seen in the in vivo marrow microenvironment.

Aging↗

PubMed2005

Manipulating the local tumor microenvironment with poxviruses expressing costimulatory molecules.

The identification of tumor-associated antigens and new insights into the molecular and cellular basis of tumor immunology have generated a variety of vaccine strategies. Although promising in animal models, data from early-phase clinical trials have not been encouraging. These studies have documented the ability of vaccines to prime T cells, but these responses have not correlated with therapeutic effectiveness. Because the location of T-cell activation and effector activity may impact T-cell function significantly, attention has been placed on the tumor microenvironment. There is now evidence that T-cell responses may be altered in the setting of established tumor growth. To alter the balance between local immune responses and tumor growth, a vaccine regimen using direct intratumoral delivery of poxvirus vaccines expressing costimulatory molecules was developed. An initial series of clinical trials has documented the safety profile of this approach and has suggested that local and systemic immunity can be induced. Herein, we review the general rationale for this approach, discuss the results of ongoing clinical trials, and highlight critical questions that can be addressed in well-designed preclinical and clinical studies.

Cancer Vaccines↗

PubMed1992

Cytokines and local factors which affect osteoclast function.

Bone remodeling is a local phenomenon which occurs in discrete packets throughout the skeleton. The cellular events which comprise the remodeling sequence are controlled by cytokines which are generated in the microenvironment of the bone resorbing pockets. These cytokines are derived from marrow mononuclear cells or from bone cells themselves, or they are incorporated into the bone matrix and released in biologically active form as bone resorbs. Evidence is accumulating that some of these cytokines play an important role not just in physiological bone remodeling, but also in common diseases of bone remodeling such as osteoporosis, osteopetrosis, Paget's disease, and malignant diseases which involve bone and chronic inflammatory diseases such as rheumatoid arthritis and periodontal disease. Normal bone remodeling is clearly under local control. It occurs in discrete packets throughout the skeleton, each of which is geographically distinct. Local packets of bone remodeling are also asynchronous with respect to each other. The cellular events which comprise the remodeling sequence are thus regulated primarily by factors which are enriched in that microenvironment. The remodeling sequence, which is continuous, is the same on cancellous bone surfaces as it is within the Haversian systems of cortical bone. Since it is now known that powerful osteoclastotropic factors are produced in the microenvironment of these bone remodelling packets, these local factors or cytokines are the most likely major regulators of osteoclast function.

Animals↗

PubMed1983

Progression of mouse thymic leukemias in thymic microenvironments.

Mouse thymic leukemogenesis has been assumed to occur in multiple steps corresponding to the stages of normal T-cell lineage development. One of the roles of the thymus in leukemogenesis is to provide permissive microenvironments for the progression of developing leukemias from thymus-dependent to independent growth. We have devised a method to consistently isolate the symbiotic complex of leukemia cells and thymic epithelium-like stromal cells from primary leukemic thymuses. In such complexes, leukemia cells were able to proliferate in close association with thymic stromal cells in pseudoemperipolesis, i.e., a unique form of cell interaction which we defined. In normal thymus, subcapsular zone blasts, mitotically active early thymic lymphocytes, were able to form similar complexes with thymic stromal cells, but this property was lost as they differentiated into cortical small lymphocytes. These observations indicate that the stage of intrathymic progression of leukemias is critically linked with the stage of subcapsular zone blasts of normal thymic lymphopoiesis. Mechanism and regulation of the complex formation was analyzed by an in vitro assay. We found that many thymic microenvironment-dependent leukemia cells were reversibly stimulated to proliferate by various tumor-promoters sharing a cellular receptor for phorbol esters. Without support by adequate stromal cells or a tumor promoter, leukemia cells rapidly ceased to grow and died. The degree of growth stimulation was well correlated with their tumor-promoting activity in mouse skin. Action of tumor promoters on microenvironment-dependent leukemias seemed to be direct rather than mediated by lymphokines. Another remarkable effect of tumor promoters was their inhibition of complex formation, presumably by affecting the cytoskeleton.

Animals↗

PubMed2005

Antioxidant up-regulation and increased nuclear DNA protection play key roles in adaptation to oxidative stress in epithelial cells.

Cells are armed with a vast repertoire of antioxidant defense mechanisms to help prevent the accumulation of oxidative damage. It is becoming increasingly apparent that the cellular adaptive response has an important antioxidant function to counteract oxidative stress. To investigate this adaptive response we assessed the effect of sublethal H2O2 on cell viability, enzymatic activity, and nuclear (nDNA) and mitochondrial DNA (mtDNA) susceptibility to damage and repair in cultured human retinal pigment epithelium (RPE) cells. This nondividing cell type exists in a highly oxidizing microenvironment in vivo. Prior exposure to sublethal H2O2 confirmed an adaptive response, resulting in a greater cellular resistance to subsequent toxic exposures compared to nonadapted RPE (p < 0.05). A greater CAT, GPX, and CuZnSOD enzymatic activity (p < 0.05) and increased nDNA protection (p < 0.05) were also observed. However, there was no adaptive benefit for mtDNA protection or repair in response to oxidative stress. This study confirms a role for the adaptive response as an important antioxidant defense for cells located in inherently oxidizing microenvironments. Furthermore, it identifies that the mitochondria are a weak link in otherwise efficient oxidative stress defenses and that this may contribute to aging and age-related disease.

Antioxidants↗

PubMed1995

Hematopoietic stem cell cytokine response.

The process of hematopoiesis can be modelled on the concept of a pluripotential stem cell able to differentiate and proliferate in multiple lineages. This process proceeds under the permissive or directive influence of "early" and "late" acting hematopoietic cytokines probably acting in synergistic combinations within the context of the marrow stromal microenvironment. Further characterization of the biochemical events that transduce cytokine signalling into cellular events and the ultimate description of the earliest progenitor cell populations and the cytokines which influence them will provide key insights into embryogenesis and tissue maintenance as well as suggest new therapeutic approaches for hematologic and malignant diseases.

Animals↗

PubMed1994

Production of RNA by a polymerase protein encapsulated within phospholipid vesicles.

Catalyzed polymerization reactions represent a primary anabolic activity of all cells. It can be assumed that early cells carried out such reactions, in which macromolecular catalysts were encapsulated within some type of boundary membrane. In the experiments described here, we show that a template-independent RNA polymerase (polynucleotide phosphorylase) can be encapsulated in dimyristoyl phosphatidylcholine vesicles without substrate. When the substrate adenosine diphosphate (ADP) was provided externally, long-chain RNA polymers were synthesized within the vesicles. Substrate flux was maximized by maintaining the vesicles at the phase transition temperature of the component lipid. A protease was introduced externally as an additional control. Free enzyme was inactivated under identical conditions. RNA products were visualized in situ by ethidium bromide fluorescence. The products were harvested from the liposomes, radiolabeled, and analyzed by polyacrylamide gel electrophoresis. Encapsulated catalysts represent a model for primitive cellular systems in which an RNA polymerase was entrapped within a protected microenvironment.

Adenosine Diphosphate↗

PubMed1979

Tight junctions adjacent to tumor stromal interface in human invasive transitional cell carcinomas.

Tight junctions adjacent to the tumor stromal interface in invading neoplastic cells of human urinary bladder carcinomas were observed. Basal lamina, collagen and elastic fibers, and cellular debris were found next to the tight junctions. An association between microenvironment (i.e., tumor necrosis) of the invading neoplastic cells and tight junction locations was suggested.

Carcinoma, Transitional Cell↗

PubMed2004

The tension mounts: mechanics meets morphogenesis and malignancy.

The tissue microenvironment regulates mammary gland development and tissue homeostasis through soluble, insoluble and cellular cues that operate within the three dimensional architecture of the gland. Disruption of these critical cues and loss of tissue architecture characterize breast tumors. The developing and lactating mammary gland are also subject to a plethora of tensional forces that shape the morphology of the gland and orchestrate its functionally differentiated state. Moreover, malignant transformation of the breast is associated with dramatic changes in gland tension that include elevated compression forces, high tensional resistance stresses and increased extracellular matrix stiffness. Chronically increased mammary gland tension may influence tumor growth, perturb tissue morphogenesis, facilitate tumor invasion, and alter tumor survival and treatment responsiveness. Because mammary tissue differentiation is compromised by high mechanical force and transformed cells exhibit altered mechanoresponsiveness, malignant transformation of the breast may be functionally linked to perturbed tensional-homeostasis. Accordingly, it will be important to define the role of tensional force in mammary gland development and tumorigenesis. Additionally, it will be critical to identify the key molecular elements regulating tensional-homeostasis of the mammary gland and thereafter to characterize their associated mechanotransduction pathways.

Animals↗