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PubMed1979

Relationship between plasma prolactin and the endocrine microenvironment of the developing human antral follicle.

The aim of the present study was to determine whether any obvious relationships exist between the circulating levels of prolactin at the time of ovariectomy and the endocrine microenvironment and developmental status of antral follicles. The concentrations of prolactin, follicle-stimulating hormone (FSH), and estradiol were measured in peripheral plasma and in antral fluid of follicles collected at varying stages of the menstrual cycle. In addition, the granulosa cells were recovered from each follicle (greater than or equal to 4 mm in diameter) and their numbers were quantitated. When the plasma levels of prolactin ranged from 11 to 100 ng/ml, the antral fluid levels of prolactin were uniformly low (less than 20 ng/ml) and the over-all level of intrafollicular activity remained unchanged. However, when the prolactin concentrations in plasma exceeded 100 ng/ml, the levels of prolactin in antral fluid were significantly elevated. Moreover, the high levels of intrafollicular prolactin were associated with a marked reduction in FSH accumulation and low levels of estradiol in antral fluid. Also, these follicles were severely deficient in granulosa cells. This marked reduction in intrafollicular activity was not associated with any significant changes in the mean levels of estradiol and FSH in peripheral plasma. These findings suggest that hyperprolactinemia is associated with a marked reduction in intraovarian activity and that the extent of this reduction may not be always apparent from the levels of circulating estradiol.

Adult↗
PubMed1997

Effects of the aged microenvironment on CD4+ T cell maturation.

Contributing to the functional alterations of the aged immune system is the accumulation of memory CD4+ T lymphocytes and decline in the proportion of naive cells occurring with advancing age. During attempts to alter the naive to memory ratio of CD4+ cells in aged mice, it was observed that regeneration of the peripheral T cell compartment resulted in a population which possessed the same memory cell-enriched characteristics as the unmanipulated age-matched controls. Thymopoiesis in aged mice does not appear to be altered in such a way as to give rise to emigrants with 'memory-like' characteristics. The aged peripheral microenvironment does, however, cause the accelerated maturation of mature, naive CD4+ T cells to the memory state.

Animals↗
PubMed2000

The indispensable role of microenvironment in the natural history of low-grade B-cell neoplasms.

Follicular lymphoma (FL) and B-cell chronic lymphocytic leukemia (B-CLL) are paradigmatic examples of lymphoid malignancies in which the relevant biological mechanisms are alterations in the control of apoptosis rather than an exaggerated proliferation. This explains why low-grade B-cell neoplasms still fail to be cured with current approaches. It is becoming increasingly clear that the defective apoptosis of FL and B-CLL has to be ascribed not only to intrinsic defects of the neoplastic cells, but also to extrinsic factors that influence their behavior. Malignant B cells retain the capacity to respond to microenvironmental signals, but have devised a monothematic responsiveness. They have a specific sensitivity to anti-apoptotic signals that favor their survival, whereas they seem to have become insensitive to pro-apoptotic signals. Bystander, nontumoral cells play a fundamental (though not sufficient) role both in the onset and in the progression of these diseases. The survival of leukemic cells appears to be dependent on direct cell-cell contacts. The localization of malignant B cells in bone marrow or neoplastic follicles is not a passive adhesion phenomenon but a crucial step for their survival. Bidirectional malignant lymphocyte-nontumoral cell interactions may lead to the amplification of a microenvironment able to inhibit the apoptosis of neoplastic B cells. The pressure of antigenic selection and the role of the tumor necrosis factor receptor family through the functional survival signal provided by CD40 together with the crippled death signal exerted by CD95 are new prominent characters on the stage.

Antigens, CD↗
PubMed2003

Thymic nurse cells: a microenvironment for thymocyte development and selection.

Thymic nurse cells (TNCs) represent a unique microenvironment in the thymus for MHC restriction and T cell repertoire selection composed of a cortical epithelial cell surrounding 20-200 immature thymocytes. TNCs have been isolated from many classes of animals from fish to humans. Studies performed using TNC lines showed that TNCs bind viable alphabetaTCRlow CD4(+)CD8(+)CD69(-) thymocytes. A subset of the bound cells is internalized, proliferates within the TNC, and matures to the alphabetaTCRhigh CD4(+)CD8(+)CD69(+) stage, indicative of positive selection. A subset of the internalized population is released while cells that remain internalized undergo apoptosis and are degraded by lysosomes within the TNC. A TNC-specific monoclonal antibody added to fetal thymic organ cultures resulted in an 80% reduction in the number of thymocytes recovered, with a block at the double positive stage of development. Together these data suggest a critical role for TNC internalization in thymocyte selection as well as the removal and degradation of negatively selected thymocytes. Recent studies have shown that in addition to thymocytes, peripheral circulating macrophages are also found within the TNC complex and can present antigens to the developing thymocytes. These circulating macrophages could provide a source of self-antigens used to ensure a self-tolerant mature T cell repertoire. A reduction in TNC numbers is associated with a variety of autoimmune diseases including thyroiditis and systemic lupus erythematosis.

Animals↗
PubMed2001

Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment.

The propensity for breast cancer cells to metastasize to bone and to induce osteolysis has long been recognized. Characteristics of both the tumor cells and the bone microenvironment contribute to this phenomenon. The presence of tumor in bone is associated with activation of osteoclasts, resulting in excessive bone resorption and subsequent osteolysis. Breast cancer cells and other tumor types influence osteoclastic bone resorption by increasing the number of osteoclasts and enhancing their resorptive activity. Parathyroid hormone-related peptide, in addition to its role in humorally mediated hypercalcemia, is secreted by metastatic breast cancer cells in bone in which it acts as a paracrine factor to stimulate osteoclasts. As bone matrix is broken down by activated osteoclasts, a rich supply of mitogenic factors is released, including insulin-like growth factors, bone morphogenetic proteins, and fibroblast growth factors. Transforming growth factor (TGF)-beta, one of the most abundant of the bone-derived factors, promotes increased production of parathyroid hormone-related peptide by tumor cells, establishing a "vicious cycle" leading to progressive tumor growth and bone destruction. Bisphosphonates interrupt this cycle by inhibiting osteoclasts, in part by inducing osteoclast apoptosis. In several animal models of breast cancer metastasis to bone, bisphosphonates decrease the number of new bone metastases and inhibit progression of existing lesions. A single 3 microg intravenous injection of zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ), a new highly potent bisphosphonate, prevented destruction of trabecular bone in an orthotopic mouse mammary tumor model. Tumor volume in bone was decreased by zoledronic acid in a dose-dependent manner in the same model, and tumor cell apoptosis was increased by zoledronic acid in bone metastases in the 4T1 murine model of mammary carcinoma metastasis. Zoledronic acid at a dose of 1.0 microg/d for 10 days also reduced bone lesion area in a nude mouse model with existing bone metastases. Although bisphosphonates, including zoledronic acid, are able to induce apoptosis in tumor cells in vitro, studies in animal models to date have generally not shown a reduction in nonosseous tumor. Therefore, bisphosphonate-associated tumor reduction in bone is most likely mediated by osteoclast inhibition or is related to high local concentrations of bisphosphonates in the bone compartment.

Animals↗
PubMed1998

A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation.

There are numerous observations reporting that phagocytes expressing major histocompatibility complex (MHC) Class II molecules are associated with the central nervous system (CNS) in normal and pathological conditions. Although MHC Class II expression is necessary for antigen presentation to CD4 + T-cells, it is not sufficient and co-stimulatory molecules are also required. We review here recent in vivo studies demonstrating that the microglia and perivascular macrophages are unable to initiate a primary immune response in the CNS microenvironment, but may support secondary immune responses. Although in vitro studies show that microglia do not support a primary immune response leading to T-cell proliferation, they do show that microglia may protect the CNS from the unwanted attentions of autoreactive T-cells by inducing their apoptosis. The lack of cells in the CNS parenchyma with the ability to initiate a primary immune response has a cost, namely that pathogens may persist in the CNS undetected by the immune system.

Animals↗
PubMed1999

Partial blockade of T-cell differentiation during ontogeny and marked alterations of the thymic microenvironment in transgenic mice with impaired glucocorticoid receptor function.

Glucocorticoids (GCs) are widely known to be potent modulators of the immune system. The role of GCs in thymopoiesis as well as the integration of the thymus with the neuroendocrine system is, however, poorly understood. In the present work, we have studied, in transgenic mice with an impaired GC function, the alterations which occur in both T-cell differentiation and thymic stroma maturation, throughout ontogeny as well as in adult condition, analyzing their possible rebounding on the status of adult splenic T lymphocyte populations. These transgenic mice have been described to present a significant decrease (60-70%) of thymic and splenic GC receptor binding capacity but maintain normal their basal plasma ACTH and corticosterone levels. The animals showed a partial blockade of T-cell differentiation and decreased percentages of apoptotic cells during fetal development but not in adult life, when thymic cellularity was significantly increased although thymocyte apoptosis response was not affected. In contrast, thymic stroma was profoundly altered from early fetal stages and large epithelium-free areas appeared in adult thymus. On the other hand, our study revealed a reduction of the splenic TcRalphabeta population accompanied by an increase in the CD4/CD8 ratio. The analysis of different adhesion molecules as well as activation markers demonstrated that most of them (CD5, CD11a, CD11b, CD69 and MHC Class II) were normally expressed in transgenic lymphocytes, whereas CD44 and CD62L expression was altered indicating the existence of an increased proportion of primed T-cells in these animals. In view of the mutual interdependence of thymic stroma and thymocyte maturation, the partial blockade of T-cell differentiation during ontogeny and the profound alterations of the stromal cell compartment in transgenic mice with impaired GR function suggest a key role for GCs in coordinating the physiological dialogue between the developing thymocytes and their microenvironment.

Age Factors↗
PubMed1997

Cellular environments and apoptosis: tissue microenvironments control activated T-cell death.

Activated T cells must be removed by apoptosis at the end of an immune response in order to maintain cellular homeostasis. Although recent attention has focused on the role of CD95 (Fas/APO-1) in the elimination of activated T cells, apoptosis can also be induced by cytokine deprivation. Here, Arne Akbar and Mike Salmon describe how both death pathways interact in activated T cells and are profoundly influenced by different tissue microenvironments.

Animals↗
PubMed1987

The radiation sensitivity of the haemopoietic microenvironment--effect of dose rate on ectopic ossicle formation.

The haemopoietic microenvironment (HM) consists of a complex mixture of cellular types and extra-cellular matrix. It is essential for prolonged haemopoiesis in both the normal situation and after bone marrow transplantation. The competence of the HM can be assessed by ectopic grafting of femoral marrow. A complete haemopoietic organ develops at the site of implantation. Stem cells (CFU-S) which inhabit the ossicle formed after ectopic implantation can be measured, to assess the function of the engrafted HM to support haemopoiesis. Using this functional endpoint we have examined the radiation sensitivity of the HM at both high and low dose rates, and conclude that high doses of gamma-irradiation delivered at 4 Gy/min or 0.016 Gy/min have widely different effects on the HM, the former proving much more damaging than the latter.

Animals↗
PubMed2000

Synaptic microenvironments--structural plasticity, adhesion molecules, proteases and their inhibitors.

Proteolytic regulation might be essential in neural plasticity in mature brain as well as the developing brain. An increasing number of studies support the idea that structural changes in the synapses are closely associated with synaptic plasticity. Proteases and their inhibitors in a synaptic microenvironment are important in the regulation of dynamic changes in the extracellular matrix components associated with synaptic plasticity. In the present article, the possible roles of neuronal proteases, protease inhibitors and extracellular macromolecules are reviewed.

Animals↗
PubMed2000

Expression and secretion of vascular endothelial growth factor-A by cytokine-stimulated hematopoietic progenitor cells. Possible role in the hematopoietic microenvironment.

In the hematopoietic microenvironment, bone marrow endothelial cells may play an important role in trafficking and maintenance of progenitor and stem cells due to adhesive interactions and paracrine secretion of hematopoietic growth factors. However, it is unknown whether progenitors in turn modulate endothelial proliferation and function. We analyzed mRNA expression (Northern blot) and release of vascular endothelial growth factor-A (VEGF-A), which specifically acts on endothelial cells, by cytokine-stimulated peripheral blood-derived CD34+ hematopoietic progenitor cells. While unstimulated CD34+ cells expressed VEGF-A mRNA weakly without cytokine release in vitro, incubation for 24 hours with a single cytokine (e.g., kit ligand [KL]) resulted in increased VEGF-A mRNA expression and significant secretion of VEGF-A into the supernatant. The amount of VEGF released was substantially augmented by incubation with a combination of cytokines (e.g., KL, IL-3, GM-CSF, G-CSF), or by exposure to hematopoietic cytokines for a longer time period. In addition, we show that VEGF induced the release of hematopoietic growth factors (GM-CSF) by bone marrow endothelial cells and that in vitro stromal cell-derived factor-1 (SDF-1) driven transendothelial progenitor cell migration was increased by the presence of VEGF, which might be due to pore formation (increased endothelial fenestration). In vivo, release of VEGF by progenitor cells may result in a paracrine loop supporting proliferation of both endothelium and progenitors and may facilitate transendothelial migration during cytokine-induced progenitor cell mobilization.

Antigens, CD34↗
PubMed2001

Augmentation of megakaryocytopoiesis within the hematopoietic microenvironment of human granulocyte colony-stimulating factor transgenic mice.

OBJECTIVE: Megakaryocytopoiesis was dramatically augmented in human granulocyte colony-stimulating factor transgenic mice (G-Tg) compared to littermates. We examined the characteristics of megakaryocytes and megakaryocyte progenitor cells in these mice. MATERIALS AND METHODS: The numbers of colony-forming unit megakaryocytes (CFU-MK) and megakaryocytes in hematopoietic organs were counted. The megakaryocytes of G-Tg were examined ultrastructurally, and bone marrow transplantation studies using congenic G-Tg (Ly5.2) and C57BL/6 (Ly5.1) were performed. The number of day-14 colony-forming unit spleen (CFU-S) that contained megakaryocytes in [Ly5.1 > G-Tg] and [G-Tg > Ly5.1] mice also was counted. RESULTS: The number of CFU-MK increased markedly in the spleen, bone marrow, and peripheral blood. The number of megakaryocytes in the spleen and bone marrow also were increased in G-Tg mice. Ultrastructural analyses revealed that megakaryocytes in G-Tg mice were immature. Bone marrow transplantation studies of [Ly5.1 > G-Tg] mice resulted in a significantly increased number of megakaryocytes compared to [G-Tg > Ly5.1] mice. The number of day-14 CFU-S that contained megakaryocytes was increased markedly in [Ly5.1 > G-Tg] mice compared to [G-Tg > Ly5.1] mice. In vitro differentiation of megakaryocytes in [Ly5.1 > G-Tg] mice was induced by interleukin-11 and thrombopoietin. CONCLUSION: The results showed that the hematopoietic marrow microenvironment of G-Tg is important in augmenting megakaryocytopoiesis. [Ly5.1 > G-Tg] mice are potentially useful as a source of murine megakaryocytes and their progenitors.

Animals↗
PubMed2001

Oncostatin M suppresses generation of lymphoid progenitors in fetal liver by inhibiting the hepatic microenvironment.

OBJECTIVE: Interaction between hematopoietic cells and stromal cells is important for regulation of hematopoiesis. Numerous soluble and membrane-bound factors directly regulating hematopoiesis have been documented, but little is known about how stromal cell activity is controlled. We previously reported that fetal hepatic cells in primary culture create the hematopoietic microenvironment and support expansion of blood cells from hematopoietic stem cells. In this study, we focused on lymphopoiesis reconstituted in our culture system and analyzed how stroma-mediated lymphopoiesis is regulated during embryonic development. MATERIALS AND METHODS: Subconfluent cultures of murine fetal hepatic cells were cocultured with hematopoietic stem cells derived from fetal liver in the presence of various cytokines. After 10 days of incubation, hematopoietic cells floating over the stromal layer were analyzed by various assays, including cell proliferation and FACS analysis. RESULTS: We found that oncostatin M, an inducer of hepatic development, strongly inhibited generation of B220(+) lymphocytic cells and colony-forming unit-interleukin-7 (CFU-IL-7) from hematopoietic stem cells in our coculture system. In contrast, oncostatin M did not directly inhibit proliferation of B cells in response to IL-7 and SCF in semisolid cultures. Analysis of antigen expression in lymphoid cells revealed that oncostatin M apparently did not arrest cells at a particular stage of B-cell development. CONCLUSIONS: The results suggest that oncostatin M inhibits lymphopoiesis by suppressing stromal activity of fetal hepatic cells to stimulate generation of CFU-IL-7 from their progenitors rather than by acting directly on lymphocytic cells.

Animals↗
PubMed2003

The symmetry of initial divisions of human hematopoietic progenitors is altered only by the cellular microenvironment.

OBJECTIVE: We examined if cellular elements or adhesive ligands were able to alter asymmetric divisions of CD34(+)/CD38(-) cells in contrast to soluble factors at a single cell level. MATERIALS AND METHODS: After single cell deposition onto 96-well plates, cells were cocultured for 10 days with the stem cell supporting cell line AFT024, fibronectin (FN), or bovine serum albumin (BSA). The divisional history was monitored with time-lapse microscopy. Subsequent function for the most primitive cells was assessed using the myeloid-lymphoid-initiating cell (ML-IC) assay. Committed progenitors were measured using colony-forming cells (CFC). RESULTS: Only contact with AFT024 recruited significant numbers of CD34(+)/CD38(-) cells into cell cycle and increased asymmetric divisions. Although most ML-IC were still identified among cells that have divided fewer than 3 times, a significant number of ML-IC shifted into the fast-dividing fraction after exposure to AFT024. The increase in ML-IC frequency was predominantly due to recruitment of quiescent and slow-dividing cells from the starting population. Increase in CFC activity induced by AFT024 was found only among rapidly dividing cells. CONCLUSIONS: For the first time, we have demonstrated that asymmetric divisions can be altered upon exposure with a stem cell-supporting microenvironment. For the primitive subset of cells (ML-IC), this was predominantly due to recruitment into cell cycle and increased rounds of cycling without loss of function. Exposure to AFT024 cells also increased proliferation and asymmetric divisions of committed CFC. Hence direct communication between hematopoietic progenitors with stroma cells is required for maintaining self-renewal potential.

ADP-ribosyl Cyclase↗
PubMed2003

The tumor microenvironment: focus on myeloma.

A wide variety of cellular responses that may afford tumor cells drug-tolerance characteristics. Overexpression of plasma membrane efflux pumps, up-regulation of anti-apoptosis factors, down-regulation of proapoptosis factors, subcellular redistribution of drug targets, and up-regulation of detoxifying enzymes are just a few known mechanisms of cancer cell resistance. In addition to these individual cell adaptations, cellular drug resistance also appears to be mediated by the binding of tumor cells to extracellular matrix (ECM) proteins. Cell adhesion-mediated drug resistance (CAM-DR) is particularly relevant in hematologic malignancies such as multiple myeloma, where myeloma cells localize in the bone marrow and interact with stroma and stromal cells, initiating the production of proteins that stimulate or support tumor survival. Thus, CAM-DR provides a plausible explanation for the protective mechanisms associated with myeloma cell adhesion and demonstrates that the tumor microenvironment may hold the key to elucidating how tumor cells resist chemotherapy.

Apoptosis↗
PubMed2002

Exploiting the differential production of angiogenic factors within the tumor microenvironment in the design of a novel vascular-targeted gene therapy-based approach to the treatment of cancer.

PURPOSE: The aim of this study is to explore a novel strategy through which the differential production of pro-angiogenic cytokines within the tumor microenvironment can be exploited as a means of selectively killing the vascular endothelial cells upon which the survival and growth of a tumor depend. METHODS AND MATERIALS: Adenoviral vectors encoding a chimeric cell surface receptor composed of the extracellular domain of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR fused in frame to the membrane spanning and cytoplasmic domain of Fas were constructed and used to transduce primary human endothelial cells in vitro. The apoptotic response of these cells induced upon ligation of the chimeric receptor with VEGF was determined by measuring caspase-3 activation, AnnexinV-FITC binding, and the release of glucose-6-phosphate dehydrogenase. RESULTS: The chimeric Flk-1/Fas protein is stable and expressed at high levels on the surface of adenovirally transduced cells. Upon the addition of exogenous VEGF, these cells undergo rapid apoptosis. CONCLUSIONS: Receptor/Fas chimeras that recognize and bind pro-angiogenic cytokines represent a novel means by which the signal transduction events normally triggered in vascular endothelial cells upon the binding of angiogenic cytokines may be redirected toward the induction of apoptotic cell death. It is proposed that these constructs will prove of value in the further development of safe and effective vascular-targeted gene therapy-based approaches to the treatment of cancer.

Adenoviridae↗
PubMed2001

Angiogenesis: the role of the microenvironment in flipping the switch.

The initiating factors in angiogenesis during development and disease are often microenvironmental changes, which induce signaling to the vasculature from affected tissues. Among these, lowered oxygen pressure, hypoxia, is one of the most potent inducers/initiators of an angiogenic response. Significant evidence indicates that hypoxia acts as a morphogen during vascularization - inducing and shaping the recruitment and formation of new vascular beds through critical transcriptional control pathways. Recent advances indicate that extensive interactions occur between developing blood vessels, the tissues that they vascularize, and the interstitial environment to control and shape the establishment of new capillary beds. Identification of the processes that control the hypoxic response intracellularly has allowed an increasingly sophisticated understanding of angiogenesis as a process that is very closely tied to the microenvironment that it occurs in. Further understanding of these processes may present powerful therapeutic opportunities for disease intervention.

Animals↗
PubMed1999

The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment.

We report that the chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within fetal liver and bone marrow microenvironment. In CXCR4-deficient embryos, pro-B cells are present in blood but hardly detectable in liver; myeloid cells are elevated in blood and reduced in liver compared to wild-type embryos. Mice reconstituted with CXCR4-deficient fetal liver cells have reduced donor-derived mature B lymphocytes in blood and lymphoid organs. The numbers of pro-B and pre-B cells are reduced in bone marrow and abnormally high in blood. Granulocytic cells are reduced in bone marrow but elevated and less mature in the blood. B lineage and granulocytic precursors are released into the periphery in absence of CXCR4.

Animals↗