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Results for “Cellular Microenvironment”

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PubMed1993

Basic fibroblast growth factor promotes the proliferation of human megakaryocyte progenitor cells.

Basic fibroblast growth factor (bFGF), a multifunctional growth factor produced by bone marrow stromal cells, is known to be a potent modulator of hematopoiesis. Because bFGF is present in both human megakaryocytes (MKs) and platelets, we have hypothesized that this growth factor might affect human megakaryocytopoiesis. To test this hypothesis, either low density bone marrow (BM) cells (LDBM), a human BM subpopulation (CD34+ DR+) enriched for the colony-forming unit megakaryocyte (CFU-MK) or a BM subpopulation (CD34+ DR-) enriched for the more primitive burst-forming unit megakaryocyte (BFU-MK) were assayed in the presence of this growth factor. The effect of bFGF on MK colony formation differed according to the cell population assayed. bFGF alone had on MK colony-stimulating activity (MK-CSA) when either CD34+ DR+ or CD34+ DR- BM cells were cloned, but exhibited MK-CSA equivalent to that of interleukin-3 (IL-3) when LDBM cells were used as the target cell population. The MK-CSA of bFGF was inhibited by the addition of neutralizing antisera to either IL-3 and/or granulocyte-macrophage colony-stimulating factor (GM-CSF) but not IL-6. The addition of excess amounts of either IL-3 or GM-CSF to cultures containing bFGF plus anti-IL-3 or anti-GM-CSF reversed the inhibition by the corresponding antisera. The addition of bFGF and IL-3 to assays containing CD34+ DR+ or CD34+ DR- cells increased the size of both CFU-MK- and BFU-MK-derived colonies, respectively, when compared with assays containing IL-3 alone. This increase in MK colony size mediated by bFGF was not affected by addition of either an anti-GM-CSF or anti-IL-6 neutralizing antisera. When LDBM cells were assayed, bFGF alone increased CFU-MK-derived colony size when compared with control values. However, this potentiation of MK colony size by bFGF could be reversed by the addition of either anti-IL-3 or anti-GM-CSF but not anti-IL-6 antisera. In addition, the effects of bFGF and IL-3 on the size of MK colonies cloned from LDBM were not additive. These results suggest that bFGF affects human megakaryocytopoiesis by directly promoting MK progenitor cell proliferation and stimulating BM accessory cells to release growth factor(s) with MK-CSA, such as IL-3 and GM-CSF. We conclude that bFGF, likely produced by cellular components of the BM microenvironment, plays an important role in the control of human megakaryocytopoiesis.

Antibodies↗

PubMed1996

Identification of multiple and distinct CD8+ T cell suppressor activities: dichotomy between infected and uninfected individuals, evolution with progression of disease, and sensitivity to gamma irradiation.

Using an in vitro model system that reflects the cellular interactions occurring in the microenvironment of lymphoid organs (i.e., the interaction between dendritic cells (DC) and CD4+ T lymphocytes), the ability of CD8+ T cells to inhibit HIV replication was investigated. DC, the most potent APC in the paracortical region of lymphoid organs, were cocultured with autologous, unstimulated CD4+ T cells resulting in viral replication in the absence of exogenous stimulation. Using two variations of DC cocultures, one an acute infection system and the other an endogenous infection system, two sets of activities were identified. One activity was expressed in both HIV-infected and -uninfected individuals, and a second was found only in HIV-infected individuals. These activities can be differentiated further by their evolution or lack thereof with disease progression in infected individuals and their sensitivity to gamma irradiation. Furthermore, the results indicate that CD8+ T cell modulation of HIV replication in CD4+ T cells is a multifactorial phenomenon involving both inhibitory and stimulatory effects on HIV replication.

CD4-Positive T-Lymphocytes↗

PubMedDate not supplied

Aplastic anemia.

Aplastic anemia is a disease that presents with a hypocellular marrow and peripheral blood pancytopenia. In Europe and the United States, it has an age-adjusted incidence per million population per year of 2.2 compared to 11.0 in Japan and Korea. Pathogenic mechanisms are varied and include intrinsic defects of hematopoietic stem cells, defects in the marrow microenvironment, and abnormal humoral or cellular immune control of hematopoiesis. In most patients, aplastic anemia is of unknown etiology, whereas in some, the disease can be related to infections, drugs and chemicals, and hereditary causes. Therapy for aplastic anemia includes blood component transfusions, antibiotics, androgenic steroids, and corticosteroids. With supportive care, most patients with aplastic anemia die within a year of diagnosis, and only approximately 20% of patients are surviving, although often with persisting hematologic abnormalities. The use of hematopoietic growth factors has shown, for the most part, only transient beneficial effects. More definitive therapy has been the use of immunosuppressive agents including antithymocyte globulin, cyclosporine, and cyclophosphamide. With immunosuppressive therapy, a variable proportion of patients respond to therapy, ranging from 20% to 80%. However, although responses may be frequent, long-term outlook is guarded because some patients may relapse with aplastic anemia, whereas others may go on to have a clonal disorder develop, including myelodysplasia, leukemia, or paroxysmal nocturnal hemoglobinuria. As a result, survival estimates at 15 to 18 years may be only on the order of 30%. More definitive therapy has been with transplants of hematopoietic stem cells from allogeneic donors. Transplants are carried out after high-dose immunosuppressive conditioning programs. Best current results show long-term, event-free survivals with successful allografts on the order of 90%.

Anemia, Aplastic↗

PubMed2004

Three-dimensional in vitro tissue culture models of breast cancer-- a review.

Three-dimensional (3D) in vitro breast tumour models have an invaluable role in tumour biology today providing some very important insights into breast cancer. As well as increasing our understanding of homeostasis, cellular differentiation and tissue organization they provide a well defined environment for cancer research in contrast to the complex host environment of an in vivo model. With the recent availability of relevant stromal elements together with the vast array of extracellular matrix constituents available, in vivo like microenvironments can be recreated. These tissue like structures more realistically model the structural architecture and differentiated function of breast cancer than a cellular monolayer providing in vivo like responses to therapeutic agents. Three dimensional in vitro models allow the study of cell-cell and cell-extracellular matrix interactions, in addition to the influence of the microenvironment on cellular differentiation, proliferation, apoptosis and gene expression. Due to their enormous potential 3D cultures are currently being exploited by many other branches of biomedical science with therapeutically orientated studies becoming the major focus of research. In return great progress in 3D culture techniques have been made, largely due to this greater interaction. At present they are being used in studies ranging from investigating the role of adhesion molecules (e.g., E-cadherin) in invasion/metastasis; VEGF and angiogenesis, to tissue modelling and remodelling. Progress in the development of complex 3D culture systems is more productive than ever, however further research is vital.

Breast Neoplasms↗

PubMed1993

Modulation of lymphohematopoiesis in long-term cultures by gamma interferon: direct and indirect action on lymphoid and stromal cells.

Gamma interferon (IFN-gamma) is the product of multiple cell types within the bone marrow microenvironment and has been demonstrated to act as a potent inhibitor of myelopoiesis in vitro and in vivo. The action of this cytokine on lymphohematopoiesis has now been examined on both long-term bone marrow cultures and representative cloned cellular components of the bone marrow microenvironment. In myelopoietic (Dexter) cultures, the half maximal inhibitory concentration of IFN-gamma was between 1 and 10 U/mL. In comparable lymphopoietic (Whitlock/Witte) cultures, IFN-gamma inhibited the production of B-lineage lymphoid cells with a half maximal effective concentration of less than 1 U/mL. In a clonal assay for pre-B cells, IFN-gamma inhibited colony formation with a half maximal concentration of 1 to 5 U/mL. Not all B-lineage lymphoid cells displayed the same sensitivity, however. Growth of the IL-7-dependent B cell line (2E8) in methylcellulose assays was unaffected by IFN-gamma while the replication of other lymphoid lines was partially or completely inhibited. IFN-gamma induced the expression of cell surface proteins (MHC Class I and II) on both B-lineage cells and stromal cells. In cloned stromal cell lines, IFN-gamma increased the steady state mRNA levels for the cytokines interleukin-6 (IL-6) and JE, a member of the IL-8 family. These data indicate that IFN-gamma acts within the lymphohematopoietic microenvironment through both direct and indirect actions on the hemopoietic and stromal cell populations.

Animals↗

PubMed2005

Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment.

Radiation exposure is an important form of environmental carcinogen and has been associated with increased risk of breast cancer. Epigenetic events, especially those involving alterations in the breast stromal microenvironment, may play an important role in radiation-induced carcinogenesis but remain not well understood. We here show that human mammary stromal fibroblasts respond to protracted low-dose ionizing radiation exposures by displaying a senescence-like phenotype. Using a three-dimensional coculture system to model the interactions of different mammary cell types with their neighbors and with their environment, we provide a direct experimental proof that ionizing radiation-induced senescence-like fibroblasts significantly perturb the mammary stromal microenvironment, which is highlighted by impaired formation of pseudopodia networks due to marked cytoskeletal alterations in senescence-like fibroblasts and increased extracellular matrix degradation because of the up-regulation of multiple secreted matrix metalloproteinases. Within such a perturbed environment, mammary ductal morphogenesis is completely disrupted and epithelial cells instead grow into enlarged cystic structures, which further develop and become disorganized cell masses on inactivation of cellular death pathways. Breast carcinoma cells growing in such an environment are enabled to fully express their malignant potential as evidenced by the alpha6beta4 integrin/phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway-dependent invasive growth. Our results suggest that ionizing radiation, in addition to causing gene mutations in epithelial cells, can contribute to breast carcinogenesis by perturbing the tissue microenvironment that leads to dysregulated cell-cell and cell-matrix interactions.

Animals↗

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↗

PubMedDate not supplied

The lipid world.

The continuity of abiotically formed bilayer membranes with similar structures in contemporary cellular life, and the requirement for microenvironments in which large and small molecules could be compartmentalized, support the idea that amphiphilic boundary structures contributed to the emergence of life. As an extension of this notion, we propose here a 'Lipid World' scenario as an early evolutionary step in the emergence of cellular life on Earth. This concept combines the potential chemical activities of lipids and other amphiphiles, with their capacity to undergo spontaneous self-organization into supramolecular structures such as micelles and bilayers. In particular, the documented chemical rate enhancements within lipid assemblies suggest that energy-dependent synthetic reactions could lead to the growth and increased abundance of certain amphiphilic assemblies. We further propose that selective processes might act on such assemblies, as suggested by our computer simulations of mutual catalysis among amphiphiles. As demonstrated also by other researchers, such mutual catalysis within random molecular assemblies could have led to a primordial homeostatic system displaying rudimentary life-like properties. Taken together, these concepts provide a theoretical framework, and suggest experimental tests for a Lipid World model for the origin of life.

Catalysis↗

PubMed2003

Endocrine/paracrine/autocrine survival factor activity of bone microenvironment participates in the development of androgen ablation and chemotherapy refractoriness of prostate cancer metastasis in skeleton.

Bone is the most frequent site of metastases of prostate cancer and is almost always the first and frequently the only site of metastases where disease will progress to stage D3. In addition, the number of skeletal metastatic foci is the most powerful independent prognostic factor of limited response to hormone ablation therapy and poor survival of patients with advanced prostate cancer. Furthermore, disease progression frequently occurs in the osteoblastic metastases, even though androgen ablation therapy still provides adequate and sustained control of disease at the primary site. Notably, the management of metastatic disease onto bones has traditionally relied on therapeutic modalities, which almost exclusively aim at directly inducing cancer cell death. However, accumulating pieces of evidence, from both the clinical and the basic research front, point to major limitations of this conventional approach. The in vivo response of malignant cells to anticancer therapies is directly influenced by the local microenvironment in which they metastasize. In particular, organ sites frequently involved in metastatic diseases, such as the bones, appear to confer to metastatic cells protection from anticancer drug-induced apoptosis. This protection is mediated by soluble growth factors and cytokines released by the normal cellular constituents of the host tissue microenvironment. The characterization of bone microenvironment-related survival factors has led to the development of a novel hormone manipulation which can re-introduce clinical responses in patients with stage D3 prostate cancer.

Androgen Antagonists↗

PubMed2006

I2 imaging: cancer biology and the tumor microenvironment.

The use of imaging techniques to understand the role of the tumor microenvironment in cancer progression was the topic of a National Cancer Institute (NCI)-sponsored think tank entitled "I2 Imaging: Cancer Biology and the Tumor Microenvironment," held in Alexandria, Virginia on June 8 to 10, 2006. Participants discussed both recent progress in the use of imaging to dissect cellular and molecular interactions within the tumor microenvironment and the challenges that remain. Recommendations made to the NCI included (a) holding an annual meeting at which biologists, clinicians, and imaging scientists could exchange data, facilitating new collaborations within this multidisciplinary field; (b) funding both research and training specifically designed to foster a cross-disciplinary focus; (c) creating and making available a variety of resources to interested investigators, such as a repository of stromal cells and extracellular matrix molecules; and (d) taking steps to encourage translation of the basic research findings into the clinic.

Biomedical Research↗

PubMed2001

Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development.

Cellular differentiation is a complex process involving integrated signals for lineage specification, proliferation, endowment of functional capacity, and survival or cell death. During embryogenesis, spatially discrete environments regulating these processes are established during the growth of tissue mass, a process that also results in temporal separation of developmental events. In tissues that undergo steady-state postnatal differentiation, another means for inducing spatial and temporal separation of developmental cues must be established. Here we show that in the postnatal thymus, this is achieved by inducing blood-borne precursors to enter the organ in a narrow region of the perimedullary cortex, followed by outward migration across the cortex before accumulation in the subcapsular zone. Notably, blood precursors do not transmigrate the cortex in an undifferentiated state, but rather undergo progressive developmental changes during this process, such that defined precursor stages appear in distinct cortical regions. Identification of these cortical regions, together with existing knowledge regarding the genetic potential of the corresponding lymphoid precursors, sets operational boundaries for stromal environments that are likely to induce these differentiative events. We conclude that active cell migration between morphologically similar but functionally distinct stromal regions is an integral component regulating differentiation and homeostasis in the steady-state thymus.

Animals↗

PubMedDate not supplied

Epithelial framework reorganization during human thymus involution.

BACKGROUND: The thymus undergoes age-related (physiological) involution in the course of normal ontogenetic development. In addition to this chronic involution, the thymus can also undergo an acute (age-independent) regression, defined as spontaneous, transient involution. This process is induced by either exogenous or endogenous factors, including some infections (infection-type involution). OBJECTIVE: The purpose of the present work was to undertake a comparative study of the epithelial framework organization and cytokeratin immunoreactivity of human thymic epithelial cells during age-related and infection-induced involution. METHODS: Routine methods for light and transmission electron microscopy, as well as indirect immunoperoxidase staining and immunogold electron microscopy, were applied. RESULTS: The epithelial thymocyte microenvironment was of a generally similar cellular composition in both chronically and acutely involuted thymus. Structurally, aged thymus glands and infection-affected thymus glands displayed a large mass of adipose tissue containing scattered islands composed of epithelial cells, lymphocytes and reticular connective tissue. Correlation between thymus involution and regional peculiarities in the presence and distribution of cytokeratin-immunopositive cells and their intermediate filaments was investigated. CONCLUSION: The epithelial framework of the thymus undergoes reorganization during both age-related and infection-induced thymus involution. The involutionary processes demonstrated essential regional and intracellular (structural and immunocytochemical) differences. The epithelial cell rearrangement and cytokeratin modulation that we observed might be involved in thymic microenvironment plasticity and reorganization in the course of these processes.

Adolescent↗

PubMed2007

Microenvironmental influences in melanoma progression.

An often overlooked facet of tumor biology research is the involvement of the surrounding tumor microenvironment. Increasing evidence is being presented to support a major role for stromal components in all stages of tumorigenesis including initiation, progression, and metastasis. Melanoma serves as a model for studying cellular and stromal interactions within the tumor microenvironment due to the array of cell types localized to these lesions. Here, we discuss the both the molecular mechanisms, as well as the extracellular and contextual input that contribute to melanoma progression. Special emphasis is given to the assorted cell types and their interactions with the extracellular matrix and adjacent cells. Melanoma progression also initiates development of intralesional hypoxic regions; the relative significance of hypoxia in disease is also addressed. Lastly, a number of laboratories are currently developing innovative strategies to study melanoma within a microenvironmental platform. These promising model systems and their potential for closing current gaps in knowledge of disease are reviewed. The development of such models holds translational value that cannot be achieved with most current systems.

Animals↗

PubMed2003

Inhibition of Rho pathways induces radiosensitization and oxygenation in human glioblastoma xenografts.

We previously demonstrated in vitro that inhibiting the biological pathways of the small GTPase Rho radiosensitizes the human glioma U87 cell line. The aim of this study was to determine if Rho might be involved in the control of in vivo radiosensitivity altogether by controlling cellular radioresistance and by modifying tumor microenvironment. We demonstrate here that the in vivo induction of the dominant negative of Rho, RhoBN19, in U87 xenografts induces a significant decrease of tumor cell survival after irradiation more important than the one we previously observed in vitro. This in vivo increased effect of RhoBN19 expression is due to the improvement of the tumor oxygenation associated with a significant decrease of the vessel density and of the metalloproteinase 2 (MMP2) expression. Moreover, in vitro RhoBN19 expression in U87 cells leads to the inhibition of MMP2 activity. Our results demonstrate for the first time that inhibiting Rho pathways modifies the in vivo radiosensitivity of human glioma cells by controlling intrinsic radioresistance, hypoxia and angiogenesis. These data strongly suggest that Rho should be a major determinant of cellular resistance to ionizing radiation.

Animals↗

PubMed2004

[Characterization of intervertebral disc--disc cells and pericellular microenvironment].

The intervertebral disc is classified as fibrocartilage, and has distinct functional and mechanical properties. The disc, composed of the nucleus pulposus and annulus fibrosus, varies in density, anatomic features, and in the morphology of their constituent cells. This heterogeneity has hampered detailed investigations of disc cellular metabolism. Focusing on the heterogeneity, we cultured disc cells under various conditions to examine the cellular metabolism, specifically glycosaminoglycan accumulation and pericellular microenvironment, and succeeded in mechanically isolating disc chondrons from annulus fibrosus. We believe that disc chondron also plays an important role in maintaining cartilageous phenotype in terms of cell-matrix interaction of the intervertebral disc.

Cell Culture Techniques↗

PubMed1996

Wild-type p53-induced apoptosis in a Burkitt lymphoma cell line is inhibited by interferon gamma.

The tumor suppressor p53 plays a central role in negative growth control, including growth arrest and apoptosis. Interferons (IFNs) are capable of modulating a variety of cellular responses, including apoptosis. In this study, we have evaluated the influence of gamma- and alpha-interferon (IFN) on wild-type (wt) p53-induced apoptosis using a Burkitt lymphoma cell line, BL41, transfected with a temperature-sensitive p53 construct, gamma-IFN, but not alpha-IFN, was found to protect cells from wt p53-induced apoptosis. The gamma-IFN-dependent protection was due neither to down-regulation of p53, nor to the p53-induced genes, p21 (WAF-1) and bax, nor to up-regulation of bcl-2 or bcl-xL. Expression of the proto-oncogene c-myc, implicated in the control of both proliferation and apoptosis, was not affected by gamma-IFN. We conclude that gamma-IFN can suppress p53-induced apoptosis, and that the cytokine microenvironment may be decisive in the cellular response to wt p53 expression.

Apoptosis↗

PubMed1998

Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells.

Mesenchymal stem cells (MSCs) are a population of pluripotent cells within the bone marrow microenvironment defined by their ability to differentiate into cells of the osteogenic, chondrogenic, tendonogenic, adipogenic, and myogenic lineages. We have developed methodologies to isolate and culture-expand MSCs from human bone marrow, and in this study, we examined the MSC's role as a stromal cell precursor capable of supporting hematopoietic differentiation in vitro. We examined the morphology, phenotype, and in vitro function of cultures of MSCs and traditional marrow-derived stromal cells (MDSCs) from the same marrow sample. MSCs are morphologically distinct from MDSC cultures, and flow cytometric analyses show that MSCs are a homogeneous cell population devoid of hematopoietic cells. RT-PCR analysis of cytokine and growth factor mRNA in MSCs and MDSCs revealed a very similar pattern of mRNAs including IL-6, -7, -8, -11, -12, -14, and -15, M-CSF, Flt-3 ligand, and SCF. Steady-state levels of IL-11 and IL-12 mRNA were found to be greater in MSCs. Addition of IL-1alpha induced steady-state levels of G-CSF and GM-CSF mRNA in both cell preparations. In contrast, IL-1alpha induced IL-1alpha and LIF mRNA levels only in MSCs, further emphasizing phenotypic differences between MSCs and MDSCs. In long-term bone marrow culture (LTBMC), MSCs maintained the hematopoietic differentiation of CD34+ hematopoietic progenitor cells. Together, these data suggest that MSCs represent an important cellular component of the bone marrow microenvironment.

Bone Marrow↗

PubMed2026

Loss of PBRM1 accelerates pancreatic cancer progression by inducing acquisition of mesenchymal phenotype and inflammatory cancer-associated fibroblasts reprogramming.

BACKGROUND: PBRM1 is an important subunit of the SWI/SNF complex, which broadly regulates gene transcription by chromatin remodeling. Genomic alterations of PBRM1 have been found in patients with pancreatic ductal adenocarcinoma (PDAC), but its molecular functions remain unclear. METHODS: Clinical relevance of PBRM1 was analyzed by using human PDAC samples and public genomic datasets. Mice with concomitant pancreas-specific Pbrm1 deletion in Kras-driven genetic PDAC models were generated. Single-cell transcriptomics were performed to determine tumor phenotype and microenvironment reprogramming. RESULTS: Reduction of PBRM1 expression was observed in human PDAC tissues and correlated with poor prognosis and metastasis. Pbrm1 loss promoted ductal metaplasia and delayed epithelial recovery in mice with caerulein-induced pancreatic injury. In PDAC model with either mutant Kras alone or in combination with Trp53 mutation, lack of Pbrm1 markedly accelerated tumor development and progression. Bulk transcriptomics and scRNA-seq identified reprogramming of both tumor compartment with mesenchymal phenotype acquisition and stroma compartment with inflammatory cancer-associated fibroblasts (iCAFs) transformation. Mechanistically, Pbrm1 deletion induced Zeb1 upregulation through epigenetic chromatin remodeling, thereby enhancing epithelial-mesenchymal and basal-like subtype transition. CONCLUSIONS: These findings indicated a tumor-suppressing role of PBRM1 in PDAC. PBRM1-deficient PDAC constitutes a specific subgroup of patients with aggressive phenotype and prognostic significance.

Animals↗