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At least 847 records · Page 47Linked to original sources
PubMed2005

Expression and nuclear location of the transcriptional repressor Kaiso is regulated by the tumor microenvironment.

Kaiso is a BTB/POZ zinc finger protein originally described as an interaction partner of p120ctn. In cultured cell lines, Kaiso is found almost exclusively in the nucleus, where it generally acts as a transcriptional repressor. Here, we describe the first in situ immunolocalization studies of Kaiso expression in normal and cancerous tissues. Surprisingly, we found striking differences between its behavior in monolayers of different cell lines, three-dimensional cell culture systems, and in vivo. Although nuclear localization was sometimes observed in tissues, Kaiso was more often found in the cytoplasm, and in some cell types it was absent. In general, Kaiso and p120ctn did not colocalize in the nucleus. To examine this phenomenon more carefully, tumor cells exhibiting strong nuclear Kaiso staining in vitro were injected into nude mice and grown as xenografts. The latter showed a progressive translocation of Kaiso towards the cytoplasm over time, and even complete loss of expression, especially in the center of the tumor nodules. When xenografted tumors were returned to cell culture, Kaiso was re-expressed and was once again found in the nucleus. Translocation of Kaiso to the cytoplasm and down-regulation of its levels were also observed under particular experimental conditions in vitro, such as formation of spheroids and acini. These data strongly imply an unexpected influence of the microenvironment on Kaiso expression and localization. As transcriptional repression is a nuclear event, this phenomenon is likely a crucial factor in the regulation of Kaiso function.

Adenocarcinoma↗
PubMed2006

Beta1 integrins modulate cell adhesion by regulating insulin-like growth factor-II levels in the microenvironment.

The interactions between cancer cells and the extracellular matrix (ECM) regulate cancer progression. The beta1C and beta1A integrins, two cytoplasmic variants of the beta1 integrin subfamily, are differentially expressed in prostate cancer. Using gene expression analysis, we show here that the beta1C variant, an inhibitor of cell proliferation, which is down-regulated in prostate cancer, up-regulates insulin-like growth factor-II (IGF-II) mRNA and protein levels. In contrast, beta1A does not affect IGF-II levels. We provide evidence that beta1C-mediated up-regulation of IGF-II levels increases adhesion to Laminin-1, a basement membrane protein down-regulated in prostate cancer, and that the beta1C cytoplasmic domain contains the structural motif sufficient to increase cell adhesion to Laminin-1. This autocrine mechanism that locally supports cell adhesion to Laminin-1 via IGF-II is selectively regulated by the beta1 cytoplasmic domain via activation of the growth factor receptor binding protein 2-associated binder-1/SH2-containing protein-tyrosine phosphatase 2/phosphatidylinositol 3-kinase pathway. Thus, the concurrent local loss of beta1C integrin, of its ligand Laminin-1, and of IGF-II in the tumor microenvironment may promote prostate cancer cell invasion and metastasis by reducing cancer cell adhesive properties. It is, therefore, conceivable that reexpression of beta1C will be sufficient to revert a neoplastic phenotype to a nonproliferative and highly adherent normal phenotype.

Adaptor Proteins, Signal Transducing↗
PubMed2005

A selective tumor microvasculature thrombogen that targets a novel receptor complex in the tumor angiogenic microenvironment.

We have previously shown that part of the heparin-binding domain of the vascular endothelial growth factor (VEGF), designated HBDt, localizes very selectively to surfaces of the endothelial cells of i.t blood vessels. Here, we have coupled the HBDt to the extracellular domain of tissue factor (TFt), to locally initiate the thrombogenic cascade. In tumor-bearing mice, infusion of this HBDt.TFt results in rapid occlusive thrombosis selective only for tumor microvasculature with resultant infarctive destruction of tumors. We now show that infusion of an optimal combination of this HBDt.TFt and its requisite cofactor (factor VIIa) in tumor models results in significant tumor eradication. Binding studies and confocal microscopy indicate that the target for the HBDt.TFt seems to be a trimolecular complex of chondroitin C sulfate proteoglycan, neuropilin-1, and VEGF receptor-2, overexpressed together only in highly angiogenic sites of the tumor microenvironment. The HBDt.TFt was also colocalized with the trimolecular receptor complex in endothelial sprouts from tumor tissues, and its binding inhibited the growth of such sprouts. In vitro, we show that the HBDt structure has its highest affinity for chondroitin 6 sulfate. We show the potential of this HBDt.TFt as a candidate therapeutic and elucidate its target in vivo.

Animals↗
PubMed2006

Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes.

Mechanisms underlying tumor vasculogenesis, the homing and engraftment of bone marrow-derived vascular progenitors, remain undefined. We hypothesized that tumor cell-secreted factors regulate vasculogenesis. We studied vasculogenic and nonvasculogenic intracranial murine gliomas. A PCR screen identified stromal-derived factor-1 (SDF-1/CXCL12) and vascular endothelial growth factor (VEGF) expression by vasculogenic glioma cells and spontaneously arising vasculogenic tumors in NF1+/-:Trp53+/- mice, but not by nonvasculogenic glioma cells. Enforced SDF-1, not VEGF, expression in nonvasculogenic cells caused vasculogenesis. Combined SDF-1 and VEGF expression augmented vasculogenesis over SDF-1 expression alone. Blocking SDF-1 receptor CXCR4 reduced short-term homing and long-term engraftment of vascular progenitors. Implanting tumor cells secreting SDF-1 was therefore necessary and sufficient to incorporate marrow-derived precursors into tumor endothelium. SDF-1 seemed to exert these effects by acting locally intratumorally and did not cause an efflux of marrow-derived progenitors into circulation. Tumor microenvironment determined additional fates of marrow-derived cells. Hypoxia, observed with ectopic s.c. murine tumors at levels approximating that of intracranial human glioblastoma, interacted with tumor-secreted SDF-1 to expand engrafted vascular progenitor differentiated phenotypes to include pericytes as well as endothelium. In contrast, less hypoxic orthotopic intracranial murine gliomas contained only marrow-derived endothelium without marrow-derived pericytes. Furthermore, we found that vasculogenesis is significant for tumors because it generates endothelium with a higher mitotic index than endothelium derived from local sources. Although CXCR4 blockade selectively targeted endothelium generated by vasculogenesis, completely inhibiting vessel formation may require combination therapy targeting locally derived and marrow-derived endothelium.

Animals↗
PubMed2006

Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment.

Recent studies have underscored the role of B-cell-activating factor (BAFF), a member of the tumor necrosis factor superfamily, in promoting the survival of malignant B cells, including human multiple myeloma. We here characterized the functional significance of BAFF in the interaction between multiple myeloma and bone marrow stromal cells (BMSC) and further defined the molecular mechanisms regulating these processes. BAFF is detected on BMSCs derived from multiple myeloma patients as evidenced by flow cytometry. BAFF secretion is 3- to 10-fold higher in BMSCs than in multiple myeloma cells, and tumor cell adhesion to BMSCs augments BAFF secretion by 2- to 5-fold, confirmed by both ELISA and immunoblotting. Adhesion of MM1S and MCCAR multiple myeloma cell lines to KM104 BMSC line transfected with a luciferase reporter vector carrying the BAFF gene promoter (BAFF-LUC) significantly enhanced luciferase activity, suggesting that nuclear factor-kappaB (NF-kappaB) activation induced by multiple myeloma adhesion to BMSCs mediates BAFF up-regulation. Moreover, BAFF (0-100 ng/mL) increases adhesion of multiple myeloma lines to BMSCs in a dose-dependent manner; conversely, transmembrane activator and calcium modulator and cyclophylin ligand interactor-Ig or B-cell maturation antigen/Fc blocked BAFF stimulation. Using adenoviruses expressing dominant-negative and constitutively expressed AKT as well as NF-kappaB inhibitors, we further showed that BAFF-induced multiple myeloma cell adhesion is primarily mediated via activation of AKT and NF-kappaB signaling. Importantly, BAFF similarly increased adhesion of CD138-expressing patient multiple myeloma cells to BMSCs. These studies establish a role for BAFF in localization and survival of multiple myeloma cells in the bone marrow microenvironment and strongly support novel therapeutics, targeting the interaction between BAFF and its receptors in human multiple myeloma.

B-Cell Activating Factor↗
PubMed2006

Eighteenth annual pezcoller symposium: tumor microenvironment and heterotypic interactions.

This symposium was held in Trento, Italy, from June 27 to 29, 2006, and was co-chaired by Robert Weinberg and Enrico Mihich. The interactions between tumor cells and their microenvironment were discussed with particular emphasis on their molecular mechanisms. The roles of transforming growth factor beta signaling, urokinase, and matrix metalloproteinases in matrix remodeling; the effects of matrix-tumor interactions on cell proliferation and migration; the tumor-promoting effects of inflammation and of related host cell and cytokine functions; the signaling mechanisms affecting the biology of the stroma; and the mechanisms governing angiogenesis were discussed.

Cell Division↗
PubMed2006

Identifying and overcoming immune resistance mechanisms in the melanoma tumor microenvironment.

The continually growing list of defined tumor antigens is broadening the potential applicability of tumor antigen-targeted cancer therapies. Although cancer vaccines and adoptive T-cell transfer have been shown to increase the frequency of circulating tumor antigen-specific T cells, these approaches cause clinical responses in a few patients. In melanoma, approximately one third of metastatic lesions contain activated T cells, including those specific for tumor antigens, arguing that the priming phase has occurred already in such individuals even without vaccination. These observations indicate that tumor resistance to immune destruction may dominate in many instances, arguing for a thorough analysis of the melanoma tumor microenvironment in individual patients. Recent work has suggested that T-cell anergy, the influence of CD4+ CD25+ regulatory T cells, the expression of inhibitory ligands, such as PD-L1, and the activity of nutrient-catabolizing enzymes, such as indoleamine 2,3-dioxygenase, may be involved. Preclinical murine models have shown that interfering with each of these processes can translate into T-cell-mediated tumor control. Importantly, each of these targets is amenable to clinical manipulation. Clinical translation of these approaches to counter negative regulation of antitumor immunity should receive high priority.

Animals↗
PubMed2006

Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment.

It is widely recognized that the vasculature of the tumor is inadequate to meet the demands of the growing mass. The malformed vasculature is at least in part responsible for regions of the tumor that are hypoxic, acidotic, and exposed to increased interstitial fluid pressure. These unique aspects of the tumor microenvironment have been shown to act as barriers to conventional chemotherapy or radiation-based therapies. It now seems that while the vasculature initiates these tumor-specific conditions, the cells within the tumor respond to these stresses and add to the unique solid tumor physiology. Gene expression changes have been reported in the tumor for vascular endothelial growth factor, carbonic anhydrase IX, and pyruvate dehydrogenase kinase 1. The activity of these gene products then influences the tumor physiology through alterations in vascular permeability and interstitial fluid pressure, extracellular acidosis, and mitochondrial oxygen consumption and hypoxia, respectively. Novel molecular strategies designed to interfere with the activities of these gene products are being devised as ways to overcome the physiologic barriers in the tumor to standard anticancer therapies.

Antineoplastic Agents↗
PubMed2025

Spatial-Temporal Diversity of Extrachromosomal DNA Shapes Urothelial Carcinoma Evolution and Tumor-Immune Microenvironment.

Extrachromosomal DNA (ecDNA) presents a promising target for cancer therapy; however, its spatial-temporal diversity and influence on tumor evolution and the immune microenvironment remain largely unclear. We apply computational methods to analyze ecDNA from whole-genome sequencing data of 595 urothelial carcinoma (UC) patients. We demonstrate that ecDNA drives clonal evolution through structural rearrangements during malignant transformation and recurrence of UC. This supports a model wherein tumors evolve via the selective expansion of ecDNA-bearing cells. Through multi-regional sampling of tumors, we demonstrate that ecDNA contributes to the evolution of multifocality and increased intratumoral heterogeneity. EcDNA is present in 36% of UC tumors and correlates with an immunosuppressive phenotype and poor prognosis. Single-cell RNA sequencing analyses reveal that ecDNA+ malignant cells exhibit diminished expression of major histocompatibility complex class I molecules, enabling them to evade T-cell immunity. Finally, we show that sequencing of urinary sediment-derived DNA has excellent specificity in detecting ecDNA.

Journal Article↗
PubMed1988

The neurohormonal thymic microenvironment: immunocytochemical evidence that thymic nurse cells are neuroendocrine cells.

Thymic neuroendocrine cells were identified by immunofluorescence in the murine thymus through the use of monoclonal antibody A2B5, and specific polyclonal antisera against neurophysin (NP), oxytocin (OT) and arginine vasopressin (AVP). Two reactive regions were clearly identified: the subcapsular cortex and the medulla. A close correspondence was observed between A2B5-reactive and NP-immunoreactive cells in the medulla. An important epithelial population of the subcapsular cortex, the thymic nurse cells (TNCs), were found to be A2B5-positive and to contain immunoreactive NP, OT and AVP. The neuroendocrine nature of TNCs was further substantiated by their high reactivity with an antiserum against neuron-specific enolase. These observations demonstrate the presence in the thymus gland of an original neuroendocrine microenvironment which could be of functional importance in the mediation of central influences upon T lymphocyte differentiation.

Animals↗
PubMed1997

Characterization of the molecules involved in the hematopoietic microenvironment provided by mouse stromal cell line MC3T3-G2/PA6 using a unique reporter system that analyzes the direct cell-to-cell interaction.

As an approach to characterizing the molecules involved in the hematopoietic microenvironment provided by a murine clonal preadipose cell line MC3T3-G2/PA6 (PA6), we developed a unique system to detect the early phase of signal transduction caused by the direct cell-to-cell interaction using the reporter plasmid pfosluc2 with the c-fos enhancer/promoter linked with the Photinus pyralis luciferase gene. The plasmid pfosluc2 was genetically introduced into a mouse myeloid leukemia cell line NFS-60 which showed a growth dependency on contact with PA6 cells, and the mechanism by which stromal PA6 cells promote the proliferation of NFS-60 cells through the direct cell-to-cell interaction was analyzed. The direct cell-to-cell interaction with PA6 cells was found to cause a significant c-fos induction to NFS-60 cells within 1 h. Approximately 10(5) cDNA clones prepared from PA6 cells were screened for their activity to promote the c-fos expression in NFS-60 cells through the direct cell-to-cell interaction, and 13 positive clones were obtained. Of these positive clones, five clones encoded the stem cell factor, and the others encoded the hepatocyte growth factor (HGF). The c-fos induction caused by the contact with PA6 cells in NFS-60 was completely inhibited by addition of both antagonistic anti-c-kit and anti-HGF antibodies. These results represent direct evidence for the action of HGF on the proliferation of hematopoietic cells through direct cell-to-cell interaction with stromal cells. Thus, our developed reporter system can be useful in investigating the direct cell-to-cell interaction between stromal and hematopoietic cells.

Animals↗
PubMed1997

Peripheral blood mobilization of hematopoietic stem cells: cytokine-mediated regulation of adhesive interactions within the hematopoietic microenvironment.

Peripheral blood (PB) mobilization of hematopoietic progenitors, presently regarded as an alternative source of cells intended for autologous or allogeneic bone marrow (BM) transplantation, supports a role for cytokines in the regulated adhesion of hematopoietic compartments to the BM microenvironment. Two major consequences might result from cytokine-induced rearrangements of adhesive interactions within the hematopoietic tissue, both potentially relevant for clinical purposes of PB grafts. The first one, arising from abrogated adhesion of hematopoietic stem cells to their microenvironmental 'niche', which is critical for the maintenance of cell cycle quiescence and endurability, might result in some impairment of the long-term repopulating potential of PB grafts. The second and possibly more harmful one is due to the inability of the cytokine to distinguish between normal and transformed cells, and would likely result in graft contamination by tumor cells, increasing the metastasizing potential of hematological malignancies and solid tumors.

Blood Cells↗
PubMed1985

Regeneration of murine megakaryocytopoiesis and the hematopoietic inductive microenvironment after sublethal whole body irradiation by treatment with an anabolic steroid.

The ability of the anabolic steroid nandrolone decanoate (ND) to increase megakaryocytopoiesis (MP) and the hematopoietic-inductive microenvironment (HIM) after sublethal irradiation was evaluated. Immediately after receiving whole body irradiation (2 Gy) and on the next 2 days, mice were injected with 1.25 mg of ND in propylene glycol intraperitoneally. Irradiated control mice received only vehicle. Compared to controls, drug-treated mice showed a 151% increase in the platelet level on day 14. Drug-treated mice also demonstrated a significant rebound in MP, as colony-forming progenitor stem cells (CFU-Mk) from bone marrow rose to 288% of control by day 8 and from spleen to 599% by day 1 following the last drug injection. In addition, drug-treated mice produced a 286% increase in bone marrow and a 378% in splenic stromal cell colonies on day 5 following drug treatment. These results demonstrate that ND enhances MP and HIM following sublethal irradiation. After hematopoietic suppression, ND may serve to stimulate MP and HIM recovery both at the stem cell level and in peripheral blood.

Anabolic Agents↗
PubMed1982

Microenvironment of Woringer-Kolopp's disease.

A localized form of 'Pagetoid reticulosis' (Woringer-Kolopp's disease) is described morphologically. It can be shown that ultrastructurally the 'Pagetoid cells' are heterogenic and that different cell types can be distinguished: there are lymphoid cells, which often look like Lutzner cells, and nonlymphoid cells which can be characterized as indeterminate cells or Langerhans' cells. Often a close topographical relation between lymphoid and nonlymphoid cells can be demonstrated. This finding is suggestive for a functional interaction between the lymphoid cells, which are most probably T cells, and indeterminate cells and Langerhans' cells, which are known to be important for the thymus-dependent immune reaction. The presence of the nonlymphoid cell population in the epidermis in Woringer-Kolopp's disease seems to build up the specific microenvironment for lymphoid cell reaction.

Epidermis↗
PubMed1989

Macrophage-derived growth factors in wound healing: regulation of growth factor production by the oxygen microenvironment.

There is a large amount of current research investigating the pathophysiologic aspects of pulmonary hypertension. Results of this research indicate the potential role of the macrophage as one possible mediator of pulmonary hypertension. The macrophage has been shown to produce numerous soluble mediators, including various growth factors, some of which may be involved in the cellular proliferation of the arterial wall. Most of the knowledge regarding oxygen microenvironments, macrophages, and growth factor production comes from research on the healing wound. A considerable amount of what has been learned about the role of the macrophage in cutaneous wound healing may have direct applicability to macrophage function in acute lung injury and repair, and pulmonary hypertension. Macrophages play a pivotal role in cutaneous wound repair. They participate in immunologic and nonspecific host defense responses and produce numerous growth factors that regulate mesenchymal cell proliferation, migration, and synthesis of extracellular matrix proteins. These same responses are probably at work during the progression of pulmonary hypertension.

Growth Substances↗
PubMed1985

A new murine monoclonal antibody reports an activation-dependent change in the conformation and/or microenvironment of the platelet glycoprotein IIb/IIIa complex.

Considerable evidence indicates that the glycoprotein (GP) IIb/IIIa complex on human platelets functions as a receptor for fibrinogen, but little is known about the mechanism of receptor "exposure." To investigate this mechanism, our previously described murine monoclonal antibody (10E5) and a new monoclonal antibody (7E3), both of which block the binding of fibrinogen to platelets and bind to GPIIb and/or GPIIIa, were radiolabeled and their rates of binding to native and ADP-activated platelets were studied. At low concentrations, 125I-10E5 bound nearly equally rapidly to both native and activated platelets, whereas 125I-7E3 bound slowly to native platelets and much more rapidly to activated platelets. This increased rate of 7E3 binding is unlikely to be due to an increase in the number of GPIIb/IIIa sites on the surface of activated platelets because: (a) the rate of 10E5 binding was unchanged; (b) the total number of surface GPIIb/IIIa sites increased by only 2-10% with activation as judged by equilibrium binding of near-saturating concentrations of 10E5 and 7E3, and (c) there was less than 1% release of platelet factor 4 with activation, indicating minimal fusion of alpha-granule membranes (a potential source of GPIIb/IIIa) with the plasma membrane. Other activators (epinephrine, thrombin, and ionophore A 23187) also increased the rate of 7E3 binding, as did digestion of platelets with chymotrypsin. Aspirin did not affect the rate of binding of 7E3, whereas apyrase, prostaglandin E1, and dibucaine all inhibited the enhancement of the 7E3-binding rate produced by ADP. These data provide evidence for an activation-dependent change in the conformation and/or microenvironment of the GPIIb/IIIa complex, and offer a method of studying the receptor exposure mechanism that does not rely on the binding of fibrinogen itself.

Adenosine Diphosphate↗
PubMed1988

Hematopoietic microenvironment. Origin, lineage, and transplantability of the stromal cells in long-term bone marrow cultures from chimeric mice.

Studies of bone marrow transplant patients have suggested that the stromal cells of the in vitro hematopoietic microenvironment are transplantable into conditioned recipients. Moreover, in patients with myeloproliferative disorders, all of the stromal cells, which include presumptive endothelial cells, appear to be derived from hematopoietic precursors. To confirm these findings, we have constructed two chimeric mouse models: (a) traditional radiation chimeras, and (b) fetal chimeras, produced by placental injection of bone marrow into genetically anemic Wx/Wv fetuses, a technique that essentially precludes engraftment of nonhematopoietic cells. Using two-color indirect immunofluorescence, the stromal cells in long-term bone marrow culture derived from these chimeras were analyzed for donor or host origin by strain-specific H-2 antigens, and for cell lineage by a variety of other specific markers. 75-95% of the stromal cells were shown to be hematopoietic cells of the monocyte-macrophage lineage, based upon donor origin, phagocytosis, and expression of specific hematopoietic surface antigens. The remaining 5-25% of the stromal cells were exclusively host in origin. Apart from occasional fat cells, these cells uniformly expressed collagen type IV, laminin, and a surface antigen associated with endothelial cells. Since these endothelial-like cells are not transplantable into radiation or fetal chimeras, they are not derived from hematopoietic stem cells. The contrast between our findings and human studies suggests either unexpected species differences in the origin of stromal lineages or limitations in the previous methodology used to detect nonhematopoietic stromal cells.

Adipose Tissue↗
PubMed1992

Transplantation of thymic autoimmune microenvironment to severe combined immunodeficiency mice. A new model of myasthenia gravis.

To study the role of the thymus in the cellular pathogenesis of myasthenia gravis (MG) we transplanted thymus tissue fragments from MG thymuses beneath the kidney capsule of severe combined immunodeficiency (SCID) mice. Immunocytochemical studies documented that the human thymus tissues are accepted as long-term grafts in the host SCID mice, with human lymphocytes, thymic stroma, and thymic myoid cells demonstrable in transplanted thymus for at least 15 weeks after transplantation. Human anti-acetylcholine receptor antibodies became detectable 1 to 2 weeks after transplantation, and in most chimeras the titers increased over at least 11 weeks to reach levels typically found in severe human MG. Human Ig deposits were detected at skeletal muscle end-plates, demonstrating that the human (auto)antibodies bound to murine acetylcholine receptor. In contrast, transfers of dissociated thymus cells only lead to a transient increase of anti-acetylcholine receptor antibodies. Our data prove that myasthenia gravis thymus is able to induce and maintain autoantibody production in immunodeprived host animals, and that this tissue contains all cellular components required for autoantibody production. Transplantation of solid thymus tissue seems to transfer an autoimmune microenvironment, which will allow direct studies of the mechanism of autosensitization inside the thymus.

Animals↗