scholarly journals Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions

2015 ◽  
Vol 291 (4) ◽  
pp. 1652-1663 ◽  
Author(s):  
Anurag Purushothaman ◽  
Shyam Kumar Bandari ◽  
Jian Liu ◽  
James A. Mobley ◽  
Elizabeth E. Brown ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Target Cell ◽  
Target Genes ◽  
Cell Interaction ◽  
Myeloma Cell ◽  
Cell Interactions ◽  
Target Cells ◽  
Heparin Binding ◽  
Downstream Target ◽  
Tumor Microenvironments

Exosomes regulate cell behavior by binding to and delivering their cargo to target cells; however, the mechanisms mediating exosome-cell interactions are poorly understood. Heparan sulfates on target cell surfaces can act as receptors for exosome uptake, but the ligand for heparan sulfate on exosomes has not been identified. Using exosomes isolated from myeloma cell lines and from myeloma patients, we identify exosomal fibronectin as a key heparan sulfate-binding ligand and mediator of exosome-cell interactions. We discovered that heparan sulfate plays a dual role in exosome-cell interaction; heparan sulfate on exosomes captures fibronectin, and on target cells it acts as a receptor for fibronectin. Removal of heparan sulfate from the exosome surface releases fibronectin and dramatically inhibits exosome-target cell interaction. Antibody specific for the Hep-II heparin-binding domain of fibronectin blocks exosome interaction with tumor cells or with marrow stromal cells. Regarding exosome function, fibronectin-mediated binding of exosomes to myeloma cells activated p38 and pERK signaling and expression of downstream target genes DKK1 and MMP-9, two molecules that promote myeloma progression. Antibody against fibronectin inhibited the ability of myeloma-derived exosomes to stimulate endothelial cell invasion. Heparin or heparin mimetics including Roneparstat, a modified heparin in phase I trials in myeloma patients, significantly inhibited exosome-cell interactions. These studies provide the first evidence that fibronectin binding to heparan sulfate mediates exosome-cell interactions, revealing a fundamental mechanism important for exosome-mediated cross-talk within tumor microenvironments. Moreover, these results imply that therapeutic disruption of fibronectin-heparan sulfate interactions will negatively impact myeloma tumor growth and progression.

scholarly journals Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2038
Author(s):  
Rada Amin ◽  
Kaushlendra Tripathi ◽  
Ralph D. Sanderson
Keyword(s):  
Tumor Suppressor ◽  
Chromatin Remodeling ◽  
Target Genes ◽  
Myeloma Cell ◽  
Chromatin Accessibility ◽  
Tumor Suppressor Function ◽  
Suppressor Activity ◽  
Downstream Target ◽  
Suppressor Function ◽  
Chromatin Opening

Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate and has been shown in various cancers to promote metastasis, angiogenesis, osteolysis, and chemoresistance. Although heparanase is thought to act predominantly extracellularly or within the cytoplasm, it is also present in the nucleus, where it may function in regulating gene transcription. Using myeloma cell lines, we report here that heparanase enhances chromatin accessibility and confirm a previous report that it also upregulates the acetylation of histones. Employing the Multiple Myeloma Research Foundation CoMMpass database, we demonstrate that patients expressing high levels of heparanase display elevated expression of proteins involved in chromatin remodeling and several oncogenic factors compared to patients expressing low levels of heparanase. These signatures were consistent with the known function of heparanase in driving tumor progression. Chromatin opening and downstream target genes were abrogated by inhibition of heparanase. Enhanced levels of heparanase in myeloma cells led to a dramatic increase in phosphorylation of PTEN, an event known to stabilize PTEN, leading to its inactivity and loss of tumor suppressor function. Collectively, this study demonstrates that heparanase promotes chromatin opening and transcriptional activity, some of which likely is through its impact on diminishing PTEN tumor suppressor activity.

Enhancing Effects of Heparin/Low Molecular Weight Heparin/Heparan Sulfate on Antigen Presentation and Antigen-Specific Cytotoxic T Lymphocyte (CTL) Induction by Monocyte-Derived Dendritic Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3816-3816
Author(s):  
Asuka Sekiguchi ◽  
Miwako Narita ◽  
Toshio Yano ◽  
Naoko Sato ◽  
Anri Saito ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Heparan Sulfate ◽  
Antigen Presentation ◽  
Binding Sites ◽  
Low Molecular Weight Heparin ◽  
Target Cells ◽  
Low Molecular Weight ◽  
Heparin Binding ◽  
Antigen Presenting ◽  
Ctl Induction

Abstract Heparin is bound with heparin-binding sites on certain cells, which induces proliferation and differentiation signals. In addition, heparin is bound with heparin-binding domains of various cytokines, which enhances the interaction between cytokines and target cells. Monocytes have been demonstrated to posses heparin-binding sites on cell surfaces. In the present study, we investigated the effects of heparin (including low molecular weight heparin) and heparan sulfate on antigen presentation and antigen-specific CTL induction of monocyte-derived DCs. Peripheral blood CD14+ cells were cultured to generate immature and mature DCs with various concentrations of heparin, low molecular weight heparin or heparan sulfate. Cultured cells were analyzed for DC-associated surface phenotypes by flow cytometry and evaluated for allogeneic antigen presenting ability by mixed leukocyte culture. In order to evaluate the effects of heparin on monocyte-derived DCs to generate antigen-specific CTL, DCs were generated from HLA-A2402 donors by serum-free culture with heparin, transfected with in vitro transcribed WT-1 mRNA on day 6 and cultured with the addition TNF-α/IL-1α/IL-6/IFN-γ/PGE2 for further 1 day. WT-1 mRNA-transfected DCs were used for priming autologous lymphocytes in co-culture at the stimulator:responder ratio of 1:10. Lymphocytes were primed with the same DCs 2-3 times in the interval of 5-7 days. CD8+ T cells were separated and used as effector cells in 51Cr-release assay. WT-1 expressing and HLA-A24+ cell line MegO1 was used as target cells. In order to evaluate the association of MHC molecules in the cytotoxicity, 51Cr-lebelled target cells were treated with anti-MHC class I or class II monoclonal antibody before cytotoxicity assay. In order to evaluate the antigen specificity of the generated CTL, unlabelled target cells were added to the cytotoxicity assay. By the addition of heparin, the expression of CD1a and CD80 on both immature and mature DCs was markedly enhanced and the allogeneic antigen presenting ability was elevated in both immature and mature DCs. By the addition of low molecular weight heparin, the expression of CD1a was enhanced and antigen presenting ability was elevated also. By the addition of heparan sulfate, similar results of elevated antigen presentation were obtained. By the priming of lymphocytes with WT-1 mRNA transfected DCs generated from monocytes by the serum-free culture with heparin, cytotoxic capability against WT-1 expressing target cells was demonstrated in the primed lymphocytes. The cytotoxic capability of the lymphocytes was blocked by the treatment of the target cells with anti-MHC class I monoclonal antibody and the addition of unlabelled target cells in the cytotoxicity reaction. The present study demonstrated that heparin/low molecular weight heparin/heparan sulfate could enhance the antigen presentation and antigen-specific CTL induction of monocyte-derived DCs. These findings suggest the usefulness of heparin for generating efficient DCs for DC-based immunotherapy and the involvement of heparan sulfate in immunological defense mechanism.

scholarly journals A naturally occurring bone marrow-chimeric primate. II. Environment dictates restriction on cytolytic T lymphocyte-target cell interactions.

1985 ◽  
Vol 162 (6) ◽  
pp. 2035-2052 ◽  
Author(s):  
J Picus ◽  
K Holley ◽  
W R Aldrich ◽  
J D Griffin ◽  
N L Letvin
Keyword(s):  
Bone Marrow ◽  
T Lymphocyte ◽  
Target Cell ◽  
Cell Interactions ◽  
Primate Species ◽  
Cell Populations ◽  
Target Cells ◽  
Functional Assay ◽  
Naturally Occurring ◽  
Cytolytic T Lymphocyte

Restriction on cytolytic T lymphocyte (CTL)-target cell-interactions are studied in the primate S. oedipus, a naturally occurring A + B----A bone marrow-chimeric species. We show that the T cell, B cell, and myelomonocytic progenitor cell populations are chimeric in this species. We selected animals for study that are populated by fully major histocompatibility complex (MHC)-disparate hematopoietic cell populations, using a functional assay system. We then developed an in vitro system for analyzing at the clonal level the genetic restrictions on the trinitrophenyl-specific CTL-target cell interactions of this species. In this system, we have shown that tolerance to foreign MHC determinants was not, of itself, sufficient to facilitate the generation of CTL specific for target cells expressing those foreign MHC determinants. Rather, a marked preference for the expansion of CTL clones with a restriction for target cells bearing the host animals' MHC determinants was seen. Hematopoietically derived cells did not affect the repertoire of these T lymphocytes. These studies represent the first demonstration of the phenomenon of an environment dictating interactional restrictions on CTL in a naturally occurring bone marrow-chimeric animal. This is also the first demonstration of the profound influence of the environment on the repertoire of the T lymphocyte in a primate species.

scholarly journals Biological Diversity of Prokaryotic Type IV Secretion Systems

2009 ◽  
Vol 73 (4) ◽  
pp. 775-808 ◽  
Author(s):  
Cristina E. Alvarez-Martinez ◽  
Peter J. Christie
Keyword(s):  
Target Cell ◽  
Biological Diversity ◽  
Cell Interaction ◽  
Type Iv Secretion ◽  
Target Cells ◽  
Secretion Systems ◽  
Extracellular Milieu ◽  
Type Iv ◽  
Type Iv Secretion Systems ◽  
Cell Envelopes

SUMMARY Type IV secretion systems (T4SS) translocate DNA and protein substrates across prokaryotic cell envelopes generally by a mechanism requiring direct contact with a target cell. Three types of T4SS have been described: (i) conjugation systems, operationally defined as machines that translocate DNA substrates intercellularly by a contact-dependent process; (ii) effector translocator systems, functioning to deliver proteins or other macromolecules to eukaryotic target cells; and (iii) DNA release/uptake systems, which translocate DNA to or from the extracellular milieu. Studies of a few paradigmatic systems, notably the conjugation systems of plasmids F, R388, RP4, and pKM101 and the Agrobacterium tumefaciens VirB/VirD4 system, have supplied important insights into the structure, function, and mechanism of action of type IV secretion machines. Information on these systems is updated, with emphasis on recent exciting structural advances. An underappreciated feature of T4SS, most notably of the conjugation subfamily, is that they are widely distributed among many species of gram-negative and -positive bacteria, wall-less bacteria, and the Archaea. Conjugation-mediated lateral gene transfer has shaped the genomes of most if not all prokaryotes over evolutionary time and also contributed in the short term to the dissemination of antibiotic resistance and other virulence traits among medically important pathogens. How have these machines adapted to function across envelopes of distantly related microorganisms? A survey of T4SS functioning in phylogenetically diverse species highlights the biological complexity of these translocation systems and identifies common mechanistic themes as well as novel adaptations for specialized purposes relating to the modulation of the donor-target cell interaction.

scholarly journals Localization of aggregated cell surface antigens of target cells bound to cytotoxic T lymphocytes.

1975 ◽  
Vol 142 (4) ◽  
pp. 1011-1016 ◽  
Author(s):  
G Berke ◽  
Z V Fishelson
Keyword(s):  
T Lymphocytes ◽  
Cell Surface ◽  
Cytotoxic T Lymphocytes ◽  
Target Cell ◽  
Cytotoxic T Lymphocyte ◽  
Surface Antigens ◽  
Cell Interaction ◽  
Target Cells ◽  
Cell Surface Antigens ◽  
Polar Localization

The redistribution of aggregated cell surface antigens of target cells bound to cytotoxic T lymphocytes was investigated. It was found that cap formation induced by antibody always occurred toward the site of binding. It is suggested that the polar localization of capped target cell surface determinants is a consequence of cytotoxic T-lymphocyte target cell interaction.

scholarly journals Monoclonal anti-Lyt-2.2 antibody blocks lectin-dependent cellular cytotoxicity of H-2-negative target cells.

1984 ◽  
Vol 159 (2) ◽  
pp. 551-558 ◽  
Author(s):  
T Hünig
Keyword(s):  
Monoclonal Antibody ◽  
T Lymphocyte ◽  
Target Cell ◽  
Cytotoxic T Lymphocyte ◽  
Cell Interaction ◽  
Target Cells ◽  
Cellular Cytotoxicity ◽  
Specific Lysis ◽  
Bearing Structure ◽  
Negative Target

The hypothesis that blocking of cytotoxic T lymphocyte (CTL)-mediated cytolysis with anti-Lyt-2 antibodies acts at the level of inhibiting the interaction of the Lyt-2-bearing structure with H-2 class I molecules was tested. In agreement with the findings of others, purified anti-Lyt-2.2 inhibited both antigen-specific lysis and lectin-dependent cellular cytotoxicity (LDCC). LDCC of H-2-positive and H-2-negative target cells was similarly inhibited by this antibody. As expected, this effect was specific for CTL expressing the Lyt-2.2 allele, in contrast to blocking with a rat monoclonal antibody to the murine LFA-1 antigen. The implications of this finding for the function of the Lyt-2 antigen in CTL-target cell interaction are discussed.

scholarly journals Involvement of CD56 (NKH-1/Leu-19 antigen) as an adhesion molecule in natural killer-target cell interaction.

1989 ◽  
Vol 170 (5) ◽  
pp. 1757-1761 ◽  
Author(s):  
T Nitta ◽  
H Yagita ◽  
K Sato ◽  
K Okumura
Keyword(s):  
Cell Adhesion ◽  
Nk Cells ◽  
Adhesion Molecule ◽  
Target Cell ◽  
Nk Cell ◽  
Cell Interaction ◽  
Target Cells ◽  
Inhibitory Effects ◽  
Neural Cell Adhesion ◽  
A Minor

The CD56 differentiation antigen, recognized by anti-Leu-19 and NKH-1 mAbs, is a 200-220-kD glycoprotein that is expressed predominantly on human NK cells and a minor subset of T lymphocytes mediating MHC-unrestricted cytotoxicity. The recent finding that CD56 is an isoform of the neural cell adhesion molecule (N-CAM) prompted us to examine the adhesive function of CD56 in the NK-target cell interaction. Synergistic inhibitory effects of anti-CD56 mAbs with anti-LFA-1 and/or anti-LFA-3 mAbs were demonstrated on NK cell-mediated cytotoxicity and on NK cell binding to target cells only when the target cells also express CD56. These findings indicate that CD56 on NK cells can serve as the third pathway of cell adhesion other than those mediated by the CD2/LFA-3 and LFA-1/ICAM-1 interactions, and is involved in NK cell cytotoxicity when interacting with the cells bearing N-CAM.

The Bactericidal Activity of Pediocin PA-1 Is Specifically Inhibited by a 15-mer Fragment That Spans the Bacteriocin from the Center toward the C Terminus

1998 ◽  
Vol 64 (12) ◽  
pp. 5057-5060 ◽  
Author(s):  
Gunnar Fimland ◽  
Ralph Jack ◽  
Günther Jung ◽  
Ingolf F. Nes ◽  
Jon Nissen-Meyer
Keyword(s):  
Target Cell ◽  
Bactericidal Activity ◽  
Cell Interaction ◽  
The Other ◽  
Target Cells ◽  
Peptide Fragment ◽  
Continuous Sequence ◽  
C Terminus ◽  
Enterocin A ◽  
Leucocin A

ABSTRACT A 15-mer peptide fragment derived from pediocin PA-1 (from residue 20 to residue 34) specifically inhibited the bactericidal activity of pediocin PA-1. The fragment did not inhibit the pediocin-like bacteriocins sakacin P, leucocin A, and curvacin A to nearly the same extent as it inhibited pediocin PA-1. Enterocin A, however, was also significantly inhibited by this fragment, although not as greatly as pediocin PA-1. This is consistent with the fact that enterocin A contains the longest continuous sequence identical to that of pediocin PA-1 in the region spanned by the fragment. The fragment inhibited pediocin PA-1 to a much greater extent than did the other 29 possible 15-mer fragments that span pediocin PA-1. The results suggest that the fragment—by interacting with the target cells and/or pediocin PA-1—interferes specifically with pediocin-target cell interaction.

scholarly journals Primary attachment of murine leukaemia virus vector mediated by particle-associated heparan sulfate proteoglycan

2006 ◽  
Vol 400 (3) ◽  
pp. 421-430 ◽  
Author(s):  
Nina Kureishy ◽  
Daisy Faruque ◽  
Colin D. Porter
Keyword(s):  
Heparan Sulfate ◽  
Target Cell ◽  
Heparan Sulfate Proteoglycan ◽  
Receptor Interaction ◽  
Target Cells ◽  
Sulfate Proteoglycan ◽  
Leukaemia Virus ◽  
Murine Leukaemia Virus ◽  
Cell Specificity ◽  
Primary Attachment

Target cell entry of murine leukaemia virus vectors proceeds via primary attachment, independent of the viral envelope protein and subsequent envelope–receptor interaction. Although much attention has been paid to modifying the latter for target cell specificity, the initial binding interaction has been overlooked, despite its opposing involvement both in providing the virus available for receptor binding and in depleting free virus. As a first step towards modifying primary attachment, both to provide specificity and to enhance vector availability, we sought to determine the nature of this interaction. Following an initial screen of GAGs (glycosaminoglycans) for their ability to inhibit virus binding and transduction, we have shown that production of virus from cells in which GAG sulfation is inhibited, or treatment of virus with heparinase III, reduces both particle attachment and infection. Detection in purified virus preparations of a neo-epitope generated by heparinase III confirmed the presence of virus-associated HSPG [HS (heparan sulfate) proteoglycan], acquired from the producer cell. We propose that host-acquired cell-surface HSPG (potentially including syndecan-2) provides a means of virus attachment to target cells that precedes specific receptor interaction and membrane fusion. Inhibition of HS biosynthesis may provide a sufficiently reduced background of primary binding such that novel mechanisms of attachment, ideally with appropriate target cell specificity, can be introduced.

scholarly journals Random migration precedes stable target cell interactions of tumor-infiltrating T cells

2006 ◽  
Vol 203 (12) ◽  
pp. 2749-2761 ◽  
Author(s):  
Paulus Mrass ◽  
Hajime Takano ◽  
Lai Guan Ng ◽  
Sachin Daxini ◽  
Marcio O. Lasaro ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Target Cell ◽  
Rational Design ◽  
Tumor Regression ◽  
Cell Interactions ◽  
Target Cells ◽  
Critical Determinant ◽  
Tumor Immune Evasion ◽  
Cognate Antigen

The tumor microenvironment is composed of an intricate mixture of tumor and host-derived cells that engage in a continuous interplay. T cells are particularly important in this context as they may recognize tumor-associated antigens and induce tumor regression. However, the precise identity of cells targeted by tumor-infiltrating T lymphocytes (TILs) as well as the kinetics and anatomy of TIL-target cell interactions within tumors are incompletely understood. Furthermore, the spatiotemporal conditions of TIL locomotion through the tumor stroma, as a prerequisite for establishing contact with target cells, have not been analyzed. These shortcomings limit the rational design of immunotherapeutic strategies that aim to overcome tumor-immune evasion. We have used two-photon microscopy to determine, in a dynamic manner, the requirements leading to tumor regression by TILs. Key observations were that TILs migrated randomly throughout the tumor microenvironment and that, in the absence of cognate antigen, they were incapable of sustaining active migration. Furthermore, TILs in regressing tumors formed long-lasting (≥30 min), cognate antigen–dependent contacts with tumor cells. Finally, TILs physically interacted with macrophages, suggesting tumor antigen cross-presentation by these cells. Our results demonstrate that recognition of cognate antigen within tumors is a critical determinant of optimal TIL migration and target cell interactions, and argue against TIL guidance by long-range chemokine gradients.

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