Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis.

Abstract:

:Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanase-neutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment.

authors

Weissmann M,Arvatz G,Horowitz N,Feld S,Naroditsky I,Zhang Y,Ng M,Hammond E,Nevo E,Vlodavsky I,Ilan N

doi

10.1073/pnas.1519453113

subject

Has Abstract

pub_date

2016-01-19 00:00:00

pages

704-9

issue

3

eissn

0027-8424

issn

1091-6490

pii

1519453113

journal_volume

113

pub_type

杂志文章
  • Lead poisoning and the deceptive recovery of the critically endangered California condor.

    abstract::Endangered species recovery programs seek to restore populations to self-sustaining levels. Nonetheless, many recovering species require continuing management to compensate for persistent threats in their environment. Judging true recovery in the face of this management is often difficult, impeding thorough analysis o...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1203141109

    authors: Finkelstein ME,Doak DF,George D,Burnett J,Brandt J,Church M,Grantham J,Smith DR

    更新日期:2012-07-10 00:00:00

  • Are the presynaptic membrane particles the calcium channels?

    abstract::The number of large intramembrane particles associated with sites of synaptic vesicle release at the squid giant synapse was determined and compared to the average maximal presynaptic calcium current in order to derive an estimate of the conductance each particle would have if it were a calcium channel. This value, 0....

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.11.7210

    authors: Pumplin DW,Reese TS,Llinás R

    更新日期:1981-11-01 00:00:00

  • Selection of an RNA molecule that mimics a major autoantigenic epitope of human insulin receptor.

    abstract::Autoimmunity often involves the abnormal targeting of self-antigens by antibodies, leading to tissue destruction and other pathologies. This process could potentially be disrupted by small ligands that bind specifically to autoantibodies and inhibit their interaction with the target antigen. Here we report the identif...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.6.2355

    authors: Doudna JA,Cech TR,Sullenger BA

    更新日期:1995-03-14 00:00:00

  • Agricultural intensification escalates future conservation costs.

    abstract::The supposition that agricultural intensification results in land sparing for conservation has become central to policy formulations across the tropics. However, underlying assumptions remain uncertain and have been little explored in the context of conservation incentive schemes such as policies for Reducing Emission...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1220070110

    authors: Phelps J,Carrasco LR,Webb EL,Koh LP,Pascual U

    更新日期:2013-05-07 00:00:00

  • Compositional heterogeneity of human heterochromatin.

    abstract::When human genome was fractionated by thermal elution chromatography, repetitious DNA was found in every arbitrary temperature segment. When these repetitious DNA families were used for in situ hybridization, the following conclusions were evident: (a) Unlike the case of mouse, where essentially all centromeric hetero...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.69.6.1464

    authors: Hsu TC,Arrighi FE,Saunders GF

    更新日期:1972-06-01 00:00:00

  • Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response.

    abstract::Many pathogenic bacteria produce extracellular DNase, but the benefit of this enzymatic activity is not understood. For example, all strains of the human bacterial pathogen group A Streptococcus (GAS) produce at least one extracellular DNase, and most strains make several distinct enzymes. Despite six decades of study...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0406641102

    authors: Sumby P,Barbian KD,Gardner DJ,Whitney AR,Welty DM,Long RD,Bailey JR,Parnell MJ,Hoe NP,Adams GG,Deleo FR,Musser JM

    更新日期:2005-02-01 00:00:00

  • Proteins conferred by the virulence-specifying plasmid of Agrobacterium tumefaciens C-58.

    abstract::Membrane-associated and periplasmic proteins of Agrobacterium tumefaciens C-58 were compared with those from avirulent (nontumrigenic) derivative strains by slab and two-dimensional gel electrophoresis. Two proteins (Per-I and Per-2), with a molecular weight of 37,500 and 37,300, respectively, were detected in the sup...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.75.8.3796

    authors: Sonoki S,Kado CI

    更新日期:1978-08-01 00:00:00

  • Primary cilia control glucose homeostasis via islet paracrine interactions.

    abstract::Pancreatic islets regulate glucose homeostasis through coordinated actions of hormone-secreting cells. What underlies the function of the islet as a unit is the close approximation and communication among heterogeneous cell populations, but the structural mediators of islet cellular cross talk remain incompletely char...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2001936117

    authors: Hughes JW,Cho JH,Conway HE,DiGruccio MR,Ng XW,Roseman HF,Abreu D,Urano F,Piston DW

    更新日期:2020-04-21 00:00:00

  • Evolution of antibiotic resistance is linked to any genetic mechanism affecting bacterial duration of carriage.

    abstract::Understanding how changes in antibiotic consumption affect the prevalence of antibiotic resistance in bacterial pathogens is important for public health. In a number of bacterial species, including Streptococcus pneumoniae, the prevalence of resistance has remained relatively stable despite prolonged selection pressur...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1617849114

    authors: Lehtinen S,Blanquart F,Croucher NJ,Turner P,Lipsitch M,Fraser C

    更新日期:2017-01-31 00:00:00

  • Primary structure of the gene encoding the bifunctional dihydrofolate reductase-thymidylate synthase of Leishmania major.

    abstract::We have determined the nucleotide sequence of the dihydrofolate reductase-thymidylate synthetase (DHFR-TS) gene of the protozoan parasite Leishmania major (dihydrofolate reductase, EC 1.5.1.3 and thymidylate synthase, EC 2.1.1.45). The DHFR-TS protein is encoded by a single 1560-base-pair open reading frame within gen...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.8.2584

    authors: Beverley SM,Ellenberger TE,Cordingley JS

    更新日期:1986-04-01 00:00:00

  • Dynamical facilitation governs glassy dynamics in suspensions of colloidal ellipsoids.

    abstract::One of the greatest challenges in contemporary condensed matter physics is to ascertain whether the formation of glasses from liquids is fundamentally thermodynamic or dynamic in origin. Although the thermodynamic paradigm has dominated theoretical research for decades, the purely kinetic perspective of the dynamical ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1413384111

    authors: Mishra CK,Hima Nagamanasa K,Ganapathy R,Sood AK,Gokhale S

    更新日期:2014-10-28 00:00:00

  • Rational design of a triple helix-specific intercalating ligand.

    abstract::DNA triple helices offer new perspectives toward oligonucleotide-directed gene regulation. However, the poor stability of some of these structures might limit their use under physiological conditions. Specific ligands can intercalate into DNA triple helices and stabilize them. Molecular modeling and thermal denaturati...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.7.3591

    authors: Escudé C,Nguyen CH,Kukreti S,Janin Y,Sun JS,Bisagni E,Garestier T,Hélène C

    更新日期:1998-03-31 00:00:00

  • Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice.

    abstract::Induction of differentiation and apoptosis in cancer cells through ligands of nuclear hormone receptors (NHRs) is a novel and promising approach to cancer therapy. All-trans-retinoic acid (ATRA), an RA receptor-specific NHR ligand, is now used for selective cancers. The NHR, peroxisome proliferator-activated receptor ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.15.8806

    authors: Elstner E,Müller C,Koshizuka K,Williamson EA,Park D,Asou H,Shintaku P,Said JW,Heber D,Koeffler HP

    更新日期:1998-07-21 00:00:00

  • Differential requirements of MHC and of DCs for endogenous proliferation of different T-cell subsets in vivo.

    abstract::T cells transferred into severe lymphopenic hosts undergo rapid proliferation known as "endogenous proliferation" that are distinct from conventional homeostatic proliferation. Unlike homeostatic proliferation, cytokines, such as IL-7 are dispensable, yet TCR:MHC interaction is essential for this process to occur. How...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0909954106

    authors: Do JS,Min B

    更新日期:2009-12-01 00:00:00

  • Kinetic evidence for a ligand-binding-induced conformational transition in the T cell receptor.

    abstract::Thermodynamics and kinetics of the interaction between T cell receptor specific for cytomegalovirus peptide (TCR(CMV)) and its specific ligand, pp65-HLA-A*0201 complex, were studied by surface plasmon resonance and stopped-flow methods. In the latter measurements, fluorescence resonance energy transfer (FRET) between ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0707061104

    authors: Gakamsky DM,Lewitzki E,Grell E,Saulquin X,Malissen B,Montero-Julian F,Bonneville M,Pecht I

    更新日期:2007-10-16 00:00:00

  • Simultaneous spatiotemporal tracking and oxygen sensing of transient implants in vivo using hot-spot MRI and machine learning.

    abstract::A varying oxygen environment is known to affect cellular function in disease as well as activity of various therapeutics. For transient structures, whether they are unconstrained therapeutic transplants, migrating cells during tumor metastasis, or cell populations induced by an immunological response, the role of oxyg...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1815909116

    authors: Spanoudaki V,Doloff JC,Huang W,Norcross SR,Farah S,Langer R,Anderson DG

    更新日期:2019-03-12 00:00:00

  • Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.

    abstract::The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.141230798

    authors: Sakamoto KM,Kim KB,Kumagai A,Mercurio F,Crews CM,Deshaies RJ

    更新日期:2001-07-17 00:00:00

  • A model for protein synthesis involving the intermediate formation of peptidyl-5S RNA.

    abstract::A model for protein synthesis is proposed in which the donor for the peptide elongation reaction is peptidyl-5S RNA. Space-filling models show that peptide bond formation between peptidyl-5S RNA and aminoacyl-tRNA is eminently feasible from a stereochemical point of view. The peptide is transferred to 5S RNA, while at...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.68.10.2357

    authors: Raacke ID

    更新日期:1971-10-01 00:00:00

  • Vinpocetine inhibits NF-kappaB-dependent inflammation via an IKK-dependent but PDE-independent mechanism.

    abstract::Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0914414107

    authors: Jeon KI,Xu X,Aizawa T,Lim JH,Jono H,Kwon DS,Abe J,Berk BC,Li JD,Yan C

    更新日期:2010-05-25 00:00:00

  • Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer.

    abstract::Helicobacter hepaticus-infected Rag2(-/-) mice emulate many aspects of human inflammatory bowel disease, including the development of colitis and colon cancer. To elucidate mechanisms of inflammation-induced carcinogenesis, we undertook a comprehensive analysis of histopathology, molecular damage, and gene expression ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1207829109

    authors: Mangerich A,Knutson CG,Parry NM,Muthupalani S,Ye W,Prestwich E,Cui L,McFaline JL,Mobley M,Ge Z,Taghizadeh K,Wishnok JS,Wogan GN,Fox JG,Tannenbaum SR,Dedon PC

    更新日期:2012-07-03 00:00:00

  • Son-biased sex ratios in the 2000 United States Census.

    abstract::We document male-biased sex ratios among U.S.-born children of Chinese, Korean, and Asian Indian parents in the 2000 U.S. Census. This male bias is particularly evident for third children: If there was no previous son, sons outnumbered daughters by 50%. By contrast, the sex ratios of eldest and younger children with a...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0800703105

    authors: Almond D,Edlund L

    更新日期:2008-04-15 00:00:00

  • Geometric diffusions as a tool for harmonic analysis and structure definition of data: diffusion maps.

    abstract::We provide a framework for structural multiscale geometric organization of graphs and subsets of R(n). We use diffusion semigroups to generate multiscale geometries in order to organize and represent complex structures. We show that appropriately selected eigenfunctions or scaling functions of Markov matrices, which d...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0500334102

    authors: Coifman RR,Lafon S,Lee AB,Maggioni M,Nadler B,Warner F,Zucker SW

    更新日期:2005-05-24 00:00:00

  • CD83-stimulated monocytes suppress T-cell immune responses through production of prostaglandin E2.

    abstract::CD83 is commonly known as a specific marker for mature dendritic cells. It has been shown to be important for CD4(+) T-cell development in the thymus. However, its function in the peripheral immune system remains enigmatic. Here, we show that CD83 inhibits proliferation and production of IL-2 and IFN-γ by T cells, and...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1018994108

    authors: Chen L,Zhu Y,Zhang G,Gao C,Zhong W,Zhang X

    更新日期:2011-11-15 00:00:00

  • Virstatin inhibits dimerization of the transcriptional activator ToxT.

    abstract::The development of antimicrobials is critical in this time of increasing antibiotic resistance of most clinically relevant bacteria. To date, all current antibiotics focus on inhibiting crucial enzymatic activities of their protein targets (i.e., trimethoprim for dihydrofolate reductase), thus disrupting in vitro esse...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0611643104

    authors: Shakhnovich EA,Hung DT,Pierson E,Lee K,Mekalanos JJ

    更新日期:2007-02-13 00:00:00

  • Gcm protein degradation suppresses proliferation of glial progenitors.

    abstract::Gliogenesis in animal development is spatiotemporally regulated so that correct numbers of glia are present to support various neuronal functions. During Drosophila embryonic development, the glial regulatory gene, glial cell missing/glial cell deficient (gcm/glide), promotes glial cell fate and differentiation. Here ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0808899106

    authors: Ho MS,Chen H,Chen M,Jacques C,Giangrande A,Chien CT

    更新日期:2009-04-21 00:00:00

  • Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants.

    abstract::Amyotrophic lateral sclerosis is a neurodegenerative syndrome associated with 114 mutations in the gene encoding the cytosolic homodimeric enzyme Cu/Zn superoxide dismutase (SOD). In this article, we report that amyotrophic lateral sclerosis-associated SOD mutations with distinctly different disease progression can be...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0501957102

    authors: Lindberg MJ,Byström R,Boknäs N,Andersen PM,Oliveberg M

    更新日期:2005-07-12 00:00:00

  • Comparative homology agreement search: an effective combination of homology-search methods.

    abstract::Many methods have been developed to search for homologous members of a protein family in databases, and the reliability of results and conclusions may be compromised if only one method is used, neglecting the others. Here we introduce a general scheme for combining such methods. Based on this scheme, we implemented a ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0405612101

    authors: Alam I,Dress A,Rehmsmeier M,Fuellen G

    更新日期:2004-09-21 00:00:00

  • Functional differentiation of T cells in the intestine of T cell receptor transgenic mice.

    abstract::The intestinal lamina propria (LP) is a major effector site of the mucosal immune system where antigen-specific and antigen-nonspecific factors shape the functional responses of CD4+ T helper cells. To study the functional differentiation of LP T helper cells we utilized DO11.10 T cell receptor (TCR) transgenic (Tg) m...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.8.3920

    authors: Hurst SD,Sitterding SM,Ji S,Barrett TA

    更新日期:1997-04-15 00:00:00

  • A potent dimeric peptide antagonist of interleukin-5 that binds two interleukin-5 receptor alpha chains.

    abstract::Two series of peptides that specifically bind to the extracellular domain of the alpha chain of the human interleukin-5 receptor (IL-5Ralpha), but share no primary sequence homology to IL-5, were identified from libraries of random recombinant peptides. Affinity maturation procedures generated a 19-aa peptide that bin...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.110053997

    authors: England BP,Balasubramanian P,Uings I,Bethell S,Chen MJ,Schatz PJ,Yin Q,Chen YF,Whitehorn EA,Tsavaler A,Martens CL,Barrett RW,McKinnon M

    更新日期:2000-06-06 00:00:00

  • Amygdala damage eliminates monetary loss aversion.

    abstract::Losses are a possibility in many risky decisions, and organisms have evolved mechanisms to evaluate and avoid them. Laboratory and field evidence suggests that people often avoid risks with losses even when they might earn a substantially larger gain, a behavioral preference termed "loss aversion." The cautionary brak...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0910230107

    authors: De Martino B,Camerer CF,Adolphs R

    更新日期:2010-02-23 00:00:00