65 results on '"Vlodavsky, Israel"'
Search Results
2. Opposing Functions of Heparanase-1 and Heparanase-2 in Cancer Progression.
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Vlodavsky, Israel, Gross-Cohen, Miriam, Weissmann, Marina, Ilan, Neta, and Sanderson, Ralph D.
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HEPARAN sulfate , *TUMOR growth , *BIOAVAILABILITY , *ENDOPLASMIC reticulum , *FIBROSIS - Abstract
Heparanase, the sole heparan sulfate (HS)-degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, metastasis, angiogenesis, and inflammation. Heparanase accomplishes this by degrading HS and thereby regulating the bioavailability of heparin-binding proteins; priming the tumor microenvironment; mediating tumor–host crosstalk; and inducing gene transcription, signaling pathways, exosome formation, and autophagy that together promote tumor cell performance and chemoresistance. By contrast, heparanase-2, a close homolog of heparanase, lacks enzymatic activity, inhibits heparanase activity, and regulates selected genes that promote normal differentiation, endoplasmic reticulum stress, tumor fibrosis, and apoptosis, together resulting in tumor suppression. The emerging premise is that heparanase is a master regulator of the aggressive phenotype of cancer, while heparanase-2 functions as a tumor suppressor. [ABSTRACT FROM AUTHOR]
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- 2018
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3. Heparanase: From basic research to therapeutic applications in cancer and inflammation.
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Vlodavsky, Israel, Singh, Preeti, Boyango, Ilanit, Gutter-Kapon, Lilach, Elkin, Michael, Sanderson, Ralph D., and Ilan, Neta
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Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Numerous clinical association studies have consistently demonstrated that upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. In contrast, knockdown of heparanase or treatments of tumor-bearing mice with heparanase-inhibiting compounds, markedly attenuate tumor progression further underscoring the potential of anti-heparanase therapy for multiple types of cancer. Heparanase neutralizing monoclonal antibodies block myeloma and lymphoma tumor growth and dissemination; this is attributable to a combined effect on the tumor cells and/or cells of the tumor microenvironment. In fact, much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis and chemoresistance. The repertoire of the physio-pathological activities of heparanase is expanding. Specifically, heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance; but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, stress response, and heparan sulfate turnover. Heparanase is upregulated in response to chemotherapy in cancer patients and the surviving cells acquire chemoresistance, attributed, at least in part, to autophagy. Consequently, heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance, providing a strong rationale for applying anti-heparanase therapy in combination with conventional anti-cancer drugs. Heparin-like compounds that inhibit heparanase activity are being evaluated in clinical trials for various types of cancer. Heparanase neutralizing monoclonal antibodies are being evaluated in pre-clinical studies, and heparanase-inhibiting small molecules are being developed based on the recently resolved crystal structure of the heparanase protein. Collectively, the emerging premise is that heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy. [ABSTRACT FROM AUTHOR]
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- 2016
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4. Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3.
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Alishekevitz, Dror, Gingis-Velitski, Svetlana, Kaidar-Person, Orit, Gutter-Kapon, Lilach, Scherer, Sandra D., Raviv, Ziv, Merquiol, Emmanuelle, Ben-Nun, Yael, Miller, Valeria, Rachman-Tzemah, Chen, Timaner, Michael, Mumblat, Yelena, Ilan, Neta, Loven, David, Hershkovitz, Dov, Satchi-Fainaro, Ronit, Blum, Galia, P. Sleeman, Jonathan, Vlodavsky, Israel, and Shaked, Yuval
- Abstract
Summary While chemotherapy strongly restricts or reverses tumor growth, the response of host tissue to therapy can counteract its anti-tumor activity by promoting tumor re-growth and/or metastases, thus limiting therapeutic efficacy. Here, we show that vascular endothelial growth factor receptor 3 (VEGFR3)-expressing macrophages infiltrating chemotherapy-treated tumors play a significant role in metastasis. They do so in part by inducing lymphangiogenesis as a result of cathepsin release, leading to VEGF-C upregulation by heparanase. We found that macrophages from chemotherapy-treated mice are sufficient to trigger lymphatic vessel activity and structure in naive tumors in a VEGFR3-dependent manner. Blocking VEGF-C/VEGFR3 axis inhibits the activity of chemotherapy-educated macrophages, leading to reduced lymphangiogenesis in treated tumors. Overall, our results suggest that disrupting the VEGF-C/VEGFR3 axis not only directly inhibits lymphangiogenesis but also blocks the pro-metastatic activity of macrophages in chemotherapy-treated mice. [ABSTRACT FROM AUTHOR]
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- 2016
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5. Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype.
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Ramani, Vishnu C., Vlodavsky, Israel, Ng, Mary, Zhang, Yi, Barbieri, Paola, Noseda, Alessandro, and Sanderson, Ralph D.
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PHYSIOLOGICAL effects of chemotherapy , *GENE expression , *HEPARANASE , *TUMOR growth , *NEOVASCULARIZATION , *PHENOTYPES - Abstract
High heparanase expression is associated with enhanced tumor growth, angiogenesis, and metastasis in many types of cancer. However, the mechanisms driving high heparanase expression are not fully understood. In the present study, we discovered that drugs used in the treatment of myeloma upregulate heparanase expression. Frontline anti-myeloma drugs, bortezomib and carfilzomib activate the nuclear factor-kappa B (NF-κB) pathway to trigger heparanase expression in tumor cells. Blocking the NF-κB pathway diminished this chemotherapy-induced upregulation of heparanase expression. Activated NF-κB signaling was also found to drive high heparanase expression in drug resistant myeloma cell lines. In addition to enhancing heparanase expression, chemotherapy also caused release of heparanase by tumor cells into the conditioned medium. This soluble heparanase was taken up by macrophages and triggered an increase in TNF-α production. Heparanase is also taken up by tumor cells where it induced expression of HGF, VEGF and MMP-9 and activated ERK and Akt signaling pathways. These changes induced by heparanase are known to be associated with the promotion of an aggressive tumor phenotype. Importantly, the heparanase inhibitor Roneparstat diminished the uptake and the downstream effects of soluble heparanase. Together, these discoveries reveal a novel mechanism whereby chemotherapy upregulates heparanase, a known promoter of myeloma growth, and suggest that therapeutic targeting of heparanase during anti-cancer therapy may improve patient outcome. [ABSTRACT FROM AUTHOR]
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- 2016
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6. The potential of heparanase as a therapeutic target in cancer.
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Pisano, Claudio, Vlodavsky, Israel, Ilan, Neta, and Zunino, Franco
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HEPARANASE , *THERAPEUTICS , *CANCER treatment , *ANTINEOPLASTIC agents , *CANCER cells , *CANCER invasiveness - Abstract
Abstract: Heparanase has generated substantial interest as therapeutic target for antitumor therapy, because its activity is implicated in malignant behavior of cancer cells and in tumor progression. Increased heparanase expression was found in numerous tumor types and correlates with poor prognosis. Heparanase, an endoglucuronidase responsible for heparan sulfate cleavage, regulates the structure and function of heparan sulfate proteoglycans, leading to disassembly of the extracellular matrix. The action of heparanase is involved in multiple regulatory events related, among other effects, to augmented bioavailability of growth factors and cytokines. Inhibitors of heparanase suppress tumor growth, angiogenesis and metastasis by modulating growth factor-mediated signaling, ECM barrier function and cell interactions in the tumor microenvironment. Therefore, targeting heparanase has potential implications for anti-tumor, anti-angiogenic and anti-inflammatory therapies. Current approaches for heparanase inhibition include development of chemically modified heparins, small molecule inhibitors and neutralizing antibodies. The available evidence supports the emerging utility of heparanase inhibition as a promising antitumor strategy, specifically in rational combination with other agents. The recent studies with compounds designed to block heparanase (e.g., modified heparins) provide a rational basis for their therapeutic application and optimization. [Copyright &y& Elsevier]
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- 2014
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7. Heparanase processing by lysosomal/endosomal protein preparation
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Cohen, Esti, Atzmon, Ruth, Vlodavsky, Israel, and Ilan, Neta
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- 2005
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8. Involvement of heparanase in atherosclerosis and other vessel wall pathologies.
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Vlodavsky, Israel, Blich, Miry, Li, Jin-Ping, Sanderson, Ralph D., and Ilan, Neta
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HEPARANASE , *ATHEROSCLEROSIS , *PATHOLOGY , *ENDOGLYCOSIDASES , *HEPARAN sulfate , *METASTASIS - Abstract
Abstract: Heparanase, the sole mammalian endoglycosidase degrading heparan sulfate, is causally involved in cancer metastasis, angiogenesis, inflammation and kidney dysfunction. Despite the wide occurrence and impact of heparan sulfate proteoglycans in vascular biology, the significance of heparanase in vessel wall disorders is underestimated. Blood vessels are highly active structures whose morphology rapidly adapts to maintain vascular function under altered systemic and local conditions. In some pathologies (restenosis, thrombosis, atherosclerosis) this normally beneficial adaptation may be detrimental to overall function. Enzymatic dependent and independent effects of heparanase on arterial structure mechanics and repair closely regulate arterial compliance and neointimal proliferation following endovascular stenting. Additionally, heparanase promotes thrombosis after vascular injury and contributes to a pro-coagulant state in human carotid atherosclerosis. Importantly, heparanase is closely associated with development and progression of atherosclerotic plaques, including stable to unstable plaque transition. Consequently, heparanase levels are markedly increased in the plasma of patients with acute myocardial infarction. Noteworthy, heparanase activates macrophages, resulting in marked induction of cytokine expression associated with plaque progression towards vulnerability. Together, heparanase emerges as a regulator of vulnerable lesion development and potential target for therapeutic intervention in atherosclerosis and related vessel wall complications. [Copyright &y& Elsevier]
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- 2013
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9. Sulfated Hexasaccharides Attenuate Metastasis by Inhibition of P-selectin and Heparanase.
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Borsig, Lubor, Vlodavsky, Israel, Ishai-Michaeli, Rivka, Torri, Giangiacomo, and Vismara, Elena
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SULFATES , *SACCHARIDES , *METASTASIS , *SELECTINS , *ENDOGLYCOSIDASES , *CANCER treatment - Abstract
Development of compounds that target both heparanase and selectins is emerging as a promising approach for cancer therapy. Selectins are vascular cell adhesion molecules that mediate tumor cell interactions with platelets, leukocytes, and the vascular endothelium. Heparanase is an endoglycosidase that degrades heparan sulfate in the tumor microenvironment, cell surfaces, and vessel wall. Acting together, these molecules facilitate tumor cell arrest, extravasation, and metastasis. Here, we report the preparation of novel semisynthetic sulfated tri mannose C-C-linked dimers (STMCs) endowed with heparanase and selectin inhibitory activity. The P-selectin specificity of the STMC was defined by the anomeric linkage of the C-C bond. This STMC hexasaccharide is an effective inhibitor of P-selectin in vivo. We show that selective inhibition of heparanase attenuates metastasis in B16-BL6 melanoma cells, expressing high levels of this endoglycosidase, but has no effect on the metastasis of MC-38 carcinoma cells that express little or no heparanase activity. P-selectin-specific STMC attenuated metastasis in both animal models, indicating that inhibition of tumor cell interaction with the vascular endothelium is critical for cancer dissemination. Thus, the small size, the stability of the C-C bond, and the chemically defined structure of the newly generated STMCs make them superior to heparin derivatives and signify STMCs as valuable candidates for further evaluation. [ABSTRACT FROM AUTHOR]
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- 2011
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10. Heparanase expression by Barrett's epithelium and during esophageal carcinoma progression.
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Brun, Rita, Naroditsky, Inna, Waterman, Matti, Ben-Izhak, Ofer, Groisman, Gabriel, Ilan, Neta, and Vlodavsky, Israel
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- 2009
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11. Heparanase upregulation by colonic epithelium in inflammatory bowel disease.
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Waterman, Matti, Ben-Izhak, Ofer, Eliakim, Rami, Groisman, Gabriel, Vlodavsky, Israel, and Ilan, Neta
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- 2007
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12. Characterization of Mechanisms Involved in Secretion of Active Heparanase.
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Shafat, Itay, Vlodavsky, Israel, and Ilan, Neta
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GLUCURONIDES , *EXTRACELLULAR matrix , *CANCER invasiveness , *NEOVASCULARIZATION , *INFLAMMATION , *AUTOIMMUNITY - Abstract
Heparanase is an endo-β-D-glucuronidase involved in extracellular matrix remodeling and degradation and implicated in tumor metastasis, angiogenesis, inflammation, and autoimmunity. The enzyme is synthesized as a latent 65-kDa protein and is processed in the lysosomal compartment to an active 58-kDa heterodimer, where it is stored in a stable form. In contrast, its heparan sulfate substrate is localized extracellularly, suggesting the existence of mechanisms that trigger heparanase secretion. Here we show that secretion of the active enzyme is mediated by the protein kinase A and C pathways. Moreover, secretion of active heparanase was observed upon cell stimulation with physiological concentrations of adenosine, ADP, and ATP, as well as by the noncleavable ATP analogue adenosine 5′-O-(thiotriphosphate). Indeed, heparanase secretion was noted upon cell stimulation with a specific P2Y1 receptor agonist and was inhibited by P2Y receptor antagonists. The kinetics of heparanase secretion resembled the secretion of cathepsin D, a lysosomal enzyme, indicating that the secreted heparanase is of lysosomal origin. We suggest that secretion of active heparanase is initiated by extracellular cues activating the protein kinase A and C signaling pathways. The secreted enzyme(s) then facilitate cell invasion associated with cancer metastasis, angiogenesis, and inflammation. [ABSTRACT FROM AUTHOR]
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- 2006
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13. Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence.
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Doviner, Victoria, Maly, Bella, Kaplan, Victoria, Gingis-Velitski, Svetlana, Ilan, Neta, Vlodavsky, Israel, and Sherman, Yoav
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- 2006
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14. A synthetic heparin-mimicking polyanionic compound inhibits central nervous system inflammation
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Irony-Tur-Sinai, Michal, Vlodavsky, Israel, Ben-Sasson, Shmuel A., Pinto, Florence, Sicsic, Camille, and Brenner, Talma
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CENTRAL nervous system diseases , *INFLAMMATION , *MULTIPLE sclerosis , *IMMUNOREGULATION - Abstract
The immunomodulating capacity of heparin led us to test the effect of the synthetic heparin-mimicking and low anticoagulant compound RG-13577 on the course of experimental autoimmune encephalomyelitis (EAE) and central nervous system (CNS) inflammation. EAE was induced in SJL mice by inoculation with whole mouse spinal cord homogenate. RG-13577, delivered intraperitoneally, inhibited the clinical signs of acute EAE and markedly ameliorated inflammation in the spinal cord, primarily by inhibiting heparanase activity in lymphocytes and astrocytes and thus impairing lymphocyte traffic. RG-13577 treatment was effective when started on day of disease induction or day 7 after induction. The low molecular weight heparin, enoxaparin, tested under the same conditions, exerted only a minor insignificant inhibitory effect. RG-13577 also inhibited the tyrosine phosphorylation of several proteins, particularly Erk1 and Erk2 of the MAP kinase signaling pathways associated with inflammation and cell proliferation. RG-13577 blocked the activity of sPLA2 and inhibited CNS PGE2 production both in vivo and in vitro. [Copyright &y& Elsevier]
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- 2003
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15. Human heparanase nuclear localization and enzymatic activity.
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Schubert, Shay Y., Ilan, Neta, Shushy, Moran, Ben-Izhak, Ofer, Vlodavsky, Israel, and Goldshmidt, Orit
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- 2004
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16. Heparanase: Multiple functions in inflammation, diabetes and atherosclerosis.
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Vlodavsky, Israel, Iozzo, Renato V., and Sanderson, Ralph D.
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- 2013
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17. Novel N-acetyl-Glycol-split heparin biotin-conjugates endowed with anti-heparanase activity.
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Esposito, Emiliano, Vlodavsky, Israel, Barash, Uri, Roscilli, Giuseppe, Milazzo, Ferdinando M., Giannini, Giuseppe, and Naggi, Annamaria
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HEPARIN , *HEPARANASE , *MOLECULAR weights , *MULTIPLE myeloma , *ANTINEOPLASTIC agents , *TARGETED drug delivery - Abstract
Heparanase is regarded as a promising target for anticancer drugs and Ronepastat is one of the most promising heparanase inhibitors insert in clinical study for Multiple Myeloma Therapy. To improve its pharmacokinetic/pharmacodynamic profile, as well to have an antidote able to neutralize its activity in case of over dosages or intolerance, a new class of its derivatives was obtained inserting non-carbohydrate moieties of different length between the polysaccharide chain and biotin or its derivatives. In vitro these novel derivatives maintain the anti-heparanase activity without induced toxicity. The newly synthesized compounds retained the ability to attenuate the growth of CAG myeloma tumors in mice with potency similar, or in one case even higher than that of the reference compound Roneparstat as well as inhibited metastatic dissemination (lung colonization) of murine B16-F10 melanoma cells in vivo. Image 1 • Heparanase is regarded as a promising target for anticancer drugs and Ronepastat is one of one of its most promising inhibitors. • A new class of biotinylated N-acetyl-gs-heparin have been synthetized through a linker of different functional groups. • Compounds were characterized by NMR and evaluation of molecular weight. • "in vitro" and "in vivo" tests showed that the chemical modifications introduced do not hinder their biological activity. [ABSTRACT FROM AUTHOR]
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- 2020
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18. Proteases and glycosidases on the surface of exosomes: Newly discovered mechanisms for extracellular remodeling.
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Sanderson, Ralph D., Bandari, Shyam K., and Vlodavsky, Israel
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EXOSOMES , *CYTOLOGY , *METALLOPROTEINASES , *INSULINASE , *NEURAMINIDASE , *EXTRACELLULAR space - Abstract
Abstract Emergence of the field of exosome biology has opened an exciting door to better understand communication between cells. These tiny nanovesicles act as potent regulators of biological function by delivering proteins, lipids and nucleic acids from the cell of origin to target cells. Recently, several enzymes including membrane-type 1 matrix metalloproteinase (MT1-MMP), insulin-degrading enzyme (IDE), sialidase and heparanase, among others, were localized on the surface of exosomes secreted by various cell types. These exosomal surface enzymes retain their activity and can degrade their natural substrates present within extracellular spaces. To date, enzymes on exosome surfaces have been associated with the mobilization of growth factors, degradation of extracellular matrix macromolecules and destruction of amyloid β plaques. This review focuses on the emerging role of exosomal surface enzymes and how this mechanism of remodeling within the extracellular space may regulate disease progression as related to cancer, inflammation and Alzheimer's disease. Highlights • Exosomes regulate cell communication by transferring proteins, lipids and nucleic acids between cells • New evidence demonstrates that enzymatically active proteases and glycosidases are present on the surface of some exosomes • These enzymes on exosome surfaces can degrade the ECM, liberate growth factors and alter cell adhesion and invasion • Enzymatic functions of exosomes have implications in the progression of cancer, inflammation and Alzheimer's disease [ABSTRACT FROM AUTHOR]
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- 2019
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19. Su2054 PG545, a Dual Heparanase and Angiogenesis Inhibitor, Induces a Potent Anti-Tumor Effect in APCMIN/+ Mice.
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Half, Elizabeth E., Gershovich, Katya, Blatt, Alexandra, Singh, Preeti, Zohar, Yaniv, Hammond, Edward, Vlodavsky, Israel, Ilan, Neta, and Chowers, Yehuda
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- 2016
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20. Tu1890 Involvement of Heparanase in the Pathogenesis of Acute Pancreatitis: Potential Therapeutic Target.
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Khamaysi, Iyad N., Singh, Preeti, Ilan, Neta, Vlodavsky, Israel, Hammond, Edward, Abu-Saleh, Niroz, Awad, Hoda, Chowers, Yehuda, and Abassi, Zaid
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- 2015
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21. Heparanase affects secretory granule homeostasis of murine mast cells through degrading heparin.
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Wang, Bo, Jia, Juan, Zhang, Xiao, Zcharia, Eyal, Vlodavsky, Israel, Pejler, Gunnar, and Li, Jin-Ping
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HEPARANASE ,SECRETORY granules ,HOMEOSTASIS ,MAST cell physiology ,HEPARIN - Abstract
Background Heparanase degradation of heparan sulfate plays important roles in a number of pathological processes, including inflammation. In vitro experiments show that heparanase is capable of degrading heparin, a polysaccharide present in mast cells (MCs), in which it has a key role in promoting the storage of secretory granule compounds. Objective We sought to investigate the functions of heparanase in MCs. Methods Primarily cultured fetal skin-derived mast cells (FSMCs) isolated from embryos and adult peritoneal MCs were analyzed for storage and release of granule molecules in response to MC activation. Results FSMCs from heparanase-overexpressing mice contained substantially shorter heparin chains and significantly less proteases than control cells. Conversely, FSMCs lacking heparanase contained heparin of larger size and more proteases than control cells. Correspondingly, heparanase-overexpressing adult MCs exhibited reduced release of heparin-bound proteases, a finding that could be attributed to spontaneous release of granular compounds. Heparanase was found to be upregulated in MCs on activation. Conclusion These findings reveal a novel function of heparanase in maintaining MC homeostasis through controlled degradation of heparin present in the MC secretory granules. [ABSTRACT FROM AUTHOR]
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- 2011
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22. Heparanase, heparin and the coagulation system in cancer progression
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Vlodavsky, Israel, Ilan, Neta, Nadir, Yona, Brenner, Benjamin, Katz, Ben-Zion, Naggi, Annamaria, Torri, Giangiacomo, Casu, Benito, and Sasisekharan, Ram
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ANTICOAGULANTS , *POLYSACCHARIDES , *METASTASIS , *CANCER invasiveness - Abstract
Abstract: Heparanase is an endoglycosidase which cleaves heparan sulfate (HS) and hence participates in degradation and remodeling of the extracellular matrix (ECM). The enzyme also releases angiogenic factors from the ECM and thereby induces an angiogenic response in vivo. Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an accelerated growth and invasive phenotype in experimental animals. In contrast, heparanase gene silencing is associated with a marked inhibition of tumor progression. Heparanase upregulation correlates with increased tumor vascularity and poor postoperative survival of cancer patients. Studies on relationships between structure and the heparanase-inhibiting activity of nonanticogulant heparins systematically differing in their O-sulfation patterns, degrees of N-acetylation, and glycol-splitting of nonsulfated uronic acid residues, have permitted to select effective inhibitors of the enzymatic activity of heparanase. N-acetylated, glycol-split heparins emerged as highly effective and specific inhibitors of heparanase and tumor growth and metastasis. Several observations support the involvement of heparanase in haemostasis. A marked induction of tissue factor (TF) was noted in response to heparanase over-expression in tumor-derived cell lines and heparanase over-expressing transgenic mice. A direct correlation was also found between heparanase and TF expression levels in leukemia patients. TF induction was even more pronounced upon exogenous addition of heparanase to primary endothelial cells that do not normally express TF, and this induction was associated with enhanced coagulation. These and other results indicate that pro-heparanase is rapidly tethered on cell surfaces, partially depending on cell surface heparan sulfate, generating a local procoagulant effect. In addition, pro-heparanase can reverse the anti-coagulant effect of unfractionated heparin and the Factor Xa inhibitory activity of low molecular weight heparin (LMWH). These effects were also demonstrated in plasma derived from patients treated with LMWH. The pro-coagulant effects of pro-heparanase were also exerted by a peptide corresponding to its major functional heparin-binding domain. Heparanase pro-coagulant activities suggest its possible role as a natural regulator of heparinoid anti-coagulant activities, and point to a possible use of this molecule or its heparin binding domain as antidote for heparinoid therapies. [Copyright &y& Elsevier]
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- 2007
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23. Heparanase 2 (Hpa2) attenuates the growth of human sarcoma.
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Knani, Ibrahim, Yanku, Yifat, Gross-Cohen, Miriam, Ilan, Neta, and Vlodavsky, Israel
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HEPARANASE , *CELL receptors , *TUMOR growth , *HUMAN growth , *SARCOMA , *FOLLICULAR dendritic cells - Abstract
• Hpa2 attenuates sarcoma tumor growth. • Tumor growth inhibition by Hpa2 involves increased stress conditions (ER stress, hypoxia, JNK phosphorylation), induction of p63, and attenuation of stemness. • In leiomyosarcoma biopsies, nuclear localization of Hpa2 was associated with low stage tumors. This finding opens a new direction in Hpa2 research. The pro-tumorigenic properties of heparanase are well documented and established. In contrast, the role of heparanase 2 (Hpa2), a close homolog of heparanase, in cancer is not entirely clear. In carcinomas, Hpa2 is thought to attenuate tumor growth, possibly by inhibiting heparanase enzymatic activity. Here, we examine the role of Hpa2 in sarcoma, a group of rare tumors of mesenchymal origin, accounting for approximately 1% of all malignant tumors. Consistently, we found that overexpression of Hpa2 attenuates tumor growth while Hpa2 gene silencing results in bigger tumors. Mechanistically, attenuation of tumor growth by Hpa2 was associated with increased tumor stress conditions, involving ER stress, hypoxia, and JNK phosphorylation, leading to increased apoptotic cell death. In addition, overexpression of Hpa2 induces the expression of the p53 family member, p63 which, in sarcoma, functions to attenuate tumor growth. Moreover, we show that Hpa2 profoundly reduces stem cell characteristics of the sarcoma cells (stemness), most evident by failure of Hpa2 cells to grow as spheroids typical of cancer stem cells. Likewise, expression of CD44, a well-established cancer stem cell marker, was prominently decreased in Hpa2 cells. CD44 is also a cell surface receptor for hyaluronic acid (HA), a nonsulfated glycosaminoglycan that is enriched in connective tissues. Reduced expression of CD44 by Hpa2 may thus represent impaired cross-talk between Hpa2 and the extracellular matrix. Clinically, we found that Hpa2 is expressed by leiomyosarcoma tumor biopsies. Interestingly, nuclear localization of Hpa2 was associated with low-stage tumors. This finding opens a new direction in Hpa2 research. [ABSTRACT FROM AUTHOR]
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- 2022
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24. Induction of heparanase 2 (Hpa2) expression by stress is mediated by ATF3.
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Knani, Ibrahim, Singh, Preeti, Gross-Cohen, Miriam, Aviram, Sharon, Ilan, Neta, Sanderson, Ralph D, Aronheim, Ami, and Vlodavsky, Israel
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HEAT shock proteins , *HEPARANASE , *HEPARAN sulfate proteoglycans , *HEPARAN sulfate , *GENETIC regulation , *TRANSCRIPTION factors - Abstract
• Expression of Hpa2 is markedly induced by stress. • Hpa2 induction by stress is mediated by ATF3. • High levels of Hpa2 and ATF3 are associated with longer survival of cancer patients. Activity of heparanase, endoglycosidase that cleaves heparan sulfate side chains in heparan sulfate proteoglycans, is highly implicated in tumor progression and metastasis. Heparanase inhibitors are therefore being evaluated clinically as anti-cancer therapeutics. Heparanase 2 (Hpa2) is a close homolog of heparanase that lacks HS-degrading activity and functions as an endogenous inhibitor of heparanase. As a result, Hpa2 appears to attenuate tumor growth but mechanisms that regulate Hpa2 expression and determine the ratio between heparanase and Hpa2 are largely unknown. We have recently reported that the expression of Hpa2 is induced by endoplasmic reticulum (ER) and proteotoxic stresses, but the mechanism(s) underlying Hpa2 gene regulation was obscure. Here we expand the notion that Hpa2 is regulated by conditions of stress. We report that while ER and hypoxia, each alone, resulted in a 3-7 fold increase in Hpa2 expression, combining ER stress and hypoxia resulted in a noticeable, over 40-fold increase in Hpa2 expression. A prominent induction of Hpa2 expression was also quantified in cells exposed to heat shock, proteotoxic stress, lysosomal stress, and chemotherapy (cisplatin), strongly implying that Hpa2 is regulated by conditions of stress. Furthermore, analyses of the Hpa2 gene promoter led to the identification of activating-transcription-factor 3 (ATF3) as a transcription factor that mediates Hpa2 induction by stress, thus revealing, for the first time, a molecular mechanism that underlies Hpa2 gene regulation. Induction of Hpa2 and ATF3 by conditions of stress that often accompany the rapid expansion of tumors is likely translated to improved survival of cancer patients. [ABSTRACT FROM AUTHOR]
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- 2022
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25. Characterization of Heparanase-induced Phosphatidylinositol a3-Kinase-AKT Activation and Its Integrin Dependence.
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Riaz, Anjum, Ilan, Neta, Vlodavsky, Israel, Jin-Ping Li, and Johansson, Staffan
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HEPARANASE , *PHOSPHATIDYLINOSITOL 3-kinases , *INTEGRINS , *PHOSPHORYLATION , *BIOCHEMISTRY - Abstract
Heparanase functions as a heparan sulfate-degrading enzyme and as a ligand for an unidentified signaling receptor(s). Here, several reactions involved in the activation of the PI3K-AKT pathway by latent heparanase were characterized. Protein suppression using specific siRNAs revealed that heparanase-induced phosphorylation of AKT at Ser-473 was RICTOR-mTOR-dependent, whereas ILK and PAK1/2 were dispensable. p110α was the PI3K catalytic isoform preferred by heparanase for AKT activation and cell proliferation because the p110α inhibitor YM024 blocked these processes. Heparanase-induced AKT phosphorylation was low in mouse embryonic fibroblast cells expressing a RAS interaction-defective p110α compared with wild type cells, indicating that RAS has an important role in the PI3K-AKT activation. The response to heparanase was also inefficient in suspension cultures of several cell lines, suggesting a requirement of integrins in this pathway. Adhesion via either αVβ3 or α5β1 promoted heparanase-induced AKT phosphorylation, and a stronger effect was seen when both integrins were engaged. Simultaneous inhibition of FAK and PYK2 using a chemical inhibitor, or suppression of their expression, inhibited heparanase-induced AKT activation and cell proliferation. Stimulation of cells with heparanase enhanced their resistance against oxidative stress- or growth factor starvation-induced apoptosis. These results demonstrate that there is an intimate cross-talk between the heparanase receptor(s) and integrins during induction of the prosurvival PI3K-AKT pathway by heparanase. [ABSTRACT FROM AUTHOR]
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- 2013
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26. Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis
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Ilan, Neta, Elkin, Michael, and Vlodavsky, Israel
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CELL nuclei , *NEOVASCULARIZATION , *BLOOD-vessel development , *METASTASIS - Abstract
Abstract: Heparanase is an endoglycosidase which cleaves heparan sulfate (HS) and hence participates in degradation and remodeling of the extracellular matrix (ECM). Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an invasive phenotype in experimental animals. The enzyme also releases angiogenic factors from the ECM and thereby induces an angiogenic response in vivo. Heparanase upregulation correlates with increased tumor vascularity and poor post-operative survival of cancer patients. Heparanase is synthesized as a 65kDa inactive precursor that undergoes proteolytic cleavage, yielding 8 and 50kDa protein subunits that heterodimerize to form an active enzyme. Human heparanase is localized primarily within late endosomes and lysosomes and occasionally on the cell surface and within the cell nucleus. Transcriptional activity of the heparanase promoter is stimulated by demethylation, early growth response 1 (EGR1) transcription factor, estrogen, inflammatory cytokines and inactivation of p53. N-acetylated glycol-split species of heparin as well as siRNA heparanase gene silencing inhibit tumor metastasis and angiogenesis in experimental models. These observations and the unexpected identification of a single functional heparanase, suggest that the enzyme is a promising target for anti-cancer and anti-inflammatory drug development. Heparanase exhibits also non-enzymatic activities, independent of its involvement in ECM degradation and changes in the extracellular microenvironment. For example, cell surface expression of heparanase elicits a firm cell adhesion, reflecting an involvement in cell–ECM interaction. Heparanase enhances Akt signaling and stimulates PI3K- and p38-dependent endothelial cell migration and invasion. It also promotes VEGF expression via the Src pathway. The enzyme may thus activate endothelial cells and elicits angiogenic and survival responses. Studies with heparanase over-expressing transgenic mice revealed that the enzyme functions in normal processes involving cell mobilization, HS turnover, tissue vascularization and remodeling. In this review, we summarize the current status of heparanase research, emphasizing molecular and cellular aspects of the enzyme, including its mode of processing and activation, control of heparanase gene expression, enzymatic and non-enzymatic functions, and causal involvement in cancer metastasis and angiogenesis. We also discuss clinical aspects and trategies for the development of heparanase inhibitors. [Copyright &y& Elsevier]
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- 2006
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27. Extracellular matrix-based cancer targeting.
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Karamanos, Nikos K., Piperigkou, Zoi, Passi, Alberto, Götte, Martin, Rousselle, Patricia, and Vlodavsky, Israel
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EXTRACELLULAR vesicles , *EXTRACELLULAR enzymes , *EXTRACELLULAR matrix , *METASTASIS , *THERAPEUTICS , *CHONDROITIN sulfate proteoglycan , *PROTEOGLYCANS - Abstract
Tumor extracellular matrix (ECM) operates in a coordinated mode with cancer and stroma cells to evoke the multistep process of metastatic potential. The remodeled tumor-associated matrix provides a point for direct or complementary therapeutic targeting. Here, we cover and critically address the importance of ECM networks and their macromolecules in cancer. We focus on the roles of key structural and functional ECM components, and their degradation enzymes and extracellular vesicles, aiming at improving our understanding of the mechanisms contributing to tumor initiation, growth, and dissemination, and discuss potential new approaches for ECM-based therapeutic targeting and diagnosis. Modified extracellular matrix in the tumor microenvironment dictates cancer cell properties, metastatic potential, and formation of premetastatic niches. Proteoglycans and hyaluronan in provisional matrix modulate the bioavailability of matrix-bound effectors, cancer cell signaling, angiogenesis, and tumor spread. The outside-in interactions of integrins with tumor matrix, the migratory tracks for cancer cells created by fibrillar collagen fiber alignment, and the intense trafficking of extracellular vesicles, impact tumor progression. Proteolytic (matrix metalloproteinases and cathepsins) and glycosidic (heparanase and hyaluronidases) enzymes mediate protumorigenic interactions and stemness, associated with therapeutic resistance. Heparanase promotes the aggressive phenotype of cancer, while heparanase-2 functions as a tumor suppressor. Interference with exosome biogenesis, miRNAs functions, provisional matrix and premetastatic niche formation, may drive future cancer therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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28. Role of heparanase 2 (Hpa2) in gastric cancer.
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Liu, Jingjing, Knani, Ibrahim, Gross-Cohen, Miriam, Hu, Jiaxi, Wang, Sumin, Tang, Li, Ilan, Neta, Yang, Shiming, and Vlodavsky, Israel
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HEPARANASE , *STOMACH cancer , *PROTEIN kinases , *HEPARAN sulfate , *SUPPLY & demand , *GENETIC regulation - Abstract
We report that gastric cancer patients exhibiting high levels of heparanase 2 (Hpa2) survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to overexpress Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. These beneficial effects were found to associate with increased phosphorylation of AMP-activated protein kinase (AMPK) that play an instrumental role in cell metabolism and is situated at the center of a tumor suppressor network. We also found that MG132, an inhibitor of the proteasome that results in proteotoxic stress, prominently enhances Hpa2 expression. Notably, Hpa2 induction by MG132 appeared to be mediated by AMPK, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, possibly leading to attenuation of gastric tumorigenesis. Heparanase is highly implicated in tumor metastasis due to its capacity to cleave heparan sulfate and, consequently, remodel the extracellular matrix underlying epithelial and endothelial cells. In striking contrast, only little attention was given to its close homolog, heparanase 2 (Hpa2), possibly because it lacks heparan sulfate-degrading activity typical of heparanase. We subjected sections of gastric carcinoma to immunostaining and correlated Hpa2 immunoreactivity with clinical records, including tumor grade, stage and patients' status. We over-expressed Hpa2 in gastric carcinoma cell lines and examined their tumorigenic properties in vitro and in vivo. We also evaluated the expression of Hpa2 by gastric carcinoma cells following inhibition of the proteasome, leading to proteotoxic stress, and the resulting signaling responsible for Hpa2 gene regulation. Here, we report that gastric cancer patients exhibiting high levels of Hpa2 survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to over-express Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. This was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), a kinase that is situated at the center of a tumor suppressor network. We also found that MG132, an inhibitor of the proteasome that results in proteotoxic stress, prominently enhances Hpa2 expression. Notably, Hpa2 induction by MG132 appeared to be mediated by AMPK, and AMPK was found to induce the expression of Hpa2, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, leading to attenuation of gastric tumorigenesis. These results indicate that high levels of Hpa2 in some tumors are due to stress conditions that tumors often experience due to their high rates of cell proliferation and high metabolic demands. This increase in Hpa2 levels by the stressed tumors appears critically important for patient outcomes. [ABSTRACT FROM AUTHOR]
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- 2021
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29. Heparanase 2 (Hpa2) attenuates tumor growth by inducing Sox2 expression.
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Gross-Cohen, Miriam, Yanku, Yifat, Kessler, Ofra, Barash, Uri, Boyango, Ilanit, Cid-Arregui, Angel, Neufeld, Gera, Ilan, Neta, and Vlodavsky, Israel
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TUMOR growth , *KERATIN , *HEPARANASE , *HEAD & neck cancer , *TUMOR suppressor genes , *HEAD tumors , *NECK tumors - Abstract
• We report that Hpa2 attenuates head and neck tumor growth, associating with induction of Sox2 expression. • We provide evidence that silencing of Sox2 resulted in bigger tumors endowed with reduced cytokeratin levels, whereas smaller tumors were developed by cells overexpressing Sox2, suggesting that in head and neck carcinoma, Sox2 functions to inhibit tumor growth. • Hpa2-null cells engineered by Crispr/Cas 9, produced bigger tumors vs control cells, and rescue of Hpa2 attenuated tumor growth. • These results strongly imply that Hpa2 functions as a tumor suppressor in head and neck cancer, involving Sox2 upregulation mediated, in part, by the high-affinity interaction of Hpa2 with heparan sulfate. The pro-tumorigenic properties of heparanase are well documented, and heparanase inhibitors are being evaluated clinically as anti-cancer therapeutics. In contrast, the role of heparanase 2 (Hpa2), a close homolog of heparanase, in cancer is largely unknown. Previously, we have reported that in head and neck cancer, high levels of Hpa2 are associated with prolonged patient survival and decreased tumor cell dissemination to regional lymph nodes, suggesting that Hpa2 functions to restrain tumorigenesis. Also, patients with high levels of Hpa2 were diagnosed as low grade and exhibited increased expression of cytokeratins, an indication that Hpa2 promotes or maintains epithelial cell differentiation and identity. To reveal the molecular mechanism underlying the tumor suppressor properties of Hpa2, and its ability to induce the expression of cytokeratin, we employed overexpression as well as gene editing (Crispr) approaches, combined with gene array and RNAseq methodologies. At the top of the list of many genes found to be affected by Hpa2 was Sox2. Here we provide evidence that silencing of Sox2 resulted in bigger tumors endowed with reduced cytokeratin levels, whereas smaller tumors were developed by cells overexpressing Sox2, suggesting that in head and neck carcinoma, Sox2 functions to inhibit tumor growth. Notably, Hpa2-null cells engineered by Crispr/Cas 9, produced bigger tumors vs control cells, and rescue of Hpa2 attenuated tumor growth. These results strongly imply that Hpa2 functions as a tumor suppressor in head and neck cancer, involving Sox2 upregulation mediated, in part, by the high-affinity interaction of Hpa2 with heparan sulfate. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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30. Heparanase 2 (Hpa2) attenuates the growth of pancreatic carcinoma.
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Kayal, Yasmin, Singh, Preeti, Naroditsky, Inna, Ilan, Neta, and Vlodavsky, Israel
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HEPARANASE , *PANCREATIC tumors , *PANCREATIC cancer , *TUMOR growth , *CARCINOMA , *PSYCHOLOGICAL feedback , *ENDOPLASMIC reticulum - Abstract
• Our findings indicate that Hpa2 attenuates pancreatic tumor growth and highlight a feedback mechanism by which Hpa2 enhances ER stress which, in turn, induces Hpa2 expression. This results in consistent and severe ER stress, leading to increased apoptotic cell death and attenuated tumor growth. Thus, compounds designed to elicit ER stress may turn beneficial therapeutics in pancreatic cancer. • Hpa2 attenuates pancreatic tumor growth by exerting a feedback mechanism where Hpa2 enhances ER stress that, in turn, induces Hpa2 expression. • This results in consistent and severe ER stress, leading to increased apoptotic cell death and attenuated tumor growth. • Compounds designed to elicit ER stress may turn beneficial therapeutics in pancreatic cancer. While the pro-tumorigenic properties of the ECM-degrading heparanase enzyme are well documented, the role of its close homolog, heparanase 2 (Hpa2), in cancer is largely unknown. We examined the role of Hpa2 in pancreatic cancer, a malignancy characterized by a dense fibrotic ECM associated with poor response to treatment and bad prognosis. We show that pancreatic ductal adenocarcinoma (PDAC) patients that exhibit high levels of Hpa2 survive longer than patients with low levels of Hpa2. Strikingly, overexpression of Hpa2 in pancreatic carcinoma cells resulted in a most prominent decrease in the growth of tumors implanted orthotopically and intraperitoneally, whereas Hpa2 silencing resulted in bigger tumors. We further found that Hpa2 enhances endoplasmic reticulum (ER) stress response and renders cells more sensitive to external stress, associating with increased apoptosis. Interestingly, we observed that ER stress induces the expression of Hpa2, thus establishing a feedback loop by which Hpa2 enhances ER stress that, in turn, induces Hpa2 expression. This leads to increased apoptosis and attenuated tumor growth. Altogether, Hpa2 emerges as a powerful tumor suppressor in pancreatic cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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31. Significance of host heparanase in promoting tumor growth and metastasis.
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Zhang, Gan-Lin, Gutter-Kapon, Lilach, Ilan, Neta, Batool, Tahira, Singh, Kailash, Digre, Andreas, Luo, Zhengkang, Sandler, Stellan, Shaked, Yuval, Sanderson, Ralph D., Wang, Xiao-Min, Li, Jin-Ping, and Vlodavsky, Israel
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HEPARANASE , *TUMOR growth , *METASTASIS , *SURVIVAL analysis (Biometry) , *HEPARAN sulfate , *CELL migration inhibition - Abstract
• Mice overexpressing heparanase (Hpa-tg) were applied to reveal the contribution of host heparanase to tumor growth and metastasis. • Xenograft tumors transplanted in Hpa-tg mice exhibited accelerated tumor progression and shorter survival time. • Accelerated tumor growth was attributed to increased levels of pro-tumorigenic factors in the plasma and bone marrow of the Hpa-tg mice. • Host heparanase impaired the overall anti-tumor activity of immune T-cell subpopulations. • Heparanase mediates the pro-tumorigenic crosstalk between the tumor, tumor microenvironment, immune cells and host factors. Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth and metastasis. We have utilized mice over-expressing (Hpa-tg) heparanase to reveal the role of host heparanase in tumor initiation, growth and metastasis. While in wild type mice tumor development in response to DMBA carcinogenesis was restricted to the mammary gland, Hpa-tg mice developed tumors also in their lungs and liver, associating with reduced survival of the tumor-bearing mice. Consistently, xenograft tumors (lymphoma, melanoma, lung carcinoma, pancreatic carcinoma) transplanted in Hpa-tg mice exhibited accelerated tumor growth and shorter survival of the tumor-bearing mice compared with wild type mice. Hpa-tg mice were also more prone to the development of metastases following intravenous or subcutaneous injection of tumor cells. In some models, the growth advantage was associated with infiltration of heparanase-high host cells into the tumors. However, in other models, heparanase-high host cells were not detected in the primary tumor, implying that the growth advantage in Hpa-tg mice is due to systemic factors. Indeed, we found that plasma from Hpa-tg mice enhanced tumor cell migration and invasion attributed to increased levels of pro-tumorigenic factors (i.e., RANKL, SPARC, MIP-2) in the plasma of Hpa-Tg vs. wild type mice. Furthermore, tumor aggressiveness and short survival time were demonstrated in wild type mice transplanted with bone marrow derived from Hpa-tg but not wild type mice. These results were attributed, among other factors, to upregulation of pro-tumorigenic (i.e., IL35+) and downregulation of anti-tumorigenic (i.e., IFN-γ+) T-cell subpopulations in the spleen, lymph nodes and blood of Hpa-tg vs. wild type mice and their increased infiltration into the primary tumor. Collectively, our results emphasize the significance of host heparanase in mediating the pro-tumorigenic and pro-metastatic interactions between the tumor cells and the host tumor microenvironment, immune cells and systemic factors. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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32. The heparanase inhibitor PG545 is a potent anti-lymphoma drug: Mode of action.
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Weissmann, Marina, Bhattacharya, Udayan, Feld, Sari, Hammond, Edward, Ilan, Neta, and Vlodavsky, Israel
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HEPARANASE , *HEPARAN sulfate , *CELL death , *DOSAGE forms of drugs , *DRUG development , *AUTOPHAGY - Abstract
Abstract It is now well recognized that heparanase, an endo -β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, promotes tumorigenesis by diverse mechanisms. Compelling evidence strongly implies that heparanase is a viable target for cancer therapy, thus encouraging the development of heparanase inhibitors as anti-cancer therapeutics. Here, we examined the efficacy and mode of action of PG545, an HS-mimetic heparanase inhibitor, in human lymphoma. We found that PG545 exhibits a strong anti-lymphoma effect, eliciting lymphoma cell apoptosis. Notably, this anti-lymphoma effect involves ER stress response that was accompanied by increased autophagy. The persistent ER stress evoked by PG545 is held responsible for cell apoptosis because apoptotic cell death was attenuated by an inhibitor of PERK, a molecular effector of ER stress. Importantly, PG545 had no such apoptotic effect on naïve splenocytes, further encouraging the development of this compound as anti-lymphoma drug. Surprisingly, we found that PG545 also elicits apoptosis in lymphoma cells that are devoid of heparanase activity (i.e., Raji), indicating that the drug also exerts heparanase-independent function(s) that together underlie the high potency of PG545 in preclinical cancer models. Highlights • Compelling evidence implies that heparanase is a viable target for cancer therapy. • We examined the mode of action of PG545, an HS-mimetic heparanase inhibitor. • PG545 exhibits a strong anti-lymphoma effect, eliciting lymphoma cell apoptosis. • This anti-lymphoma effect involves ER stress response accompanied by increased autophagy. • PG545 has no such effects on naïve splenocytes, supporting its development as anti-lymphoma drug. • PG545 also elicits apoptosis in lymphoma cells that are devoid of heparanase activity. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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33. Targeting heparanase to the mammary epithelium enhances mammary gland development and promotes tumor growth and metastasis.
- Author
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Boyango, Ilanit, Barash, Uri, Fux, Liat, Naroditsky, Inna, Ilan, Neta, and Vlodavsky, Israel
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HEPARANASE , *EPITHELIUM , *DEVELOPMENT of mammary glands , *METASTASIS , *HEPARAN sulfate proteoglycans , *EXTRACELLULAR matrix proteins - Abstract
Heparanase is an endoglucuronidase that uniquely cleaves the heparan sulfate side chains of heparan sulfate proteoglycans. This activity ultimately alters the structural integrity of the ECM and basement membrane that becomes more prone to cellular invasion by metastatic cancer cells and cells of the immune system. In addition, enzymatically inactive heparanase was found to facilitate the proliferation and survival of cancer cells by activation of signaling molecules such as Akt, Src, signal transducer and activation of transcription (Stat), and epidermal growth factor receptor. This function is thought to be executed by the C-terminal domain of heparanase (8c), because over expression of this domain in cancer cells accelerated signaling cascades and tumor growth. We have used the regulatory elements of the mouse mammary tumor virus (MMTV) to direct the expression heparanase and the C-domain (8c) to the mammary gland epithelium of transgenic mice. Here, we report that mammary gland branching morphogenesis is increased in MMTV-heparanase and MMTV-8c mice, associating with increased Akt, Stat5 and Src phosphorylation. Furthermore, we found that the growth of tumors generated by mouse breast cancer cells and the resulting lung metastases are enhanced in MMTV-heparanase mice, thus supporting the notion that heparanase contributed by the tumor microenvironment (i.e., normal mammary epithelium) plays a decisive role in tumorigenesis. Remarkably, MMTV-8c mice develop spontaneous tumors in their mammary and salivary glands. Although this occurs at low rates and requires long latency, it demonstrates decisively the pro-tumorigenic capacity of heparanase signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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34. Chemotherapy induces secretion of exosomes loaded with heparanase that degrades extracellular matrix and impacts tumor and host cell behavior.
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Bandari, Shyam K., Purushothaman, Anurag, Ramani, Vishnu C., Brinkley, Garrett J., Chandrashekar, Darshan S., Varambally, Sooryanarayana, Mobley, James A., Zhang, Yi, Brown, Elizabeth E., Vlodavsky, Israel, and Sanderson, Ralph D.
- Subjects
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EXOSOMES , *HEPARANASE , *EXTRACELLULAR matrix proteins , *CANCER chemotherapy , *CANCER cell proliferation , *METASTASIS - Abstract
The heparan sulfate-degrading enzyme heparanase promotes the progression of many cancers by driving tumor cell proliferation, metastasis and angiogenesis. Heparanase accomplishes this via multiple mechanisms including its recently described effect on enhancing biogenesis of tumor exosomes. Because we recently discovered that heparanase expression is upregulated in myeloma cells that survive chemotherapy, we were prompted to investigate the impact of anti-myeloma drugs on exosome biogenesis. When myeloma cells were exposed to the commonly utilized anti-myeloma drugs bortezomib, carfilzomib or melphalan, exosome secretion by the cells was dramatically enhanced. These chemotherapy-induced exosomes (chemoexosomes) have a proteome profile distinct from cells not exposed to drug including a dramatic elevation in the level of heparanase present as exosome cargo. The chemoexosome heparanase was not found inside the chemoexosome, but was present on the exosome surface where it was capable of degrading heparan sulfate embedded within an extracellular matrix. When exposed to myeloma cells, chemoexosomes transferred their heparanase cargo to those cells, enhancing their heparan sulfate degrading activity and leading to activation of ERK signaling and an increase in shedding of the syndecan-1 proteoglycan. Exposure of chemoexosomes to macrophages enhanced their secretion of TNF-α, an important myeloma growth factor. Moreover, chemoexosomes stimulated macrophage migration and this effect was blocked by H1023, a monoclonal antibody that inhibits heparanase enzymatic activity. These data suggest that anti-myeloma therapy ignites a burst of exosomes having a high level of heparanase that remodels extracellular matrix and alters tumor and host cell behaviors that likely contribute to chemoresistance and eventual patient relapse. Summary We find that anti-myeloma chemotherapy dramatically stimulates secretion of exosomes and alters exosome composition. Exosomes secreted during therapy contain high levels of heparanase on their surface that can degrade ECM and also can be transferred to both tumor and host cells, altering their behavior in ways that may enhance tumor survival and progression. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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35. Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis.
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Oskarsson, Marie E., Singh, Kailash, Jian Wang, Vlodavsky, Israel, Jin-ping Li, and Westermark, Gunilla T.
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HEPARAN sulfate proteoglycans , *AMYLOID , *TYPE 2 diabetes , *POLYPEPTIDES , *HEPARANASE , *APOPTOSIS , *CASPASES - Abstract
Deposition of β cell toxic islet amyloid is a cardinal finding in type 2 diabetes. In addition to the main amyloid component islet amyloid polypeptide (IAPP), heparan sulfate proteoglycan is constantly present in the amyloid deposit. Heparan sulfate (HS) side chains bind to IAPP, inducing conformational changes of the IAPP structure and an acceleration of fibril formation. We generated a double-transgenic mouse strain (hpa-hIAPP) that overexpresses human heparanase and human IAPP but is deficient of endogenous mouse IAPP. Culture of hpa-hIAPP islets in 20 mM glucose resulted in less amyloid formation compared with the amyloid load developed in cultured islets isolated from littermates expressing human IAPP only. A similar reduction of amyloid was achieved when human islets were cultured in the presence of heparin fragments. Furthermore, we usedCHOcells and the mutant CHO pgsD-677 cell line (deficient in HS synthesis) to explore the effect of cellular HS on IAPP-induced cytotoxicity. Seeding of IAPP aggregation on CHO cells resulted in caspase-3 activation and apoptosis that could be prevented by inhibition of caspase-8. No IAPP-induced apoptosis was seen in HS-deficient CHO pgsD-677 cells. These results suggest that β cell death caused by extracellular IAPP requires membrane-bound HS. The interaction between HS and IAPP or the subsequent effects represent a possible therapeutic target whose blockage can lead to a prolonged survival of β cells. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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36. Overexpression of Heparanase Lowers the Amyloid Burden in Amyloid-β Precursor Protein Transgenic Mice.
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Jendresen, Charlotte B., Hao Cui, Xiao Zhang, Vlodavsky, Israel, Nilsson, Lars N. G., and Jin-Ping Li
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HEPARAN sulfate , *HEPARAN sulfate proteoglycans , *PROTEOGLYCANS , *GLYCOSAMINOGLYCANS , *AMYLOID beta-protein precursor , *TRANSGENIC mice - Abstract
Heparan sulfate (HS) and HS proteoglycans (HSPGs) colocalize with amyloid-β (Aβ) deposits in Alzheimer disease brain and in Aβ precursor protein (AβPP) transgenic mouse models. Heparanase is an endoglycosidase that specifically degrades the unbranched glycosaminoglycan side chains of HSPGs. The aim of this study was to test the hypothesis that HS and HSPGs are active participators of Aβ pathogenesisin vivo. We therefore generated a double-transgenic mouse model overexpressing both human heparanase and human AβPP harboring the Swedish mutation (tgHpa*Swe). Overexpression of heparanase did not affect AβPP processing because the steady-state levels of Aβ1-40, Aβ1-42, and soluble AβPP β were the same in 2- to 3-month-old double-transgenic tgHpa*Swe and single-transgenic tgSwe mice. In contrast, the Congo red-positive amyloid burden was significantly lower in 15-month-old tgHpa*Swe brain than in tgSwe brain. Likewise, the Aβ burden, measured by Aβx-40 and Aβx-42 immunohistochemistry, was reduced significantly in tgHpa*Swe brain. The intensity of HS-stained plaques correlated with the Aβx-42 burden and was reduced in tgHpa*Swe mice. Moreover, the HS-like molecule heparin facilitated Aβ1-42-aggregation in an in vitro Thioflavin T assay. The findings suggest that HSPGs contribute to amyloid deposition in tgSwe mice by increasing Aβ fibril formation because heparanase-induced fragmentation of HS led to a reduced amyloid burden. Therefore, drugs interfering with Aβ-HSPG interactions might be a potential strategy for Alzheimer disease treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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37. Heparanase Regulates Secretion, Composition, and Function of Tumor Cell-derived Exosomes.
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Thompson, Camilla A., Purushothaman, Anurag, Ramani, Vishnu C., Vlodavsky, Israel, and Sanderson, Ralph D.
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EXOSOMES , *PHENOTYPES , *CANCER cells , *HEPARANASE , *BREAST cancer , *EXTRACELLULAR matrix - Abstract
Emerging evidence indicates that exosomes play a key role in tumor-host cross-talk and that exosome secretion, composition, and functional capacity are altered as tumors progress to an aggressive phenotype. However, little is known regarding the mechanisms that regulate these changes. Heparanase is an enzyme whose expression is up-regulated as tumors become more aggressive and is associated with enhanced tumor growth, angiogenesis, and metastasis. We have discovered that in human cancer cells (myeloma, lymphoblastoid, and breast cancer), when expression of heparanase is enhanced or when tumor cells are exposed to exogenous heparanase, exosome secretion is dramatically increased. Heparanase enzyme activity is required for robust enhancement of exosome secretion because enzymatically inactive forms of heparanase, even when present in high amounts, do not dramatically increase exosome secretion. Heparanase also impacts exosome protein cargo as reflected by higher levels of syndecan-1, VEGF, and hepatocyte growth factor in exosomes secreted by heparanase-high expressing cells as compared with heparanase-low expressing cells. In functional assays, exosomes from heparanase-high cells stimulated spreading of tumor cells on fibronectin and invasion of endothelial cells through extracellular matrix better than did exosomes secreted by heparanase-low cells. These studies reveal that heparanase helps drive exosome secretion, alters exosome composition, and facilitates production of exosomes that impact both tumor and host cell behavior, thereby promoting tumor progression. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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38. Heparanase Regulates Thrombosis in Vascular Injury and Stent-Induced Flow Disturbance
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Baker, Aaron B., Gibson, William J., Kolachalama, Vijaya B., Golomb, Mordechai, Indolfi, Laura, Spruell, Christopher, Zcharia, Eyal, Vlodavsky, Israel, and Edelman, Elazer R.
- Subjects
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THROMBOSIS , *BLOOD vessels , *WOUNDS & injuries , *SURGICAL stents , *BLOOD flow , *HEPARIN , *HEPARAN sulfate , *LABORATORY mice - Abstract
Objectives: The purpose of this study was to examine the role of heparanase in controlling thrombosis following vascular injury or endovascular stenting. Background: The use of endovascular stents are a common clinical intervention for the treatment of arteries occluded due to vascular disease. Both heparin and heparan sulfate are known to be potent inhibitors of thrombosis. Heparanase is the major enzyme that degrades heparan sulfate in mammalian cells. This study examined the role of heparanase in controlling thrombosis following vascular injury and stent-induced flow disturbance. Methods: This study used mice overexpressing human heparanase and examined the time to thrombosis using a laser-induced arterial thrombosis model in combination with vascular injury. An ex vivo system was used to examine the formation of thrombus to stent-induced flow disturbance. Results: In the absence of vascular injury, wild type and heparanase overexpressing (HPA Tg) mice had similar times to thrombosis in a laser-induced arterial thrombosis model. However, in the presence of vascular injury, the time to thrombosis was dramatically reduced in HPA Tg mice. An ex vivo system was used to flow blood from wild type and HPA Tg mice over stents and stented arterial segments from both animal types. These studies demonstrate markedly increased thromboses on stents with blood isolated from HPA Tg mice in comparison to blood from wild type animals. We found that blood from HPA Tg animals had markedly increased thrombosis when applied to stented arterial segments from either wild type or HPA Tg mice. Conclusions: Taken together, this study''s results indicate that heparanase is a powerful mediator of thrombosis in the context of vascular injury and stent-induced flow disturbance. [Copyright &y& Elsevier]
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- 2012
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39. Heparanase overexpression reduces carrageenan-induced mechanical and cold hypersensitivity in mice
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Li, Lili, Wang, Bo, Gao, Tianle, Zhang, Xiao, Hao, Jing-Xia, Vlodavsky, Israel, Wiesenfeld-Hallin, Zsuzsanna, Xu, Xiao-Jun, and Li, Jin-Ping
- Subjects
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ENZYMES , *GENE expression , *CARRAGEENANS , *COLD (Temperature) , *ALLERGIES , *LABORATORY mice , *EXTRACELLULAR matrix , *HEPARAN sulfate , *CYTOKINES , *INFLAMMATION prevention , *HYPERALGESIA , *PREVENTION - Abstract
Abstract: Heparanase controls the structure and functions of extracellular matrix (ECM) by degrading heparan sulfate proteoglycans. Heparanase is involved in inflammatory process through modulating the functions of inflammatory cytokines. The present study aimed to find out whether overexpression of heparanase in mice affects carrageenan-induced localized inflammation and inflammatory hyperalgesia. Without challenge, the heparanase overexpression did not significantly affect the mice in response to mechanical, cold and heat stimulation. Unilateral subcutaneous administration of carrageenan produced hypersensitivity to mechanical and cold in both wildtype and the heparanase overexpression (Hpa-tg) mice 24h after treatment. In comparison to wildtype animals, the Hpa-tg mice showed significantly reduced mechanical and cold hypersensitivity. This may, at least partially, due to the reduced mast cell infiltration at the site of inflammation in Hpa-tg mice. These data support a role for heparanase that reduces localized inflammation and inflammatory hyperalgesia in mice. [Copyright &y& Elsevier]
- Published
- 2012
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40. Heparanase Induces Signal Transducer and Activator of Transcription (STAT) Protein Phosphorylation PRECLINICAL AND CLINICAL SIGNIFICANCE IN HEAD AND NECK CANCER.
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Cohen-Kaplan, Victoria, Jrbashyan, Jenny, Yanir, Yoav, Naroditsky, Inna, Ben-Izhak, Ofer, Ilan, Neta, Doweck, Ilana, and Vlodavsky, Israel
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PROTEINS , *TUMORS , *CELL tumors , *PHOSPHORYLATION , *IMMUNE system , *CANCER - Abstract
Activity of heparanase is implicated strongly in dissemination of metastatic tumor cells and cells of the immune system. In addition, heparanase enhances the phosphorylation of selected signaling molecules, including SRC and EGFR, in a manner that requires secretion but not enzymatic activity of heparanase and is mediated by its C-terminal domain. Clinically, heparanase staining is associated with larger tumors and increased EGFR phosphorylation in head and neck carcinoma. We hypothesized that signal transducer and activator of transcription (STAT) proteins mediate the protumorigenic function of heparanase downstream of the EGFR. We provide evidence that heparanase enhances the phosphorylation of STAT3 and STAT5b but not STAT5a. Moreover, enhanced proliferation of heparanase transfected cells was attenuated by STAT3 and STAT5b siRNA, but not STAT5a or STAT1 siRNA. Clinically, STAT3 phosphorylation was associated with head and neck cancer progression, EGFR phosphorylation, and heparanase expression and cellular localization. Notably, cytoplasmic rather than nuclear phospho- STAT3 correlated with increased tumor size (T-stage; p = 0.007), number of metastatic neck lymph nodes (p = 0.05), and reduced survival of patients (p = 0.04). [ABSTRACT FROM AUTHOR]
- Published
- 2012
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41. Heparanase 2 Interacts with Heparan Sulfate with High Affinity and Inhibits Heparanase Activity.
- Author
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Levy-Adam, Flonia, Feld, Sari, Cohen-Kaplan, Victoria, Shteingauz, Anna, Gross, Miriam, Arvatz, Gil, Naroditsky, Inna, Ilan, Neta, Doweck, Ilana, and Vlodavsky, Israel
- Subjects
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CELL physiology , *TUMORS , *GENE expression , *HOMOLOGY (Biology) , *HEAD & neck cancer - Abstract
Heparanase activity is highly implicated in cell dissemination associated with tumor metastasis, angiogenesis, and inflammation. Heparanase expression is induced in many hematological and solid tumors, associated with poor prognosis. Heparanase homolog, termed heparanase 2 (Hpa2), was cloned based on sequence homology. Detailed characterization of Hpa2 at the biochemical, cellular, and clinical levels has not been so far reported, and its role in normal physiology and pathological disorders is obscure. We provide evidence that unlike heparanase, Hpa2 is not subjected to proteolytic processing and exhibits no enzymatic activity typical of heparanase. Notably, the full-length Hpa2c protein inhibits heparanase enzymatic activity, likely due to its high affinity to heparin and heparan sulfate and its ability to associate physically with heparanase. Hpa2 expression was markedly elevated in head and neck carcinoma patients, correlating with prolonged time to disease recurrence (follow-up to failure; p = 0.006) and inversely correlating with tumor cell dissemination to regional lymph nodes (N-stage; p = 0.03). Hpa2 appears to restrain tumor metastasis, likely by attenuating heparanase enzymatic activity, conferring a favorable outcome of head and neck cancer patients. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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42. Heparanase upregulates Th2 cytokines, ameliorating experimental autoimmune encephalitis
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Bitan, Menachem, Weiss, Lola, Reibstein, Israel, Zeira, Michael, Fellig, Yakov, Slavin, Shimon, Zcharia, Eyal, Nagler, Arnon, and Vlodavsky, Israel
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CYTOKINES , *GLUCURONIDASE , *ENCEPHALITIS , *AUTOIMMUNE diseases , *LABORATORY mice , *MULTIPLE sclerosis , *INFLAMMATION - Abstract
Abstract: Heparanase is an endo-β-d-glucuronidase that cleaves heparan sulfate (HS) saccharide chains. The enzyme promotes cell adhesion, migration and invasion and plays a significant role in cancer metastasis, angiogenesis and inflammation. The present study focuses on the involvement of heparanase in autoimmunity, applying the murine experimental autoimmune encephalitis (EAE) model, a T-cell dependent disease often used to investigate the pathophysiology of multiple sclerosis (MS). Intraperitoneal administration of recombinant heparanase ameliorated, in a dose dependent manner, the clinical signs of the disease. In vitro and in vivo studies revealed that heparanase inhibited mitogen induced splenocyte proliferation and mixed lymphocyte reaction (MLR) through modulation of their repertoire of cytokines indicated by a marked increase in the levels of IL-4, IL-6 and IL-10, and a parallel decrease in IL-12 and TNF-α. Similar results were obtained with active, latent, or point mutated inactive heparanase, indicating that the observed inhibitory effect is attributed to a non-enzymatic activity of the heparanase protein. We suggest that heparanase induces upregulation of Th2 cytokines, resulting in inhibition of the inflammatory lesion of EAE. [Copyright &y& Elsevier]
- Published
- 2010
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43. Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase
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Waern, Ida, Jia, Juan, Pejler, Gunnar, Zcharia, Eyal, Vlodavsky, Israel, Li, Jin-Ping, and Wernersson, Sara
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BIOACCUMULATION , *CELL migration , *GLUCURONIDASE , *MACROPHAGES , *LABORATORY mice , *BRONCHOALVEOLAR lavage , *TRANSMISSION electron microscopy , *PROTEOGLYCANS - Abstract
Abstract: Heparanase is a heparan sulfate (HS) degrading endoglucuronidase that has been implicated in cell migration and inflammatory conditions. Here we used mice deficient of heparanase (Hpse −/−) to study the impact of heparanase on airway leukocytes. Normal numbers of macrophages and lymphocytes were present in bronchoalveolar lavage fluid of Hpse −/− mice, indicating that heparanase is not essential for proper homing of leukocytes to airways. While lymphocytes from Hpse −/− mice displayed normal morphology, Hpse −/− alveolar macrophages showed a striking, age-dependent appearance of granule-like structures in the cytoplasm. Transmission electron microscopy revealed that these structures corresponded to membrane-enclosed crystalline bodies that closely resembled the intracellular crystals known to be formed by the HS-binding protein Ym1, suggesting that heparanase deficiency is associated with intracellular Ym1 deposition. Indeed, applying immunocytochemistry, we found markedly higher levels of intracellular Ym1 protein in Hpse −/− versus WT alveolar macrophages, and there was a significant correlation between levels of Ym1 protein detected by immunoblotting and amounts of crystalline material in BAL cells. Biosynthetic radio-labeling of the macrophages revealed accumulation of non-degraded HS chains in Hpse −/− macrophages. Together, these findings implicate heparanase in normal processing of HS in macrophages, and indicate that heparanase regulates intracellular Ym1 accumulation and crystal formation in airways. [Copyright &y& Elsevier]
- Published
- 2010
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44. Heparanase: busy at the cell surface
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Fux, Liat, Ilan, Neta, Sanderson, Ralph D., and Vlodavsky, Israel
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EXTRACELLULAR matrix , *PHOSPHORYLATION , *PROTEIN kinases , *GENETIC transcription , *HEPARIN , *XENOGRAFTS , *CELL physiology - Abstract
Heparanase activity is strongly implicated in structural remodeling of the extracellular matrix, a process which can lead to invasion by tumor cells. In addition, heparanase augments signaling cascades leading to enhanced phosphorylation of selected protein kinases and increased gene transcription associated with aggressive tumor progression. This function is apparently independent of heparan sulfate and enzyme activity, and is mediated by a novel protein domain localized at the heparanase C-terminus. Moreover, the functional repertoire of heparanase is expanded by its regulation of syndecan clustering, shedding, and mitogen binding. Recent reports indicate that modified glycol-split heparin, which inhibits heparanase activity, can profoundly inhibit the progression of tumor xenografts produced by myeloma and carcinoma cells, thus moving anti-heparanase therapy closer to reality. [Copyright &y& Elsevier]
- Published
- 2009
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45. Molecular Structure of Heparan Sulfate from Spalax IMPLICATIONS OF HEPARANASE AND HYPOXIA.
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Sandwall, Elina, Bodevin, Sabrina, Nasser, Nicola J., Nevo, Eviatar, Avivi, Aaron, Vlodavsky, Israel, and Jin-Ping Li
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MOLECULAR structure , *ENZYMES , *MITOGEN-activated protein kinases , *HYPOXEMIA , *OLIGOSACCHARIDES , *GENE expression , *UKRAINIAN blind mole rats - Abstract
Spalax, a subterranean blind mole rat, is well adapted to live in an extreme hypoxic environment through up-regulated expression of growth factors and enzymes for ensuring sufficient oxygen supply. One of the overexpressed enzymes is heparanase, an endoglucuronidase that selectively cleaves heparan sulfate (HS) and is implicated in angiogenesis. To assess the implications of the heparanase in Spalax, we have characterized the structure of HS isolated from various organs of the animal. The oligosaccharides obtained after deaminative cleavage of HS samples from the tissues show an overall higher sulfation degree, distinct from that of murine tissues. Of particular significance was the appearance of a trisaccharide moiety in the tissues examined, apart of the even numbered oligosaccharide fractions typically found in HS from human and mouse tissues. The formation of this odd-numbered saccharide is a consequence of heparanase action, in agreement with the notion of high expression of the enzyme in this species. Analysis of HS extracted from human embryonic kidney cells (HEK293) after exposure to hypoxic condition revealed a structural change in the distribution of oligosaccharides similar to HS derived from Spalax organs. The alterations are likely due to up- regulated activity of heparanase, as real-time RT-PCR showed a 2-fold increase in heparanase mRNA expression in the hypoxia treated cells. HEK293 cells stably overexpressing Spalax heparanase produced HS sharing similarity with that from the Spalax organs, and exhibited enhanced MAPK activity in comparison with HEK293 cells, indicating a regulation role of the heparanase in the activity of growth factors. [ABSTRACT FROM AUTHOR]
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- 2009
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46. Low and high affinity receptors mediate cellular uptake of heparanase
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Ben-Zaken, Olga, Shafat, Itay, Gingis-Velitski, Svetlana, Bangio, Haim, Kelson, Idil Kasuto, Alergand, Tal, Amor, Yehudit, Maya, Ruth Ben-Yakar, Vlodavsky, Israel, and Ilan, Neta
- Subjects
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HYDROLASES , *ENDOGLYCOSIDASES , *TUMORS , *CELLS - Abstract
Abstract: Heparanase is an endoglycosidase which cleaves heparan sulfate and hence participates in degradation and remodeling of the extracellular matrix. Importantly, heparanase activity correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of heparan sulfate cleavage and remodeling of the extracellular matrix barrier. Heparanase has been characterized as a glycoprotein, yet glycan biochemical analysis was not performed to date. Here, we applied the Qproteome™ GlycoArray kit to perform glycan analysis of heparanase, and compared the kit results with the more commonly used biochemical analyses. We employed fibroblasts isolated from patients with I-cell disease (mucolipidosis II), fibroblasts deficient of low density lipoprotein receptor-related protein and fibroblasts lacking mannose 6-phosphate receptor, to explore the role of mannose 6-phosphate in heparanase uptake. Iodinated heparanase has been utilized to calculate binding affinity. We provide evidence for hierarchy of binding to cellular receptors as a function of heparanase concentration. We report the existence of a high affinity, low abundant (i.e., low density lipoprotein receptor-related protein, mannose 6-phosphate receptor), as well as a low affinity, high abundant (i.e., heparan sulfate proteoglycan) receptors that mediate heparanase binding, and suggest that these receptors co-operate to establish high affinity binding sites for heparanase, thus maintaining extracellular retention of the enzyme tightly regulated. [Copyright &y& Elsevier]
- Published
- 2008
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47. Clinical Significance of Urine Heparanase in Bladder Cancer Progression.
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Shafat, Itay, Pode, Dov, Peretz, Tamar, Ilan, Neta, Vlodavsky, Israel, and Nisman, Benjamin
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BETA-glucuronidase genes , *BLADDER cancer , *CANCER diagnosis , *METASTASIS , *URINALYSIS - Abstract
Heparanase is an endo-β-glucuronidase capable of cleaving heparan sulfate (HS), an activity implicated in tumor metastasis. Heparanase expression is upregulated in primary human tumors, correlating with reduced post operative survival and elevated microvessel density. An ELISA method was used to quantify heparanase in urine from 282 individuals. Urine was collected from healthy volunteers (n = 41), patients diagnosed with noncancerous pathologic disorders (n = 90), and bladder cancer patients (n = 92). Fifty-nine bladder carcinoma patients after transurethral resection (TUR) with no evidence of disease (NED) were also included. Heparanase levels were significantly elevated in urine from bladder cancer patients compared with healthy controls (P < .001) and with noncancerous urinary disorders (P < .05). Heparanase elevation strongly correlated with tumor grade (P < .001) and stage (P = .027). An optimal cutoff value of 154 pg/ml was determined. Of 199 individuals enrolled (59 patients after TUR and 24 patients with recurring disease were excluded), 65 had heparanase levels above 154 pg/ml. Only 3 of 65 (4.6%) were healthy individuals. In contrast, 52.3% (34 of 65) of individuals with heparanase levels above 154 pg/ml were bladder cancer patients. The results indicate that urine heparanase levels are elevated during bladder cancer progression, suggesting that the ELISA method may be applied for bladder cancer diagnosis. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
48. Heparanase Levels Are Elevated in the Plasma of Pediatric Cancer Patients and Correlate with Response to Anticancer Treatment.
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Shafat, Itay, Barak, Ayelet Ben, Postovsky, Sergey, Elhasid, Ronit, Ilan, Neta, Vlodavsky, Israel, and Arush, Miriam Weyl Ben
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ENDOGLYCOSIDASES , *CHILDHOOD cancer , *ANTINEOPLASTIC agents , *CANCER treatment , *ENZYME-linked immunosorbent assay - Abstract
Heparanase is an endoglycosidase that specifically cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans, the major proteoglycan in the extracellular matrix (ECM) and cell surfaces. Heparanase upregulation was documented in an increasing number of primary human tumors, correlating with reduced postoperative survival rate and enhanced tumor angiogenesis. The purpose of the current study was to determine heparanase levels in blood samples collected from pediatric cancer patients using an ELISA method. Heparanase levels were elevated four-fold in the plasma of cancer patients compared with healthy controls (664 ± 143 vs 163 ± 18 pg/ml, respectively). Evaluating plasma samples following anticancer therapy revealed reduced heparanase levels (664 ± 143 vs 429 ± 82 pg/ml), differences that are statistically highly significant (P = .0048). Of the 55 patients with complete remission (CR) or very good partial remission (VGPR) at restaging, 41 (74.5%) had lower heparanase amounts, whereas 14 patients (25.5%) had similar or higher amounts of plasma heparanase. All nine patients with stable or advancing disease had similar or elevated levels of heparanase on restaging. The results show that heparanase levels are elevated in the plasma of pediatric cancer patients and closely correlate with treatment responsiveness, indicating that heparanase levels can be used to diagnose and monitor patient's response to anticancer treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
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49. Heparanase Enhances Syndecan-1 Shedding.
- Author
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Yang Yang, MacLeod, Veronica, Hua-Quan Mia, Theus, Allison, Fenghuang Zhan, Shaughnessy Jr., John D., Sawyers, Jeffrey, Jin-Ping Li, Zcharia, Eyal, Vlodavsky, Israel, and Sanderson, Ralph D.
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CANCER cells , *TUMOR growth , *ONCOLOGY , *BIOCHEMISTRY , *CLINICAL biochemistry - Abstract
When shed from the cell surface, the heparan sulfate proteoglycan syndecan-1 can facilitate the growth, angiogenesis, and metastasis of tumors. Here we report that tumor cell expression of heparanase, an enzyme known to be a potent promoter of tumor progression and metastasis, regulates both the level and location of syndecan-1 within the tumor microenvironment by enhancing its synthesis and subsequent shedding from the tumor cell surface. Heparanase regulation of syndecan-1 is detected in both human myeloma and breast cancer cell lines. This regulation requires the presence of active enzyme, because mutated forms of heparanase lacking heparan sulfate-degrading activity failed to influence syndecan-1 expression or shedding. Removal of heparan sulfate from the cell surface using bacterial heparitinase dramatically accelerated syndecan-1 shedding, suggesting that the effects of heparanase on syndecan-1 expression by tumor cells may be due, at least in part, to enzymatic removal or reduction in the size of heparan sulfate chains. Animals bearing tumors formed from cells expressing high levels of heparanase or animals transgenic for heparanase expression exhibited elevated levels of serum syndecan-1 as compared with controls, indicating that heparanase regulation of syndecan-1 expression and shedding can occur in vivo and impact cancer progression and perhaps other pathological states. These results reveal a new mechanism by which heparanase promotes an aggressive tumor phenotype and suggests that heparanase and syndecan-1 act synergistically to fine tune the tumor microenvironment and ensure robust tumor growth. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
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50. Heparanase Localization and Expression by Head and Neck Cancer: Correlation with Tumor Progression and Patient Survival.
- Author
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Doweck, Ilana, Kaplan-Cohen, Victoria, Naroditsky, Inna, Sabo, Edmond, Ilan, Neta, and Vlodavsky, Israel
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- *
ENDOGLYCOSIDASES , *SQUAMOUS cell carcinoma , *PROTEOGLYCANS , *EXTRACELLULAR matrix , *CANCER invasiveness , *TUMORS , *NEOVASCULARIZATION - Abstract
Heparanase is an endoglycosidase that specifically cleaves heparan sulfate (HS) side chains of HS proteoglycans, the major proteoglycans in the extracellular matrix and cell surfaces. Traditionally, heparanase activity was implicated in cellular invasion associated with angiogenesis, inflammation, and cancer metastasis. More recently, heparanase upregulation was documented in an increasing number of primary human tumors, correlating with reduced postoperative survival rate and enhanced tumor angiogenesis. In the present study, we examined the expression of heparanase in squamous cell carcinoma of the head and neck by means of immunostaining, and we correlated expression levels with patient outcome. The intensity and extent of heparanase staining correlated with tumor stage (P = .049 and P = .027, respectively), and the extent of staining further correlated with tumor grade (P = .047). Moreover, heparanase expression inversely correlated with patient status at the end of the study (P = .012). Notably, heparanase localization was found to be an important parameter for patient status. Thus, 63% of patients with nuclear staining, compared to 19% of patients with cytoplasmic staining (P = .0043), were alive, indicating that nuclear localization of the enzyme predicts a favorable outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
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