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Israel Vlodavsky - One of the best experts on this subject based on the ideXlab platform.

  • New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis
    'MDPI AG', 2021
    Co-Authors: Uri Barash, Israel Vlodavsky, Ilanit Boyango, Shobith Rangappa, Chakrabhavi Dhananjaya Mohan, Divakar Vishwanath, Basappa Basappa, Kanchugarakoppal S. Rangappa
    Abstract:

    Compelling evidence ties Heparanase, an endoglycosidase that cleaves heparan sulfate side (HS) chains of proteoglycans, with all steps of tumor development, including tumor initiation, angiogenesis, growth, metastasis, and chemoresistance. Moreover, Heparanase levels correlate with shorter postoperative survival of cancer patients, encouraging the development of Heparanase inhibitors as anti-cancer drugs. Heparanase-inhibiting heparin/heparan sulfate-mimicking compounds and neutralizing antibodies are highly effective in animal models of cancer progression, yet none of the compounds reached the stage of approval for clinical use. The present study focused on newly synthesized triazolo–thiadiazoles, of which compound 4-iodo-2-(3-(p-tolyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)phenol (4-MMI) was identified as a potent inhibitor of Heparanase enzymatic activity, cell invasion, experimental metastasis, and tumor growth in mouse models. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with small molecules that inhibit Heparanase enzymatic activity. This result encourages the optimization of 4-MMI for preclinical and clinical studies primarily in cancer but also other indications (i.e., colitis, pancreatitis, diabetic nephropathy, tissue fibrosis) involving Heparanase, including viral infection and COVID-19

  • glycobiology 2020 the heparan sulfate proteoglycan syndecan 1 and Heparanase are novel regulators of cancer stem cell function and therapeutic resistance martin gotte munster university hospital
    Journal of Molecular and Cellular Biochemistry, 2020
    Co-Authors: Martin Gotte, Israel Vlodavsky, Sampath Kumar Katakam, Valeria Tria, George W Yip, Paride Pelucchi, Cinzia Cocola, Ileana Zucchi, Burkhard Greve
    Abstract:

    The heparan sulfate proteoglycan Syndecan-1 binds cytokines, morphogens and extracellular matrix components, regulating cancer stem cell properties and invasiveness. Syndecan-1 is modulated by the heparan sulfate-degrading enzyme Heparanase, but the underlying regulatory mechanisms are only poorly understood (1). In colon cancer pathogenesis, complex changes occur in the expression pattern of Syndecan-1 and Heparanase during progression from well-differentiated to undifferentiated tumors. Loss of Syndecan-1 and increased expression of Heparanase are associated with a change in phenotypic plasticity and an increase in invasiveness, metastasis and dedifferentiation. Here we investigated the regulatory and functional interplay of Syndecan-1 and Heparanase employing siRNA-mediated silencing and plasmid-based overexpression approaches in human colon cancer cell lines and in a xenograft model . Sdc-1 small-interfering RNA knockdown in the human colon cancer cell lines Caco2 and HT-29 resulted in an increased side population (SP), enhanced aldehyde dehydrogenase 1 activity, and higher expression of CD133, LGR5, EPCAM, NANOG, SRY (sex-determining region Y)-box 2, KLF2, and TCF4/TCF7L2. Notably, Heparanase expression and activity were upregulated in Syndecan-1 depleted cells. This increase was linked to an upregulation of the transcription factor Egr1, which regulates Heparanase at the promoter level. Sdc-1 knockdown enhanced sphere formation, cell viability, Matrigel invasiveness, and epithelial-to-mesenchymal transition-related gene expression. Likewise, upregulation of Heparanase increased the colon cancer stem cell phenotype based on sphere formation assays and phenotypic marker analysis (Side-population, NANOG, KLF4, NOTCH, Wnt, and TCF4 expression). Sdc-1-depleted HT-29 xenograft growth was increased compared to controls. Decreased Sdc-1 expression was associated with an increased activation of β1-integrins, focal adhesion kinase (FAK), and wingless-type (Wnt) signaling. Pharmacological FAK, Wnt and Heparanase inhibition blocked the enhanced stem cell phenotype and invasive growth. Sequential flow cytometric SP enrichment substantially enhanced the stem cell phenotype of Sdc-1-depleted cells, which showed increased resistance to doxorubicin chemotherapy and irradiation. In addition, upregulated expression of Heparanase resulted in increased resistance to radiotherapy, whereas high expression of enzymatically inactive Heparanase promoted chemoresistance to paclitaxel and cisplatin. In conclusion, Sdc-1 depletion cooperatively enhances expression of Heparanase and activation of integrins and FAK, which then generates signals for increased invasiveness and cancer stem cell properties. Our findings provide a new avenue to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence.

  • targeting Heparanase to the mammary epithelium enhances mammary gland development and promotes tumor growth and metastasis
    Matrix Biology, 2017
    Co-Authors: Ilanit Boyango, Uri Barash, Neta Ilan, Inna Naroditsky, Liat Fux, Israel Vlodavsky
    Abstract:

    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.

  • The Heparanase Inhibitor PG545 Attenuates Colon Cancer Initiation and Growth, Associating with Increased p21 Expression
    Elsevier, 2017
    Co-Authors: Preeti Singh, Israel Vlodavsky, Neta Ilan, Sari Feld, Alexandra Blatt, Yaniv Zohar, Esraa Saadi, Liza Barki-harrington, Edward Hammond, Yehuda Chowers
    Abstract:

    Heparanase activity is highly implicated in cellular invasion and tumor metastasis, a consequence of cleavage of heparan sulfate and remodeling of the extracellular matrix underlying epithelial and endothelial cells. Heparanase expression is rare in normal epithelia, but is often induced in tumors, associated with increased tumor metastasis and poor prognosis. In addition, Heparanase induction promotes tumor growth, but the molecular mechanism that underlines tumor expansion by Heparanase is still incompletely understood. Here, we provide evidence that Heparanase down regulates the expression of p21 (WAF1/CIP1), a cyclin-dependent kinase inhibitor that attenuates the cell cycle. Notably, a reciprocal effect was noted for PG545, a potent Heparanase inhibitor. This compound efficiently reduced cell proliferation, colony formation, and tumor xenograft growth, associating with a marked increase in p21 expression. Utilizing the APC Min+/− mouse model, we show that Heparanase expression and activity are increased in small bowel polyps, whereas polyp initiation and growth were significantly inhibited by PG545, again accompanied by a prominent induction of p21 levels. Down-regulation of p21 expression adds a novel feature for the emerging pro-tumorigenic properties of Heparanase, while the potent p21 induction and anti-tumor effect of PG545 lends optimism that it would prove an efficacious therapeutic in colon carcinoma patients

  • Heparanase from basic research to therapeutic applications in cancer and inflammation
    Drug Resistance Updates, 2016
    Co-Authors: Israel Vlodavsky, Ralph D. Sanderson, Preeti Singh, Ilanit Boyango, Lilach Gutterkapon, Michael Elkin, Neta Ilan
    Abstract:

    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.

Neta Ilan - One of the best experts on this subject based on the ideXlab platform.

  • targeting Heparanase to the mammary epithelium enhances mammary gland development and promotes tumor growth and metastasis
    Matrix Biology, 2017
    Co-Authors: Ilanit Boyango, Uri Barash, Neta Ilan, Inna Naroditsky, Liat Fux, Israel Vlodavsky
    Abstract:

    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.

  • The Heparanase Inhibitor PG545 Attenuates Colon Cancer Initiation and Growth, Associating with Increased p21 Expression
    Elsevier, 2017
    Co-Authors: Preeti Singh, Israel Vlodavsky, Neta Ilan, Sari Feld, Alexandra Blatt, Yaniv Zohar, Esraa Saadi, Liza Barki-harrington, Edward Hammond, Yehuda Chowers
    Abstract:

    Heparanase activity is highly implicated in cellular invasion and tumor metastasis, a consequence of cleavage of heparan sulfate and remodeling of the extracellular matrix underlying epithelial and endothelial cells. Heparanase expression is rare in normal epithelia, but is often induced in tumors, associated with increased tumor metastasis and poor prognosis. In addition, Heparanase induction promotes tumor growth, but the molecular mechanism that underlines tumor expansion by Heparanase is still incompletely understood. Here, we provide evidence that Heparanase down regulates the expression of p21 (WAF1/CIP1), a cyclin-dependent kinase inhibitor that attenuates the cell cycle. Notably, a reciprocal effect was noted for PG545, a potent Heparanase inhibitor. This compound efficiently reduced cell proliferation, colony formation, and tumor xenograft growth, associating with a marked increase in p21 expression. Utilizing the APC Min+/− mouse model, we show that Heparanase expression and activity are increased in small bowel polyps, whereas polyp initiation and growth were significantly inhibited by PG545, again accompanied by a prominent induction of p21 levels. Down-regulation of p21 expression adds a novel feature for the emerging pro-tumorigenic properties of Heparanase, while the potent p21 induction and anti-tumor effect of PG545 lends optimism that it would prove an efficacious therapeutic in colon carcinoma patients

  • Heparanase from basic research to therapeutic applications in cancer and inflammation
    Drug Resistance Updates, 2016
    Co-Authors: Israel Vlodavsky, Ralph D. Sanderson, Preeti Singh, Ilanit Boyango, Lilach Gutterkapon, Michael Elkin, Neta Ilan
    Abstract:

    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.

  • processing of Heparanase is mediated by syndecan 1 cytoplasmic domain and involves syntenin and α actinin
    Cellular and Molecular Life Sciences, 2014
    Co-Authors: Anna Shteingauz, Neta Ilan, Israel Vlodavsky
    Abstract:

    Heparanase activity plays a decisive role in cell dissemination associated with cancer metastasis. Cellular uptake of Heparanase is considered a pre-requisite for the delivery of latent 65-kDa Heparanase to lysosomes and its subsequent proteolytic processing and activation into 8- and 50-kDa protein subunits by cathepsin L. Heparan sulfate proteoglycans, and particularly syndecan, are instrumental for Heparanase uptake and activation, through a process that has been shown to occur independent of rafts. Nevertheless, the molecular mechanism underlying syndecan-mediated internalization outside of rafts is unclear. Here, we examined the role of syndecan-1 cytoplasmic domain in Heparanase processing, utilizing deletion constructs lacking the entire cytoplasmic domain (Delta), the conserved (C1 or C2), or variable (V) regions. Heparanase processing was markedly increased following syndecan-1 over-expression; in contrast, Heparanase was retained at the cell membrane and its processing was impaired in cells over-expressing syndecan-1 deleted for the entire cytoplasmic tail. We have next revealed that conserved domain 2 (C2) and variable (V) regions of syndecan-1 cytoplasmic tail mediate Heparanase processing. Furthermore, we found that syntenin, known to interact with syndecan C2 domain, and α actinin are essential for Heparanase processing.

  • Heparanase induces signal transducer and activator of transcription stat protein phosphorylation preclinical and clinical significance in head and neck cancer
    Journal of Biological Chemistry, 2012
    Co-Authors: Victoria Cohenkaplan, Neta Ilan, Jenny Jrbashyan, Yoav Yanir, Inna Naroditsky, Ofer Benizhak, Ilana Doweck, Israel Vlodavsky
    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).

Ralph D. Sanderson - One of the best experts on this subject based on the ideXlab platform.

  • Heparanase from basic research to therapeutic applications in cancer and inflammation
    Drug Resistance Updates, 2016
    Co-Authors: Israel Vlodavsky, Ralph D. Sanderson, Preeti Singh, Ilanit Boyango, Lilach Gutterkapon, Michael Elkin, Neta Ilan
    Abstract:

    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.

  • the Heparanase syndecan 1 axis in cancer mechanisms and therapies
    FEBS Journal, 2013
    Co-Authors: Vishnu C. Ramani, Israel Vlodavsky, Anurag Purushothaman, Mark D. Stewart, Camilla A. Thompson, Ralph D. Sanderson
    Abstract:

    Heparanase is an endoglucuronidase that cleaves heparan sulfate chains of proteoglycans. In many malignancies, high Heparanase expression and activity correlate with an aggressive tumour phenotype. A major consequence of Heparanase action in cancer is a robust up-regulation of growth factor expression and increased shedding of syndecan-1 (a transmembrane heparan sulfate proteoglycan). Substantial evidence indicates that Heparanase and syndecan-1 work together to drive growth factor signalling and regulate cell behaviours that enhance tumour growth, dissemination, angiogenesis and osteolysis. Preclinical and clinical studies have demonstrated that therapies targeting the Heparanase/syndecan-1 axis hold promise for blocking the aggressive behaviour of cancer.

  • Heparanase enhances the insulin receptor signaling pathway to activate extracellular signal regulated kinase in multiple myeloma
    Journal of Biological Chemistry, 2012
    Co-Authors: Anurag Purushothaman, Stephen K Babitz, Ralph D. Sanderson
    Abstract:

    ERK signaling regulates proliferation, survival, drug resistance, and angiogenesis in cancer. Although the mechanisms regulating ERK activation are not fully understood, we previously demonstrated that ERK phosphorylation is elevated by Heparanase, an enzyme associated with aggressive behavior of many cancers. In the present study, myeloma cell lines expressing either high or low levels of Heparanase were utilized to determine how Heparanase stimulates ERK signaling. We discovered that the insulin receptor was abundant on cells expressing either high or low levels of Heparanase, but the receptor was highly phosphorylated in Heparanase-high cells compared with Heparanase-low cells. In addition, protein kinase C activity was elevated in Heparanase-high cells, and this enhanced expression of insulin receptor substrate-1 (IRS-1), the principle intracellular substrate for phosphorylation by the insulin receptor. Blocking insulin receptor function with antibody or a small molecule inhibitor or knockdown of IRS-1 expression using shRNA diminished Heparanase-mediated ERK activation in the tumor cells. In addition, up-regulation of the insulin signaling pathway by Heparanase and the resulting ERK activation were dependent on Heparanase retaining its enzyme activity. These results reveal a novel mechanism whereby Heparanase enhances activation of the insulin receptor signaling pathway leading to ERK activation and modulation of myeloma behavior.

  • Heparanase mediated loss of nuclear syndecan 1 enhances histone acetyltransferase hat activity to promote expression of genes that drive an aggressive tumor phenotype
    Journal of Biological Chemistry, 2011
    Co-Authors: Anurag Purushothaman, Douglas R Hurst, Claudio Pisano, Shuji Mizumoto, Kazuyuki Sugahara, Ralph D. Sanderson
    Abstract:

    Heparanase acts as a master regulator of the aggressive tumor phenotype in part by enhancing expression of proteins known to drive tumor progression (e.g. VEGF, MMP-9, hepatocyte growth factor (HGF), and RANKL). However, the mechanism whereby this enzyme regulates gene expression remains unknown. We previously reported that elevation of Heparanase levels in myeloma cells causes a dramatic reduction in the amount of syndecan-1 in the nucleus. Because syndecan-1 has heparan sulfate chains and because exogenous heparan sulfate has been shown to inhibit the activity of histone acetyltransferase (HAT) enzymes in vitro, we hypothesized that the reduction in nuclear syndecan-1 in cells expressing high levels of Heparanase would result in increased HAT activity leading to stimulation of protein transcription. We found that myeloma cells or tumors expressing high levels of Heparanase and low levels of nuclear syndecan-1 had significantly higher levels of HAT activity when compared with cells or tumors expressing low levels of Heparanase. High levels of HAT activity in Heparanase-high cells were blocked by SST0001, an inhibitor of Heparanase. Restoration of high syndecan-1 levels in Heparanase-high cells diminished nuclear HAT activity, establishing syndecan-1 as a potent inhibitor of HAT. Exposure of Heparanase-high cells to anacardic acid, an inhibitor of HAT activity, significantly suppressed their expression of VEGF and MMP-9, two genes known to be up-regulated following elevation of Heparanase. These results reveal a novel mechanistic pathway driven by Heparanase expression, which leads to decreased nuclear syndecan-1, increased HAT activity, and up-regulation of transcription of multiple genes that drive an aggressive tumor phenotype.

  • proteoglycans in health and disease new concepts for Heparanase function in tumor progression and metastasis
    FEBS Journal, 2010
    Co-Authors: Uri Barash, Ralph D. Sanderson, Neta Ilan, Victoria Cohenkaplan, Ilana Dowek, Israel Vlodavsky
    Abstract:

    Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains at a limited number of sites, yielding heparan sulfate fragments of still appreciable size. Importantly, Heparanase activity correlates 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 and basement membrane underlying epithelial and endothelial cells. Similarly, Heparanase activity is implicated in neovascularization, inflammation and autoimmunity, involving the migration of vascular endothelial cells and activated cells of the immune system. The cloning of a single human Heparanase cDNA 10 years ago enabled researchers to critically approve the notion that heparan sulfate cleavage by Heparanase is required for structural remodeling of the extracellular matrix, thereby facilitating cell invasion. Progress in the field has expanded the scope of Heparanase function and its significance in tumor progression and other pathologies. Notably, although Heparanase inhibitors attenuated tumor progression and metastasis in several experimental systems, other studies revealed that Heparanase also functions in an enzymatic activity-independent manner. Thus, inactive Heparanase was noted to facilitate adhesion and migration of primary endothelial cells and to promote phosphorylation of signaling molecules such as Akt and Src, facilitating gene transcription (i.e. vascular endothelial growth factor) and phosphorylation of selected Src substrates (i.e. endothelial growth factor receptor). The concept of enzymatic activity-independent function of Heparanase gained substantial support by the recent identification of the Heparanase C-terminus domain as the molecular determinant behind its signaling capacity. Identification and characterization of a human Heparanase splice variant (T5) devoid of enzymatic activity and endowed with protumorigenic characteristics, elucidation of cross-talk between Heparanase and other extracellular matrix-degrading enzymes, and identification of single nucleotide polymorphism associated with Heparanase expression and increased risk of graft versus host disease add other layers of complexity to Heparanase function in health and disease.

Mark D Hulett - One of the best experts on this subject based on the ideXlab platform.

  • Leukocyte Heparanase: A Double-Edged Sword in Tumor Progression
    'Frontiers Media SA', 2019
    Co-Authors: Alyce J. Mayfosh, Nikola Baschuk, Mark D Hulett
    Abstract:

    Heparanase is a β-D-endoglucuronidase that cleaves heparan sulfate, a complex glycosaminoglycan found ubiquitously throughout mammalian cells and tissues. Heparanase has been strongly associated with important pathological processes including inflammatory disease and tumor metastasis, through its ability to promote various cellular functions such as cell migration, invasion, adhesion, and cytokine release. A number of cell types express Heparanase including leukocytes, cells of the vasculature as well as tumor cells. However, the relative contribution of Heparanase from these different cell sources to these processes is poorly defined. It is now well-established that the immune system plays a critical role in shaping tumor progression. Intriguingly, leukocyte-derived Heparanase has been shown to either assist or impede tumor progression, depending on the setting. This review covers our current knowledge of Heparanase in immune regulation of tumor progression, as well as the potential applications and implications of exploiting or inhibiting Heparanase in cancer therapy

  • Soluble Heparan Sulfate Fragments Generated by Heparanase Trigger the Release of Pro-Inflammatory
    2016
    Co-Authors: Cytokines Through Tlr, Ivan K H Poon, Katharine J Goodall, Mark D Hulett
    Abstract:

    Heparanase is a b-D-endoglucuronidase that cleaves heparan sulfate (HS), facilitating degradation of the extracellular matrix (ECM) and the release of HS-bound biomolecules including cytokines. The remodeling of the ECM by Heparanase is important for various physiological and pathological processes, including inflammation, wound healing, tumour angiogenesis and metastasis. Although Heparanase has been proposed to facilitate leukocyte migration through degradation of the ECM, its role in inflammation by regulating the expression and release of cytokines has not been fully defined. In this study, the role of Heparanase in regulating the expression and release of cytokines from human and murine immune cells was examined. Human peripheral blood mononuclear cells treated ex vivo with Heparanase resulted in the release of a range of pro-inflammatory cytokines including IL-1b, IL-6, IL-8, IL-10 and TNF. In addition, mouse splenocytes treated ex vivo with Heparanase resulted in the release of IL-6, MCP-1 and TNF. A similar pattern of cytokine release was also observed when cells were treated with soluble HS. Furthermore, Heparanase-induced cytokine release was abolished by enzymatic-inhibitors of Heparanase, suggesting this process is mediated via the enzymatic release of cell surface HS fragments. As soluble HS can signal through the Toll-like receptor (TLR) pathway, Heparanase may promote the upregulation of cytokines through the generation of Heparanase-cleaved fragments of HS. In support of this hypothesis, mouse spleen cells lacking the key TLR adaptor molecule MyD88 demonstrated an abolition of cytokine release afte

  • soluble heparan sulfate fragments generated by Heparanase trigger the release of pro inflammatory cytokines through tlr 4
    PLOS ONE, 2014
    Co-Authors: Katharine J Goodall, Ivan K H Poon, Simon Phipps, Mark D Hulett
    Abstract:

    Heparanase is a β-D-endoglucuronidase that cleaves heparan sulfate (HS), facilitating degradation of the extracellular matrix (ECM) and the release of HS-bound biomolecules including cytokines. The remodeling of the ECM by Heparanase is important for various physiological and pathological processes, including inflammation, wound healing, tumour angiogenesis and metastasis. Although Heparanase has been proposed to facilitate leukocyte migration through degradation of the ECM, its role in inflammation by regulating the expression and release of cytokines has not been fully defined. In this study, the role of Heparanase in regulating the expression and release of cytokines from human and murine immune cells was examined. Human peripheral blood mononuclear cells treated ex vivo with Heparanase resulted in the release of a range of pro-inflammatory cytokines including IL-1β, IL-6, IL-8, IL-10 and TNF. In addition, mouse splenocytes treated ex vivo with Heparanase resulted in the release of IL-6, MCP-1 and TNF. A similar pattern of cytokine release was also observed when cells were treated with soluble HS. Furthermore, Heparanase-induced cytokine release was abolished by enzymatic-inhibitors of Heparanase, suggesting this process is mediated via the enzymatic release of cell surface HS fragments. As soluble HS can signal through the Toll-like receptor (TLR) pathway, Heparanase may promote the upregulation of cytokines through the generation of Heparanase-cleaved fragments of HS. In support of this hypothesis, mouse spleen cells lacking the key TLR adaptor molecule MyD88 demonstrated an abolition of cytokine release after Heparanase stimulation. Furthermore, TLR4-deficient spleen cells showed reduced cytokine release in response to Heparanase treatment, suggesting that TLR4 is involved in this response. Consistent with these observations, the pathway involved in cytokine upregulation was identified as being NF-κB-dependent. These data identify a new mechanism for Heparanase in promoting the release of pro-inflammatory cytokines that is likely to be important in regulating cell migration and inflammation.

  • cell surface expressed cation independent mannose 6 phosphate receptor cd222 binds enzymatically active Heparanase independently of mannose 6 phosphate to promote extracellular matrix degradation
    Journal of Biological Chemistry, 2008
    Co-Authors: Robert J Wood, Mark D Hulett
    Abstract:

    Heparanase is a beta-D-endoglucuronidase that cleaves heparan sulfate, an important structural component of the extracellular matrix (ECM) and vascular basement membrane (BM). The cleavage of heparan sulfate by Heparanase-expressing cells, such as activated leukocytes, metastatic tumor cells, and proliferating endothelial cells, facilitates degradation of the ECM/BM to promote cell invasion associated with inflammation, tumor metastasis, and angiogenesis. In addition to its enzymatic function, Heparanase has also recently been shown to act as a cell adhesion and/or signaling molecule upon interaction with cell surfaces. Despite the obvious importance of the mechanisms for the binding of Heparanase to cell surfaces, the receptor(s) for Heparanase remain poorly defined. In this study, we identify the 300-kDa cation-independent mannose 6-phosphate receptor (CIMPR) as a cell surface receptor for Heparanase. Purified platelet Heparanase was shown to bind the human CIMPR expressed on the surface of a transfected mouse L cell line. Optimal binding was determined to be at a slightly acidic pH (6.5-7.0) with Heparanase remaining on the cell surface for up to 10 min at 37 degrees C. In contrast, mouse L cells or Chinese hamster ovary cells expressing the cation-dependent mannose 6-phosphate receptor (CDMPR) showed no binding of Heparanase. Interestingly, the binding of Heparanase to CIMPR was independent of Man-6-P moieties. Significantly, primary human T cells upon activation were shown to dramatically up-regulate levels of cell surface-expressed CIMPR, which showed a concomitant increase in their capacity to bind Heparanase. Furthermore, the tethering of Heparanase to the surface of cells via CIMPR was found to increase their capacity to degrade an ECM or a reconstituted BM. These data suggest an important role for CIMPR in the cell surface presentation of enzymatically active Heparanase for the efficient passage of T cells into an inflammatory site and have implications for the use of this mechanism by other cell types to enhance cell invasion.

  • early growth response gene 1 egr1 regulates Heparanase gene transcription in tumor cells
    Journal of Biological Chemistry, 2005
    Co-Authors: Amanda M De Mestre, Sudha Rao, June R Hornby, Thura Soehtwe, Levon M Khachigian, Mark D Hulett
    Abstract:

    Heparanase is an endoglycosidase that degrades heparan sulfate chains of heparan sulfate proteoglycans, a key component of extracellular matrix and basement membranes. Studies using Heparanase inhibitors and gene silencing have provided evidence to support an important role for Heparanase in tumor metastasis and angiogenesis. The expression of Heparanase is normally very tightly controlled, however, it is commonly deregulated in tumor cells, which express elevated Heparanase activity that correlates with high levels of Heparanase mRNA. We recently identified the transcription factor early growth response gene 1, EGR1, as a key regulator of inducible Heparanase transcription in T cells. In this study using chromatin immunoprecipitation, we demonstrate for the first time that EGR1 binds to the Heparanase gene promoter in vivo. The important question of the role of EGR1 in regulating Heparanase transcription in tumor cells was then assessed. Studies were carried out in four epithelial tumor lines of different tissue origin. Functional dissection of the Heparanase promoter identified a 280-bp region that was critical for transcription of the Heparanase gene. Transactivation studies using an EGR1 expression vector co-transfected with a reporter construct containing the 280-bp region showed EGR1-activated Heparanase promoter activity in a dose-dependent manner in prostate or breast adenocarcinoma and colon carcinoma cell lines. In contrast, overexpression of EGR1 resulted in a dose-dependent repression of promoter activity in melanoma cells. Using site-directed mutagenesis the 280-bp region was found to contain two functional EGR1 sites and electrophoretic mobility shift assays showed binding of EGR1 to both of these sites upon activation of tumor cells. Furthermore, the Heparanase promoter region containing the EGR1 sites was also inducible in tumor cells and induction corresponded to HPSE expression levels. These studies show that EGR1 regulates Heparanase transcription in tumor cells and importantly, can have a repressive or activating role depending on the tumor type.

Yona Nadir - One of the best experts on this subject based on the ideXlab platform.

  • jak 2 v617f mutation increases Heparanase procoagulant activity
    Thrombosis and Haemostasis, 2015
    Co-Authors: Inna Kogan, Elena Axelman, Dafna Chap, Ron Hoffman, Benjamin Brenner, Yona Nadir
    Abstract:

    Patients with polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are at increased risk of arterial and venous thrombosis. In patients with ET a positive correlation was observed between JAK-2 V617F mutation, that facilitates erythropoietin receptor signalling, and thrombotic events, although the mechanism involved is not clear. We previously demonstrated that Heparanase protein forms a complex and enhances the activity of the blood coagulation initiator tissue factor (TF) which leads to increased factor Xa production and subsequent activation of the coagulation system. The present study was aimed to evaluate Heparanase procoagulant activity in myeloproliferative neoplasms. Forty bone marrow biopsies of patients with ET, PV, PMF and chronic myelogenous leukaemia (CML) were immunostained to Heparanase, TF and TF pathway inhibitor (TFPI). Erythropoietin receptor positive cell lines U87 human glioma and MCF-7 human breast carcinoma were studied. Heparanase and TFPI staining were more prominent in ET, PV and PMF compared to CML. The strongest staining was in JAK-2 positive ET biopsies. Heparanase level and procoagulant activity were higher in U87 cells transfected to over express JAK-2 V617F mutation compared to control and the effect was reversed using JAK-2 inhibitors (Ruxolitinib, VZ3) and hydroxyurea, although the latter drug did not inhibit JAK-2 phosphorylation. Erythropoietin increased while JAK-2 inhibitors decreased the Heparanase level and procoagulant activity in U87 and MCF-7 parental cells. In conclusion, JAK-2 is involved in Heparanase up-regulation via the erythropoietin receptor. The present findings may potentially point to a new mechanism of thrombosis in JAK-2 positive ET patients.

  • Heparanase procoagulant activity factor xa and plasminogen activator inhibitor 1 are increased in shift work female nurses
    Annals of Hematology, 2015
    Co-Authors: Yona Nadir, Ron Hoffman, Benjamin Brenner, Gleb Saharov, Anat Kerenpolitansky, Inna Tzoran, Tamar Shochat
    Abstract:

    Epidemiologic studies indicate on an increased risk of cardiovascular disease and cancer in shift workers, although the underling mechanism is obscure. Heparanase directly enhances tissue factor (TF) activity leading to increased factor Xa production and subsequent activation of the coagulation system. In the present study, a comparison of coagulation markers among healthy shift working (SW) vs. healthy daytime working (DW) female nurses was performed. Thirty SW and 30 DW female nurses were enrolled. For each of the 60 participants, blood was drawn between 7:00 and 8:00 a.m. and at least 8 h after the last work shift. Plasma was studied for coagulation marker that included TF/Heparanase procoagulant activity, TF activity, Heparanase procoagulant activity, Heparanase level, factor Xa level, plasminogen activator inhibitor 1 (PAI-1), plasminogen, α2-antiplasmin, fibrinogen, global protein C, von Willebrand factor, and D-dimer by chromogenic assays and enzyme-linked immunosorbent assays (ELISAs). Sleep quality was assessed by self-report according to the Pittsburgh Sleep Quality Index. The Heparanase procoagulant activity increased by 2-fold and the TF/Heparanase procoagulant activity increased by 1.5-fold in SW nurses compared to DW nurses (P < 0.05). Factor Xa levels and PAI-1 levels were significantly higher among SW nurses compared to the DW group (22 vs. 18 ng/ml, P < 0.05, and 32 vs. 22 ng/ml, P < 0.005, respectively). No significant differences were found in the other tested coagulation markers between the study groups. Heparanase procoagulant activity, factor Xa level, and PAI-1 level were significantly higher in SW nurses compared to the DW group. These alterations of blood coagulation activation may potentially contribute to cardiovascular and cancer morbidity.

  • Heparanase procoagulant activity is elevated and predicts survival in non small cell lung cancer patients
    Thrombosis Research, 2014
    Co-Authors: Yona Nadir, Itay Shafat, Adi Meir, Michelle Wöllner, Elena Axelman, Israel Vlodavsky, Galit Sarig, R. Hoffman, Nissim Ben-haim
    Abstract:

    Abstract Background Heparanase is implicated in angiogenesis and tumor progression. We had earlier demonstrated that Heparanase may also affect the hemostatic system in a non-enzymatic manner. It forms a complex and enhances the activity of the blood coagulation initiator- tissue factor (TF). Although increased Heparanase antigen level in the plasma and biopsies of cancer patients was previously demonstrated, in the present study we evaluated, for the first time, the Heparanase procoagulant activity in the plasma of patients with lung cancer. Materials and Methods Sixty five patients with non-small cell lung cancer at presentation and twenty controls were recruited. Plasma was studied for TF / Heparanase procoagulant activity, TF activity and Heparanase procoagulant activity using chromogenic assay and Heparanase antigen levels by ELISA. Results Heparanase antigen levels were higher in the study group compared to control (P = 0.05). TF / Heparanase activity, and even more apparent, Heparanase procoagulant activity were significantly higher in the study group compared to controls (P = 0.008, P  Conclusions Elevated Heparanase procoagulant activity in patients with lung cancer reveals a new mechanism of coagulation system activation in malignancy. Heparanase procoagulant activity can potentially be used as a predictor for survival.

  • Heparanase procoagulant activity is elevated in women using oral contraceptives
    Human Reproduction, 2013
    Co-Authors: Moshe Matan, Elena Axelman, Benjamin Brenner, Yona Nadir
    Abstract:

    STUDY QUESTION: What is the effect of estrogen on Heparanase procogulant activity? SUMMARY ANSWER: Estrogen increases Heparanase procoagulant activity. WHAT IS KNOWN ALREADY: Estrogen therapy increases the risk of thrombosis and was previously found to up-regulate Heparanase expression. Heparanase is involved in angiogenesis and metastasis and has been shown to form a complex with tissue factor (TF) and also shown to enhance the generation of factor Xa. STUDY DESIGN SIZE DURATION: A case-control study. Thirty-four healthy women using oral contraceptives (OC) and 41 women not using hormonal therapy and not pregnant per history were enrolled over a 5-month period at the Rambam Medical Center Haifa Israel. In vitro estrogen receptor-positive (MCF-7) and -negative (MDA-231) cell lines were incubated with estrogen tamoxifen and ICI-182.780 a pure estrogen receptor antagonist. The cell medium was evaluated for TF/Heparanase complex activity TF activity and Heparanase procoagulant activity by chromogenic substrate. PARTICIPANTS/MATERIALS SETTING METHODS: Exclusion criteria included age <18 years post-menopausal women concomitant medications other than supplement minerals and vitamins acute or chronic illness. MAIN RESULTS AND THE ROLE OF CHANCE: The study demonstrates increased risk of high Heparanase procoagulant activity in OC users. When a cutoff level of 0.25 (absorbance 405-490 nm) was set the odds ratio was 131 (P < 0.0001). When all results were studied by quartiles in quartiles 3 and 4 the results were almost exclusively of the OC users (P < 0.0001). In cell cultures estrogen and tamoxifen increased Heparanase procoagulant activity in the medium of estrogen receptor-positive (MCF-7) cells. LIMITATIONS REASONS FOR CAUTION: The main limitation of the current study is that the two estrogens given to the women and cell cultures ethinyl estradiol (EE) and 17-beta-estradiol (E2) respectively may have different effects on the coagulation system although an increase in Heparanase procoagulant activity was demonstrated in both of them. Although the sample size of the study group was limited significant differences in the activation of the extrinsic coagulation pathway were demonstrated. WIDER IMPLICATIONS OF THE FINDINGS: The clinical relevance of the Heparanase procoagulant activity assay as a screening tool in thrombophilia work-up should further be elucidated. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought for this study. Authors Nadir and Brenner are named in a US Provisional Patent Application No. 29509/WO/12 filed on 18.01.2012. The other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

  • heapranase role in the treatment of avascular necrosis of femur head
    Thrombosis Research, 2013
    Co-Authors: Eli Peled, Elena Axelman, Matthew J Davis, Doron Norman, Yona Nadir
    Abstract:

    Abstract Background Idiopathic avascular necrosis (AVN) of bone causes significant morbidity in adults although the pathophysiology is unknown. The present treatment options include systemic biphosphonate therapy and local bone drilling decompression, ameliorating the healing process and their by render the weight bearing femur head less vulnerable to collapse. In the present study we demonstrate the involvement of Heparanase in AVN and in the acceptable treatments. Methods 56 female rats were studied. In 8 control rats AVN was induced by ligamentum teres ligation of the right femur while the left femur remained intact. In the rest of the rats, in addition to right femur AVN, treatment was added by subcutaneous biphosphonate therapy, femoral head drilling or combination of the treatments. All rats were scarified after 6 weeks. Immunostaining of the femur heads were performed to Heparanase, tissue factor pathway inhibitor (TFPI), tissue factor (TF) and hematoxylin-eosin. Results Staining of Heparanase, TFPI and TF were most prominent in the bone-marrow tissue of the femur heads. Staining by hematoxylin-eosin revealed damaged femur heads with prominent Heparanase and TFPI staining in the femur with AVN compared to the contra lateral side of the same rat. No difference was found in the TF staining between the two sides. In the drilling and / or biphosphonate therapy groups, in contrast to the control group, femur heads were preserved with no significant difference in Heparanase and TFPI staining between the two sides. Conclusions Heparanase and TFPI are locally elevated in the process of AVN and are normalized by the acceptable treatments. Inhibition of Heparanase by heparins can potentially improve the nowadays therapy modalities.