FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2515538046> ?p ?o ?g. }

• W2515538046 endingPage "1012" @default.
• W2515538046 startingPage "1002" @default.
• W2515538046 abstract "•The role of heparanase and heparanase inhibitors in cancer biology and therapy is reviewed.•Heparanase promotes invasion, angiogenesis, and tumor metastasis in preclinical models.•Inhibition of heparanase results in decreased tumor growth and metastasis in vivo.•Several classes of heparanase inhibitors are presently being investigated. Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains contributing to breakdown of the extracellular matrix. Increased expression of heparanase has been observed in numerous malignancies and is associated with a poor prognosis. It has generated significant interest as a potential antineoplastic target because of the multiple roles it plays in tumor growth and metastasis. The protumorigenic effects of heparanase are enhanced by the release of heparan sulfate side chains, with subsequent increase in bioactive fragments and cytokine levels that promote tumor invasion, angiogenesis, and metastasis. Preclinical experiments have found heparanase inhibitors to substantially reduce tumor growth and metastasis, leading to clinical trials with heparan sulfate mimetics. In this review, we examine the role of heparanase in tumor biology and its interaction with heparan surface proteoglycans, specifically syndecan-1, as well as the mechanism of action for heparanase inhibitors developed as antineoplastic therapeutics. Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains contributing to breakdown of the extracellular matrix. Increased expression of heparanase has been observed in numerous malignancies and is associated with a poor prognosis. It has generated significant interest as a potential antineoplastic target because of the multiple roles it plays in tumor growth and metastasis. The protumorigenic effects of heparanase are enhanced by the release of heparan sulfate side chains, with subsequent increase in bioactive fragments and cytokine levels that promote tumor invasion, angiogenesis, and metastasis. Preclinical experiments have found heparanase inhibitors to substantially reduce tumor growth and metastasis, leading to clinical trials with heparan sulfate mimetics. In this review, we examine the role of heparanase in tumor biology and its interaction with heparan surface proteoglycans, specifically syndecan-1, as well as the mechanism of action for heparanase inhibitors developed as antineoplastic therapeutics. The extracellular matrix (ECM) is composed of different proteins that maintain cellular organization and architecture. It was initially felt to be inactive, but later appreciated as a dynamic entity, where significant cell signaling interactions occur [1Iozzo R. San Antonia J.D. Heparan sulfate proteoglycans: Heavy hitters in the angiogenesis arena.J Clin Invest. 2001; 108: 349-355Crossref PubMed Scopus (0) Google Scholar]. The ECM contains heparan sulfate proteoglycans (HSPGs), collagen, fibronectin, laminin, and growth factors [1Iozzo R. San Antonia J.D. Heparan sulfate proteoglycans: Heavy hitters in the angiogenesis arena.J Clin Invest. 2001; 108: 349-355Crossref PubMed Scopus (0) Google Scholar]. HSPGs are ubiquitous macromolecules that are integral parts of normal tissue architecture. They possess various functions, including cell attachment/adhesion, components of structural integrity, and reservoirs for growth factors; and act as cofactors in signaling pathways [2Kim S.H. Turnbull J. Guimond S. Extracellular matrix and cell signalling: The dynamic cooperation of integrin, proteoglycan and growth factor receptor.J Endocrinol. 2011; 209: 139-151Crossref PubMed Scopus (426) Google Scholar, 3Soares M. Teixeira F.C. Fontes M. et al.Heparan sulfate proteoglycans may promote or inhibit cancer progression by interacting with integrins and affecting cell migration.Biomed Res Int. 2015; 2015: 453801Crossref PubMed Scopus (0) Google Scholar]. HSPGs are composed of a core protein attached to one of several negatively charged polysaccharide chains of heparan sulfate glycosaminoglycans (GAGs). Heparan sulfate (HS) is composed of repeating units of glucosamine and glucuronic/iduronic acid residues [4Vlodavsky I. Beckhove P. Lerner I. et al.Significance of heparanase in cancer and inflammation.Cancer Microenviron. 2012; 5: 115-132Crossref PubMed Scopus (107) Google Scholar]. Heparanase is an endo-β-D-glucuronidase that cleaves HS side chains. This results in structural changes and the release of bioactive HS fragments from the ECM [5Friedmann Y. Vlodavsky I. Aingorn H. et al.Expression of heparanase in normal, dysplastic, and neoplastic human colonic mucosa and stroma: Evidence for its role in colonic tumorigenesis.Am J Pathol. 2000; 157: 1167-1175Abstract Full Text Full Text PDF PubMed Google Scholar]. Over the past two decades, much work has been dedicated to examining the role of heparanase in cancer biology. Various methods of analysis have revealed that heparanase expression is augmented in numerous cancers, including hematologic malignancies, carcinomas, and sarcomas [6Sato T. Yamaguchi A. Goi T. et al.Heparanase expression in human colorectal cancer and its relationship to tumor angiogenesis, hematogenous metastasis, and prognosis.J Surg Oncol. 2004; 87: 174-181Crossref PubMed Scopus (64) Google Scholar, 7Xu X. Quiros R.M. Maxhimer J.B. et al.Inverse correlation between heparan sulfate composition and heparanase-1 gene expression in thyroid papillary carcinomas: A potential role in tumor metastasis.Clin Cancer Res. 2003; 9: 5968-5979PubMed Google Scholar, 8Rohloff J. Zinke J. Schoppmeyer K. et al.Heparanase expression is a prognostic indicator for postoperative survival in pancreatic adenocarcinoma.Br J Cancer. 2002; 86: 1270-1275Crossref PubMed Scopus (92) Google Scholar, 9Gohji K. Okamoto M. Kitazawa S. et al.Heparanase protein and gene expression in bladder cancer.J Urol. 2001; 166: 1286-1290Abstract Full Text Full Text PDF PubMed Google Scholar, 10Masola V. Maran C. Tassone E. et al.Heparanase activity in alveolar and embryonal rhabdomyosarcoma: Implications for tumor invasion.BMC Cancer. 2009; 28: 304Crossref Scopus (0) Google Scholar, 11Maxhimer J. Quiros R.M. Stewart R. et al.Heparanase-1 expression is associated with the metastatic potential of breast cancer.Surgery. 2002; 132: 326-333Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 12Takaoka M. Naomoto Y. Ohkawa T. et al.Heparanase expression correlates with invasion and poor prognosis in gastric cancers.Lab Invest. 2003; 83: 613-622Crossref PubMed Scopus (148) Google Scholar, 13Beckhove P. Helmke B.M. Ziouta Y. et al.Heparanase expression at the invasion front of human head and neck cancers and correlation with poor prognosis.Clin Cancer Res. 2005; 11: 2899-2906Crossref PubMed Scopus (0) Google Scholar, 14Kelly T. Miao H.Q. Yang Y. et al.High heparanase activity in multiple myeloma is associated with elevated microvessel density.Cancer Res. 2003; 63: 8749-8756PubMed Google Scholar, 15Bitan M. Polliack A. Zecchina G. et al.Heparanase expression in human leukemias is restricted to acute myeloid leukemias.Exp Hematol. 2002; 30: 34-41Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Furthermore, elevated heparanase levels are associated with reduced postoperative survival, increased angiogenesis, and metastasis [8Rohloff J. Zinke J. Schoppmeyer K. et al.Heparanase expression is a prognostic indicator for postoperative survival in pancreatic adenocarcinoma.Br J Cancer. 2002; 86: 1270-1275Crossref PubMed Scopus (92) Google Scholar, 12Takaoka M. Naomoto Y. Ohkawa T. et al.Heparanase expression correlates with invasion and poor prognosis in gastric cancers.Lab Invest. 2003; 83: 613-622Crossref PubMed Scopus (148) Google Scholar, 13Beckhove P. Helmke B.M. Ziouta Y. et al.Heparanase expression at the invasion front of human head and neck cancers and correlation with poor prognosis.Clin Cancer Res. 2005; 11: 2899-2906Crossref PubMed Scopus (0) Google Scholar, 16Vreys V. David G. Mammalian heparanase: What is the message?.J Cell Mol Med. 2007; 11: 427-452Crossref PubMed Scopus (143) Google Scholar]. All of these factors have sparked the development of heparanase inhibitors as novel anticancer agents. In this article, we review the function of heparanase in cancer biology and focus on the development of heparanase inhibitors, their specific mechanism of action, and relevant clinical findings to date. Mammalian cells express a single functional heparanase enzyme, heparanase-1 [17Ilan N. Elkin M. Vlodacsky I. Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis.Int J Biochem Cell Biol. 2006; 38: 2018-2039Crossref PubMed Scopus (337) Google Scholar]. Heparanase-2, a heparanase homolog, was cloned but is incapable of HS-degrading activity [18McKenzie E. Tyson K. Stamps A. et al.Cloning and expression profiling of Hpa2, a novel mammalian heparanase family member.Biochem Biophys Res Commun. 2000; 276: 1170-1177Crossref PubMed Scopus (121) Google Scholar, 19Levy–Adam F. Feld S. Cohen–Kaplan V. et al.Heparanase 2 interacts with heparan sulfate with high affinity and inhibits heparanase activity.J Biol Chem. 2010; 285: 28010-28019Crossref PubMed Scopus (45) Google Scholar]. It may, however, regulate heparanase-1 activity [20Arvatz G. Shafat I. Levy–Adam F. et al.The heparanase system and tumor metastasis: Is heparanase the seed and soil?.Cancer Metastasis Rev. 2011; 30: 253-268Crossref PubMed Scopus (76) Google Scholar]. The heparanase gene is located on chromosome 4q21.3 and is highly conserved throughout different species [21Dong J. Kukula A. Toyoshima M. et al.Genomic organization and chromosome localization of the newly identified human heparanase gene.Gene. 2000; 253: 171-178Crossref PubMed Scopus (0) Google Scholar]. It is first expressed as pre-proheparanase, with the N-terminal signal removed on translocation to the endoplasmic reticulum, generating a 65-kDa proheparanase; it is then moved to the Golgi apparatus, where it is encapsulated and secreted. Once secreted, it interacts with extracellular components before being internalized and mobilized to the late endosome/lysosome where it undergoes posttranslational proteolysis and alternative splicing to become active heparanase [22Kussie P. Hulmes J.D. Ludwig D.L. et al.Cloning and Functionl expression of a human heparanase gene.Biochem Biophys Res Commun. 1999; 261: 183-187Crossref PubMed Scopus (0) Google Scholar, 23Toyoshima M. Nakajima M. Human heparanase: Purification, characterization, cloning and expression.J Biol Chem. 1999; 274: 24153-24160Crossref PubMed Scopus (0) Google Scholar, 24Vlodavsky I. Friedman Y. Elkin M. et al.Mammalian heparanase: Gene cloning, expression and function in tumor progression and metastasis.Nat Med. 1999; 5: 793-802Crossref PubMed Scopus (620) Google Scholar, 25Zetser A. Levy-Adam F. Kaplan V. et al.Processing and activation of latent heparanase occurs in lysosomes.J Cell Sci. 2004; 117: 2249-2258Crossref PubMed Scopus (157) Google Scholar]. The active form of heparanase consists of a heterodimer composed of 8- and 50-kDa subunits that are noncovalently liked. The heparanase structure contains a TIM barrel fold, which incorporates the enzyme's active site, and a distinct C-terminus domain that has noncatalytic properties and is involved in heparanase's nonenzymatic signaling and secretory function [26Fux L. Ilan N. Sanderson R.D. et al.Heparanase: Busy at the cell surface.Trends Biochem Sci. 2009; 34: 511-519Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 27Zhou Z. Bates M. Madura J.D. Structure modeling, ligand binding, and binding affinity calculation (LR–MM–PBSA) of human heparanase for inhibition and drug design.Proteins. 2006; 65: 580-592Crossref PubMed Scopus (0) Google Scholar, 28Levy-Adam F. Abboud–Jarrous G. Guerrini M. et al.Identification and characterization of heparin/heparan sulfate binding domains of the endoglycosidase heparanase.J Biol Chem. 2005; 280: 20457-20466Crossref PubMed Scopus (0) Google Scholar]. Recently, the human heparanase enzyme structure was solved, confirming the TIM barrel fold structure [29Wu L. Viola C.M. Brzozowski A.M. et al.Structural characterization of human heparanase reveals insights into substrate recognition.Nat Struct Mol Biol. 2015; 22: 1016-1022Crossref PubMed Scopus (25) Google Scholar]. Heparanase expression is under tight regulation. In noncancerous cells, the heparanase promoter is constitutively inhibited secondary to promoter methylation and activity of wild-type p53, which suppresses transcription of the heparanase gene by directly binding to its promoter [30Baraz L. Haupt Y. Elkin M. et al.Tumor suppressor p53 regulates heparanase gene expression.Oncogene. 2006; 25: 3939-3947Crossref PubMed Scopus (0) Google Scholar]. Furthermore, additional regulation occurs during posttranslational processing. Cathepsin L is necessary for posttranslational activation of heparanase, and inhibitors of cathepsin L impede the formation of active heparanase [31Abboud–Jarrous G. Rangini–Guetta Z. Aingorn H. et al.Site-directed mutagenesis, proteolytic cleavage, and activation of human proheparanase.J Biol Chem. 2005; 280: 13568-13575Crossref PubMed Scopus (0) Google Scholar]. In nonpathologic states, heparanase expression is restricted primarily to platelets, activated white blood cells, and the placenta, with little or no expression in connective tissue or normal epithelium [5Friedmann Y. Vlodavsky I. Aingorn H. et al.Expression of heparanase in normal, dysplastic, and neoplastic human colonic mucosa and stroma: Evidence for its role in colonic tumorigenesis.Am J Pathol. 2000; 157: 1167-1175Abstract Full Text Full Text PDF PubMed Google Scholar]. Moreover, it is most active under acidic conditions (pH 5–6), during inflammation or within the tumor microenvironment [16Vreys V. David G. Mammalian heparanase: What is the message?.J Cell Mol Med. 2007; 11: 427-452Crossref PubMed Scopus (143) Google Scholar]. The syndecans (SDCs) are a family of four HSPGs that are either membrane bound or soluble. They have diverse functions including cell differentiation, cell adhesion, cytoskeletal organization, cell migration/invasion, and angiogenesis [32Liu W. Litwack E.D. Stanley M.J. et al.Heparan sulfate proteoglycans as adhesive and anti-invasive molecules: Syndecans and glypican have distinct functions.J Biol Chem. 1998; 273: 22825-22832Crossref PubMed Scopus (0) Google Scholar, 33Beauvais D.M. Burbach B.J. Rapraeger A.C. The syndecan-1 ectodomain regulates alphavbeta3 integrin activity in human mammary carcinoma cells.J Cell Biol. 2004; 167: 171-181Crossref PubMed Scopus (0) Google Scholar, 34Lee H. Kim Y. Choi Y. et al.Syndecan-2 cytoplasmic domain regulates colon cancer cell migration via interaction with syntenin-1.Biochem Biophys Res Commun. 2011; 409: 148-153Crossref PubMed Scopus (0) Google Scholar, 35Lee J. Park H. Chung H. et al.Syndecan-2 regulates the migratory potential of melanoma cells.J Biol Chem. 2009; 280: 27167-27175Crossref Scopus (0) Google Scholar]. Syndecan-1 (SDC-1) has been the most extensively studied and is found principally on epithelial cell surfaces. However, it is also present during different stages of lymphoid development, specifically on pre-B cells and plasma cells [36Sanderson R. Lalor P. Bernfield M. B lymphocytes express and lose syndecan at specific stages of differentiation.Cell Regul. 1989; 1: 27-35Crossref PubMed Google Scholar, 37Chilosi M. Adami F. Lestani M. et al.CD138/syndecan-1: A useful immunohistochemical marker of normal and neoplastic plasma cells on routine trephine bone marrow biopsies.Mod Pathol. 1999; 12: 1101-1106PubMed Google Scholar]. Loss of both syndecan-1 and E-cadherin from the cell surface is considered an integral step in neoplastic epithelial–mesenchymal cell transition [38Kalluri R. Weinberg R.A. The basics of epithelial–mesenchymal transition.J Clin Invest. 2009; 119: 1420-1428Crossref PubMed Scopus (3870) Google Scholar]. The heparanase/SDC-1 axis is a key regulator of cell signaling within tumor cells and the microenvironment, especially in multiple myeloma [39Ramani V. Purushothaman A. Stewart M.D. et al.The heparanase/syndecan-1 axis in cancer: Mechanisms and therapies.FEBS J. 2013; 280: 2294-2306Crossref PubMed Scopus (90) Google Scholar]. Syndecan-1 is made of three domains: (1) an extracellular domain composed mostly of heparan sulfate GAGs; (2) a transmembrane domain; and (3) a highly conserved cytoplasmic domain [40Bernfield M. Götte M. Park P.W. et al.Functions of cell surface heparan sulfate proteoglycans.Annu Rev Biochem. 1999; 68: 729-777Crossref PubMed Scopus (2006) Google Scholar]. Syndecan-1 can be shed and mobilized via proteolytic cleavage of the extracellular domain near the plasma membrane. This is performed primarily by shedases, frequently matrix metalloproteinases (MMPs) [41Hammond E. Khurana A. Shridhar V. et al.The role of heperanase and sulfatases in the modification of heparan sulfate proteoglycans within the tumor microenvironment and opportunities for novel cancer therapeutics.Front Oncol. 2014; 24: 195Google Scholar]. Shed syndecan-1 contains bound HS chains within the ectodomain (which typically contain bound growth factor) and, thus, can become a paracrine signaler by transferring signaling proteins from one cell to another [41Hammond E. Khurana A. Shridhar V. et al.The role of heperanase and sulfatases in the modification of heparan sulfate proteoglycans within the tumor microenvironment and opportunities for novel cancer therapeutics.Front Oncol. 2014; 24: 195Google Scholar]. In the case of malignancy, this is often from a cancer cell to a stromal cell [42Su G. Blaine S.A. Qiao D. et al.Shedding of syndecan-1 by stromal fibroblasts stimulates human breast cancer cell proliferation via FGF2 activation.J Biol Chem. 2007; 282: 14906-14915Crossref PubMed Scopus (0) Google Scholar, 43Purushothaman A. Uyama T. Kobayashi F. et al.Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis.Blood. 2010; 115: 2449-2457Crossref PubMed Scopus (0) Google Scholar]. Syndecan-1 shedding is regulated by various extracellular mechanisms including heparanase, growth factors (fibroblast growth factor-2 [FGF-2]), and chemokines [44Ramani V. Pruett P.S. Thompson C.A. et al.Heparan sulfate chains of syndecan-1 regulate ectodomain shedding.J Biol Chem. 2012; 287: 9952-9961Crossref PubMed Scopus (0) Google Scholar, 45Ding K. Lopez–Burks M. Sánchez-Duran J.A. et al.Growth factor-induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells.J Cell Biol. 2005; 171: 729-738Crossref PubMed Scopus (0) Google Scholar, 46Bass M.D. Morgan M.R. Humphries M.J. Syndecans shed their reputation as inert molecules.Sci Signal. 2009; 2: pe18Crossref PubMed Scopus (0) Google Scholar]. Heparanase increases syndecan-1 shedding, both in human myeloma and in breast cancer cell lines, by augmenting expression of MMP-9 through upregulation of ERK phosphorylation [47Yang Y. Macleod V. Miao H.Q. et al.Heparanase enhances syndecan-1 shedding: A novel mechanism for stimulation of tumor growth and metastasis.J Biol Chem. 2007; 282: 13326-13333Crossref PubMed Scopus (0) Google Scholar]. Heparanase also reduces the length of HS chains attached to syndecan-1, enhancing the rate at which shedases cleave the core protein [47Yang Y. Macleod V. Miao H.Q. et al.Heparanase enhances syndecan-1 shedding: A novel mechanism for stimulation of tumor growth and metastasis.J Biol Chem. 2007; 282: 13326-13333Crossref PubMed Scopus (0) Google Scholar]. Syndecan-1 is also shed constitutively, which is accelerated in tumors, typically in response to growth factors, chemokines, or other agonists [48Manon–Jensen T. Itoh Y. Couchman J.R. Proteoglycans in health and disease: The multiple roles of syndecan shedding.FEBS J. 2010; 277: 3876-3889Crossref PubMed Scopus (0) Google Scholar]. Recently, it was found that chemotherapy stimulates syndecan-1 shedding in colorectal cancer, pancreatic cancer, and human myeloma cell lines, increasing the risk for relapse and chemotherapy resistance [49Ramani V. Sanderson R.D. Chemotherapy stimulates syndecan-1 shedding: A potentially negative effect of treatment that may promote tumor relapse.Matrix Biol. 2014; 35: 215-222Crossref PubMed Scopus (0) Google Scholar, 50Ramani V. Vlodavsky I. Ng M. et al.Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype.Matrix Biol. 2016; ([EPub ahead of print])https://doi.org/10.1016/j.matbio.2016.03.006Crossref PubMed Scopus (13) Google Scholar]. The heparanase/syndecan-1 axis regulates growth factor release, thus modulating cellular proliferation [51Szatmári T. Ötvös R. Hjerpe A. et al.Syndecan-1 in cancer: Implications for cell signaling, differentiation, and prognostication.Dis Markers. 2015; 2015: 796052Crossref PubMed Scopus (7) Google Scholar]. Both hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are regulated by the heparanase/syndecan-1 axis. HGF is a cytokine that enhances growth, motility, and angiogenesis of tumor cells [52Ramani V. Yang Y. Ren Y. et al.Heparanase plays a dual role in driving hepatocyte growth factor (HGF) signaling by enhancing HGF expression and activity.J Biol Chem. 2011; 286: 6490-6499Crossref PubMed Scopus (62) Google Scholar]. Heparanase has been found to increase expression of HGF in myeloma cell lines. Shed syndecan-1 binds to secreted HGF, facilitating a paracrine and autocrine signaling cascade via cell surface receptor c-Met [52Ramani V. Yang Y. Ren Y. et al.Heparanase plays a dual role in driving hepatocyte growth factor (HGF) signaling by enhancing HGF expression and activity.J Biol Chem. 2011; 286: 6490-6499Crossref PubMed Scopus (62) Google Scholar]. Similarly, heparanase enhances VEGF secretion from tumor cells. Secreted VEGF subsequently binds shed sydecan-1 in the ECM, stimulating angiogenesis and endothelial invasion via the Erk pathway [43Purushothaman A. Uyama T. Kobayashi F. et al.Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis.Blood. 2010; 115: 2449-2457Crossref PubMed Scopus (0) Google Scholar]. In breast cancer, shed syndecan-1 promotes angiogenesis and growth via activation of FGF2 [42Su G. Blaine S.A. Qiao D. et al.Shedding of syndecan-1 by stromal fibroblasts stimulates human breast cancer cell proliferation via FGF2 activation.J Biol Chem. 2007; 282: 14906-14915Crossref PubMed Scopus (0) Google Scholar]. In multiple myeloma, shed syndecan-1 in the bone marrow ECM enhances growth, angiogenesis, and metastasis of myeloma cells within the bone. Cell membrane syndecan-1 promotes myeloma cell adhesion and inhibits invasion. Conversely, heparanase facilitates invasion of myeloma by increasing the expression and shedding of syndecan-1 [43Purushothaman A. Uyama T. Kobayashi F. et al.Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis.Blood. 2010; 115: 2449-2457Crossref PubMed Scopus (0) Google Scholar, 47Yang Y. Macleod V. Miao H.Q. et al.Heparanase enhances syndecan-1 shedding: A novel mechanism for stimulation of tumor growth and metastasis.J Biol Chem. 2007; 282: 13326-13333Crossref PubMed Scopus (0) Google Scholar, 53Yang Y. Yaccoby S. Liu W. et al.Soluble syndecan-1 promotes growth of myeloma tumors in vivo.Blood. 2002; 100: 610-617Crossref PubMed Scopus (0) Google Scholar]. Heparanase and syndecan-1 can also be transported to the nucleus to regulate gene expression. Shed syndecan-1 and the full syndecan-1 protein have been identified in the nucleus [51Szatmári T. Ötvös R. Hjerpe A. et al.Syndecan-1 in cancer: Implications for cell signaling, differentiation, and prognostication.Dis Markers. 2015; 2015: 796052Crossref PubMed Scopus (7) Google Scholar]. Similarly, HS has also been identified in the nucleus, both as free chains and bound to syndecan-1. Syndecan-1 transports HS to the nucleus, as it does for FGF2. In general, nuclear HS and syndecan-1 are antiproliferative and decrease gene transcription. Specifically, highly sulfated nuclear HS chains are mostly inhibitory [51Szatmári T. Ötvös R. Hjerpe A. et al.Syndecan-1 in cancer: Implications for cell signaling, differentiation, and prognostication.Dis Markers. 2015; 2015: 796052Crossref PubMed Scopus (7) Google Scholar, 54Cheng F. Petersson P. Arroyo-Yanguas Y. et al.Differences in the uptake and nuclear localization of anti-proliferative heparan sulfate between human lung fibroblasts and human lung carcinoma cells.J Cell Biochem. 2001; 83: 597-606Crossref PubMed Scopus (0) Google Scholar]. This is in contrast to extracellular shed syndecan-1, which promotes cell migration, angiogenesis, invasion, and proliferation [51Szatmári T. Ötvös R. Hjerpe A. et al.Syndecan-1 in cancer: Implications for cell signaling, differentiation, and prognostication.Dis Markers. 2015; 2015: 796052Crossref PubMed Scopus (7) Google Scholar]. Once in the nucleus, HS can regulate gene expression by decreasing histone acetylation and inhibiting transcription factors [55Dudás J. Ramadori G. Knittel T. et al.Effect of heparin and liver heparan sulphate on interaction of HepG2-derived transcription factors and their cis-acting elements: altered potential of hepatocellular carcinoma heparan sulphate.Biochem J. 2000; 350: 245-251Crossref PubMed Scopus (0) Google Scholar]. Both syndecan-1 and HS can inhibit histone acetyl transferase enzyme (HAT), reducing gene expression and tumor growth [56Buczek–Thomas J. Hsia E. Rich C.B. et al.Inhibition of histone acetyltransferase by glycosaminoglycans.J Cell Biochem. 2008; 105: 108-120Crossref PubMed Scopus (0) Google Scholar, 57Stewart M. Ramani V.C. Sanderson R.D. Shed syndecan-1 translocates to the nucleus of cells delivering growth factors and inhibiting histone acetylation: A novel mechanism of tumor–host cross-talk.J Biol Chem. 2015; 290: 941-949Crossref PubMed Scopus (0) Google Scholar]. Conversely, heparanase augments gene expression in the nucleus and promotes growth [58He Y. Sutcliffe E.L. Bunting K.L. et al.The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes.Transcription. 2012; 3: 130-145Crossref PubMed Google Scholar]. In T-lymphocytes, heparanase binds to euchromatin, altering gene transcription [58He Y. Sutcliffe E.L. Bunting K.L. et al.The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes.Transcription. 2012; 3: 130-145Crossref PubMed Google Scholar]. Heparanase increases DNA topoisomerase I activity in metastatic breast cancer [59Zhang L. Sullivan P. Suyama J. et al.Epidermal growth factor-induced heparanase nucleolar localization augments DNA topoisomerase I activity in brain metastatic breast cancer.Mol Cancer Res. 2010; 8: 278-290Crossref PubMed Scopus (0) Google Scholar]. Lastly, heparanase decreases nuclear syndecan-1 levels, increasing gene expression and promoting aggressive tumor phenotype secondary to augmented HAT expression [60Purushothaman A. Hurst D.R. Pisano C. et al.Heparanase-mediated loss of nuclear syndecan-1 enhances histone acetyltransferase (HAT) activity to promote expression of genes that drive an aggressive tumor phenotype.J Biol Chem. 2011; 286: 30377-30383Crossref PubMed Scopus (51) Google Scholar]. Many studies have examined syndecan-1 expression as a prognostic tool in solid and hematologic malignancies. High levels of stromal expression of syndecan-1 are a negative prognostic factor in multiple malignancies. Low levels of epithelial syndecan-1 are generally an indicator of advanced disease and poor prognosis. It is believed that the loss of syndecan-1 represents cancer cells with high malignant and metastatic potential. Increased levels of soluble (shed) syndecan-1 also signify advanced disease and poor prognosis. However, this has not been consistent for all malignancies, as increased levels of soluble syndecan-1 have also been associated with improved prognosis [51Szatmári T. Ötvös R. Hjerpe A. et al.Syndecan-1 in cancer: Implications for cell signaling, differentiation, and prognostication.Dis Markers. 2015; 2015: 796052Crossref PubMed Scopus (7) Google Scholar, 61Götte M. Kersting C. Ruggiero M. et al.Predictive value of syndecan-1 expression for the response to neoadjuvant chemotherapy of primary breast cancer.Anticancer Res. 2006; 26: 621-627PubMed Google Scholar, 62Nguyen T. Grizzle W.E. Zhang K. et al.Syndecan-1 overexpression is associated with nonluminal subtypes and poor prognosis in advanced breast cancer.Am J Clin Pathol. 2013; 140: 468-474Crossref PubMed Scopus (0) Google Scholar, 63Juuti A. Nordling S. Lundin J. et al.Syndecan-1 expression––A novel prognostic marker in pancreatic cancer.Oncology. 2005; 68: 97-106Crossref PubMed Scopus (0) Google Scholar, 64Wiksten J. Lundin J. Nordling S. et al.Epithelial and stromal syndecan-1 expression as predictor of outcome in patients with gastric cancer.Int J Cancer. 2001; 95: 1-6Crossref PubMed Scopus (0) Google Scholar, 65Hasengaowa Kodama J. Kusumoto T. Shinyo Y. Seki N. Hiramatsu Y. Prognostic significance of syndecan-1 expression in human endometrial cancer.Ann Oncol. 2005; 16: 1109-1115Crossref PubMed Scopus (27) Google Scholar, 66Kusumoto T. Kodama J. Seki N. et al.Clinical significance of syndecan-1 and versican expression in human epithelial ovarian cancer.Oncol Rep. 2010; 23: 917-925PubMed Google Scholar, 67Mundt F. Heidari-Hamedani G. Nilsonne G. et al.Diagnostic and prognostic value of soluble syndecan-1 in pleural malignancies.Biomed Res Int. 2014; 2014: 419853Crossref PubMed Scopus (0) Google Sch" @default.
• W2515538046 created "2016-09-16" @default.
• W2515538046 creator A5047231615 @default.
• W2515538046 creator A5071675435 @default.
• W2515538046 date "2016-11-01" @default.
• W2515538046 modified "2023-10-16" @default.
• W2515538046 title "Mechanisms of heparanase inhibitors in cancer therapy" @default.
• W2515538046 cites W1469104101 @default.
• W2515538046 cites W1491748226 @default.
• W2515538046 cites W1499046649 @default.
• W2515538046 cites W1513452909 @default.
• W2515538046 cites W1535201509 @default.
• W2515538046 cites W1537480471 @default.
• W2515538046 cites W1554961657 @default.
• W2515538046 cites W1571736940 @default.
• W2515538046 cites W1789272384 @default.
• W2515538046 cites W1858622440 @default.
• W2515538046 cites W1886753592 @default.
• W2515538046 cites W1911803680 @default.
• W2515538046 cites W1942404486 @default.
• W2515538046 cites W1948889300 @default.
• W2515538046 cites W1963805168 @default.
• W2515538046 cites W1968152808 @default.
• W2515538046 cites W1971939635 @default.
• W2515538046 cites W1972215168 @default.
• W2515538046 cites W1973037169 @default.
• W2515538046 cites W1973733841 @default.
• W2515538046 cites W1974135108 @default.
• W2515538046 cites W1975475235 @default.
• W2515538046 cites W1976218313 @default.
• W2515538046 cites W1976649122 @default.
• W2515538046 cites W1977877980 @default.
• W2515538046 cites W1977960519 @default.
• W2515538046 cites W1982684154 @default.
• W2515538046 cites W1983398289 @default.
• W2515538046 cites W1985641370 @default.
• W2515538046 cites W1986740039 @default.
• W2515538046 cites W1988452415 @default.
• W2515538046 cites W1988887339 @default.
• W2515538046 cites W1991070017 @default.
• W2515538046 cites W1991286340 @default.
• W2515538046 cites W1992602391 @default.
• W2515538046 cites W1992734140 @default.
• W2515538046 cites W1992893580 @default.
• W2515538046 cites W1996514275 @default.
• W2515538046 cites W1997733193 @default.
• W2515538046 cites W1998265013 @default.
• W2515538046 cites W2004105893 @default.
• W2515538046 cites W2004299041 @default.
• W2515538046 cites W2008869013 @default.
• W2515538046 cites W2009962397 @default.
• W2515538046 cites W2011705594 @default.
• W2515538046 cites W2012056018 @default.
• W2515538046 cites W2012339228 @default.
• W2515538046 cites W2013200943 @default.
• W2515538046 cites W2013232219 @default.
• W2515538046 cites W2015714938 @default.
• W2515538046 cites W2017310477 @default.
• W2515538046 cites W2017430133 @default.
• W2515538046 cites W2018242510 @default.
• W2515538046 cites W2020098579 @default.
• W2515538046 cites W2022532273 @default.
• W2515538046 cites W2023101728 @default.
• W2515538046 cites W2025353695 @default.
• W2515538046 cites W2025396422 @default.
• W2515538046 cites W2025448846 @default.
• W2515538046 cites W2027789202 @default.
• W2515538046 cites W2027886908 @default.
• W2515538046 cites W2029176649 @default.
• W2515538046 cites W2033096051 @default.
• W2515538046 cites W2034622353 @default.
• W2515538046 cites W2037490988 @default.
• W2515538046 cites W2038276233 @default.
• W2515538046 cites W2042483947 @default.
• W2515538046 cites W2042802733 @default.
• W2515538046 cites W2046287218 @default.
• W2515538046 cites W2047059447 @default.
• W2515538046 cites W2048489220 @default.
• W2515538046 cites W2049811381 @default.
• W2515538046 cites W2050750274 @default.
• W2515538046 cites W2053785196 @default.
• W2515538046 cites W2054402970 @default.
• W2515538046 cites W2057581357 @default.
• W2515538046 cites W2058334081 @default.
• W2515538046 cites W2061858190 @default.
• W2515538046 cites W2062110955 @default.
• W2515538046 cites W2062606014 @default.
• W2515538046 cites W2062799405 @default.
• W2515538046 cites W2065209727 @default.
• W2515538046 cites W2066974889 @default.
• W2515538046 cites W2069565722 @default.
• W2515538046 cites W2071913509 @default.
• W2515538046 cites W2072160034 @default.
• W2515538046 cites W2072832503 @default.
• W2515538046 cites W2075994362 @default.
• W2515538046 cites W2076097930 @default.
• W2515538046 cites W2082418977 @default.
• W2515538046 cites W2082548786 @default.

• next