Cloning and Expression Profiling of Hpa2, a Novel Mammalian Heparanase Family Member

McKenzie, Edward A.; Tyson, Kerry; Stamps, Alasdair C.; Smith, Paul N.; Turner, Paul; Barry, Richard D.; Hircock, Margaret L.; Patel, Sonal; Barry, E; Stubberfield, Colin R.; Terrett, Jon; Pagé, Martin

doi:10.1006/bbrc.2000.3586

Cited by 173 publications

(144 citation statements)

References 38 publications

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“…Importantly, like the proteolytically cleaved collagen fragment endostatin, distinct HSGAG oligosaccharides, upon release by enzymatic cleavage from the tumor-cell surface, can serve as potent inhibitors of tumor progression. With the continuing discovery of mammalian HSGAG-degrading enzymes (6,7,38), our findings have direct implications for human tumor biology. Thus, the present study not only allows a paradigm of how the polysaccharides modulate tumor growth and metastasis, but it also identifies a therapeutic target by providing a framework toward the development of HSGAG-based anti-cancer molecules.…”

Section: Mechanism Of Action: Hsgags Impinge On the Biological Activimentioning

confidence: 89%

Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis

Liu

Shriver²,

Venkataraman³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

207

109

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Heparan sulfate glycosaminoglycans, present at the cell surface and in the extracellular matrix that surrounds cells, are important mediators of complex biological processes. Furthermore, it is now apparent that cells dynamically regulate the structure of their heparan sulfate ''coat'' to differentially regulate extracellular signals. In the present study, the importance of sequence information contained within tumor cell-surface heparan sulfate was investigated. Herein, we demonstrate that the heparan sulfate glycosaminoglycan coat present on tumor cells contains bioactive sequences that impinge on tumor-cell growth and metastasis. Importantly, we find that growth promoting as well as growth inhibiting sequences are contained within the polysaccharide coat. Furthermore, we find that the dynamic balance between these distinct polysaccharide populations regulates specific intracellular signal-transduction pathways. This study not only provides a framework for the development of polysaccharide-based anti-cancer molecules but also underscores the importance of understanding a cell's polysaccharide array in addition to its protein complement, to understand how genotype translates to phenotype in this postgenomic age.

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Section: Mechanism Of Action: Hsgags Impinge On the Biological Activimentioning

confidence: 89%

Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis

Liu

Shriver²,

Venkataraman³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

207

109

View full text Add to dashboard Cite

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“…The degradation of HS by these PMA-treated cells should be dependent on heparanase because only one heparanase gene was identified in humans (24). Using an internal sequence of the heparanase gene as a competitor, semiquantitative RT-PCR of heparanase mRNA expression was performed.…”

Section: Expression Level Of Heparanase Gene Did Not Alter After Pma mentioning

confidence: 99%

Cell Surface Localization of Heparanase on Macrophages Regulates Degradation of Extracellular Matrix Heparan Sulfate

Sasaki

Higashi

Taka

et al. 2004

The Journal of Immunology

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Extravasation of peripheral blood monocytes through vascular basement membranes requires degradation of extracellular matrix components including heparan sulfate proteoglycans (HSPGs). Heparanase, the heparan sulfate-specific endo-β-glucuronidase, has previously been shown to be a key enzyme in melanoma invasion, yet its involvement in monocyte extravasation has not been elucidated. We examined a potential regulatory mechanism of heparanase in HSPG degradation and transmigration through basement membranes in leukocyte trafficking using human promonocytic leukemia U937 and THP-1 cells. PMA-treated cells were shown to degrade 35S-sulfated HSPG in endothelial extracellular matrix into fragments of an approximate molecular mass of 5 kDa. This was not found with untreated cells. The gene expression levels of heparanase or the enzyme activity of the amount of cell lysates were no different between untreated and treated cells. Immunocytochemical staining with anti-heparanase mAb revealed pericellular distribution of heparanase in PMA-treated cells but not in untreated cells. Cell surface heparanase capped into a restricted area on PMA-treated cells when they were allowed to adhere. Addition of a chemoattractant fMLP induced polarization of the PMA-treated cells and heparanase redistribution at the leading edge of migration. Therefore a major regulatory process of heparanase activity in the cells seems to be surface expression and capping of the enzyme. Addition of the anti-heparanase Ab significantly inhibited enzymatic activity and transmigration of the PMA-treated cells, suggesting that the cell surface redistribution of heparanase is involved in monocyte extravasation through basement membranes.

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“…32) To identify the responsible transcriptional factor for the overexpression of heparanase mRNA in tumor cells, several groups have carried out promoter analyses of the heparanase gene. Two independent studies have recently suggested the Ets family transcription factors as potential regulators of basal heparanase mRNA expression in tumor cell lines.…”

Section: Heparanase Gene Expressionmentioning

confidence: 99%

Heparanase as a molecular target of cancer chemotherapy

2004

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Cancer cells require the ability to degrade the extracellular matrix (ECM) in order to turn into invasive and metastatic cancer cells. Many proteases and glycosidases are essential in the process of dissolving the components of the ECM. An endo-β β β β-D-glucuronidase, heparanase, is capable of specifically degrading one of the ECM components, heparan sulfate, and this activity is associated with the metastatic potential of tumor cells. Since heparanase mRNA is overexpressed in many human tumors (e.g., hepatomas, head and neck tumors, and esophageal carcinomas), the mechanisms regulating the activity of heparanase should be clarified; considering the possible role of heparanase in cancer, the development of heparanase inhibitors would appear to be advantageous. This review will focus on recent findings that have contributed to the characterization of heparanase and to the elucidation of the transcriptional regulation of heparanase mRNA expression, as well as the development of heparanase inhibitors. tudies of the biological function of extracellular matrix (ECM) molecules have revealed the central role of heparan sulfate proteoglycans (HSPGs) in many biological events, such as early embryogenesis and angiogenesis.1, 2) Heparan sulfate (HS) chains, consisting of strongly anionic linear polysaccharides, are structurally heterogeneous and bind a diverse repertoire of proteins under physiological conditions. Cell surface HS provides cells with a mechanism to snare a wide variety of extracellular effectors. These cell surface HSPGs modulate the activity of a wide variety of HS-binding proteins, acting as coreceptors with signaling receptors and directly as endocytosis receptors.3) As co-receptors, they potentiate the activity of sparse ligands by enhancing the formation of ligand-receptor complexes. In addition, intracellular signaling and endocytosis are augmented when HSPGs interact with soluble ligands. 1-3)HS/HSPG is known to interact with various molecules, 3) such as growth factors (e.g., fibroblast growth factors), cytokines (e.g., interleukin-2), ECM proteins (e.g., collagens), factors involved in blood coagulation (e.g., heparin cofactor II), and other proteins such as β-amyloid proteins and matrix metalloproteinase-7.1, 2, 4) Since HS chains are very similar among organisms as diverse as insects, mollusks, and mammals, the conservation of HS binding to extracellular proteins suggests that the association of these proteins with HS is conserved and functionally relevant. Because of the important and pleiotropic roles of HSPGs in cell physiology, the cleavage of HSPGs is likely to alter the integrity and functional state of tissues and to provide a mechanism by which cells can respond rapidly to changes in the extracellular environment. HS/HSPG carbohydrate chains are cleaved either by lyases (eliminative cleavage) or hydrolases (hydrolytic cleavage). These cleaving enzymes are therefore in part responsible for the modulation of the biological functions of HS/HSPGs-binding proteins. The enzymatic degradation o...

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Cloning and Expression Profiling of Hpa2, a Novel Mammalian Heparanase Family Member

Cited by 173 publications

References 38 publications

Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis

Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis

Cell Surface Localization of Heparanase on Macrophages Regulates Degradation of Extracellular Matrix Heparan Sulfate

Heparanase as a molecular target of cancer chemotherapy

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