Inhibition of heparanase activity and tumor metastasis by laminarin sulfate and synthetic phosphorothioate oligodeoxynucleotides

Miao, Hua‐Quan; Elkin, Michael; Aingorn, Elena; Ishai‐Michaeli, Rivka; Stein, C. A.; Vlodavsky, Israël

doi:10.1002/(sici)1097-0215(19991029)83:3<424::aid-ijc20>3.3.co;2-c

Cited by 30 publications

(40 citation statements)

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“…Cell adhesion was not affected by laminaran sulfate, a potent inhibitor of heparanase activity and experimental metastasis (42). This result indicates that heparanase-mediated cell adhesion does not necessarily require its enzymatic activity.…”

Section: Discussionmentioning

confidence: 83%

“…It is therefore conceivable that the heparanasemediated cell adhesion may be independent of its endoglycosidase activity. To investigate this possibility, we examined the adhesive properties of heparanasetransfected cells in the absence or presence of laminaran sulfate, a potent inhibitor of heparanase activity and experimental metastasis (42). Laminaran sulfate is not a substrate for heparanase, but binds to the enzyme and inhibits its hydrolytic activity.…”

Section: Heparanase-mediated Cell Adhesion Does Not Require Heparanasmentioning

confidence: 99%

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Heparanase mediates cell adhesion independent of its enzymatic activity

Goldshmidt¹,

Zcharia²,

Cohen³

et al. 2003

FASEB j.

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173

162

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Heparanase is an endo-beta-D-glucuronidase that cleaves heparan sulfate and is implicated in diverse physiological and pathological processes. In this study we report on a novel direct involvement of heparanase in cell adhesion. We demonstrate that expression of heparanase in nonadherent lymphoma cells induces early stages of cell adhesion, provided that the enzyme is expressed on the cell surface. Heparanase-mediated cell adhesion to extracellular matrix (ECM) results in integrin-dependent cell spreading, tyrosine phosphorylation of paxillin, and reorganization of the actin cytoskeleton. The surface-bound enzyme also augments cell invasion through a reconstituted basement membrane. Cell adhesion was augmented by cell surface heparanase regardless of whether the cells were transfected with active or point mutated inactive enzyme, indicating that heparanase functions as an adhesion molecule independent of its endoglycosidase activity. The combined feature of heparanase as an ECM-degrading enzyme and a cell adhesion molecule emphasizes its significance in processes involving cell adhesion, migration, and invasion, including embryonic development, neovascularization, and cancer metastasis.

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Section: Discussionmentioning

confidence: 83%

Section: Heparanase-mediated Cell Adhesion Does Not Require Heparanasmentioning

confidence: 99%

Heparanase mediates cell adhesion independent of its enzymatic activity

Goldshmidt¹,

Zcharia²,

Cohen³

et al. 2003

FASEB j.

Self Cite

173

162

View full text Add to dashboard Cite

show abstract

“…Specific heparanase inhibitors are expected to provide pivotal tools for studying heparanase functions under normal and pathological conditions. Currently available heparanase inhibitors are various sulfated poly-and oligosaccharides such as heparin fragments, laminaran sulfate, and PI-88 (52)(53)(54). These compounds were shown to inhibit heparanase activity and elicit anti-metastatic and anti-angiogenic effects (52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

Heparanase accelerates wound angiogenesis and wound healing in mouse and rat models

Zcharia

Zilka

Yaar³

et al. 2005

FASEB j.

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143

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Orchestration of the rapid formation and reorganization of new tissue observed in wound healing involves not only cells and polypeptides but also the extracellular matrix (ECM) microenvironment. The ability of heparan sulfate (HS) to interact with major components of the ECM suggests a key role for HS in maintaining the structural integrity of the ECM. Heparanase, an endoglycosidase-degrading HS in the ECM and cell surface, is involved in the enzymatic machinery that enables cellular invasion and release of HS-bound polypeptides residing in the ECM. Bioavailabilty and activation of multitude mediators capable of promoting cell migration, proliferation, and neovascularization are of particular importance in the complex setting of wound healing. We provide evidence that heparanase is normally expressed in skin and in the wound granulation tissue. Heparanase stimulated keratinocyte cell migration and wound closure in vitro. Topical application of recombinant heparanase significantly accelerated wound healing in a flap/punch model and markedly improved flap survival. These heparanase effects were associated with enhanced wound epithelialization and blood vessel maturation. Similarly, a marked elevation in wound angiogenesis, evaluated by MRI analysis and histological analyses, was observed in heparanase-overexpressing transgenic mice. This effect was blocked by a novel, newly developed, heparanase-inhibiting glycol-split fragment of heparin. These results clearly indicate that elevation of heparanase levels in healing wounds markedly accelerates tissue repair and skin survival that are mediated primarily by an enhanced angiogenic response.-Zcharia, E., Zilka, R., Yaar, A., Yacoby-Zeevi, O., Zetser, A., Metzger, S., Sarid, R., Naggi, A., Casu, B., Ilan, N., Vlodavsky, I., Abramovitch, R. Heparanase accelerates wound angiogenesis and wound healing in mouse and rat models.

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“…Therapeutic benefits are expected to be obtained by strategies preventing enzymatic degradation of HS in the ECM, inhibiting heparanaseactivated signaling pathways, or reversing heparanase effects on immunocytes. Several inhibitory compounds are being developed and preclinically tested (Table 1), including small-molecule inhibitors and polyanionic molecules such as laminaran sulfate, suramin, phosphomannopentaose sulfate (PI-88), the synthetic fully sulfated HS mimetic PG545, and modified species of heparin [128][129][130][131][132][133][134][135][136]. Recently, a novel heparanase inhibitor, SST0001 [134,137] (chemically modified nonanticoagulant heparin), has entered clinical testing in a phase I trial for multiple myeloma.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Heparanase in inflammation and inflammation‐associated cancer

et al. 2013

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Recent years have seen a growing body of evidence that enzymatic remodeling of heparan sulfate proteoglycans profoundly affects a variety of physiological and pathological processes, including inflammation, neovasvularization and tumor development. Heparanase is the sole mammalian endoglycosidase that cleaves heparan sulfate. Extensively studied in cancer progression and aggressiveness, heparanase enzyme was recently implicated in several inflammatory disorders as well. Although the precise mode of heparanase action in inflammatory reactions is still not completely understood, the fact that heparanase activity is mechanistically important both in malignancy and in inflammation argues that this enzyme is a candidate molecule linking inflammation and tumorigenesis in inflammation-associated cancers. The elucidation of the specific effects of heparanase in cancer development, particularly when inflammation is a causal factor, will accelerate the development of novel therapeutic/chemopreventive interventions and help to better define target patient populations in which heparanase-targeting therapies could be particularly beneficial.

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Inhibition of heparanase activity and tumor metastasis by laminarin sulfate and synthetic phosphorothioate oligodeoxynucleotides

Cited by 30 publications

References 0 publications

Heparanase mediates cell adhesion independent of its enzymatic activity

Heparanase mediates cell adhesion independent of its enzymatic activity

Heparanase accelerates wound angiogenesis and wound healing in mouse and rat models

Heparanase in inflammation and inflammation‐associated cancer

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