Comparative analysis of the ability of leucocytes, endothelial cells and platelets to degrade the subendothelial basement membrane: Evidence for cytokine dependence and detection of a novel sulfatase

Bartlett, Mark; Underwood, P.A.; Parish, Christopher R.

doi:10.1038/icb.1995.19

Cited by 75 publications

(69 citation statements)

References 36 publications

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“…Among the few cell types that express heparanase under normal physiological conditions are placental cytothrophoblasts, skin keratinocytes and blood borne cells such as lymphocytes, neutrophils, macrophages and platelets. 2,3 Heparanase was localized to tertiary granules of neutrophils 6,27 and mast cells, 28 and its release by degranulation has been implicated in diapedesis of a number of immune cells, including neutrophils, macrophages, mast cells, dendritic cells and lymphocytes, 13,29,30 thus strongly implying heparanase as a pro-inflammatory mediator. Surprisingly, however, only a weak heparanase staining was observed in immune cells of IBD specimens ( Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Heparanase upregulation by colonic epithelium in inflammatory bowel disease

et al. 2007

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Heparanase is an endo-b-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, yielding HS fragments of still appreciable size (B5-7 kDa). Heparanase activity has long been detected in a number of cell types and tissues. Importantly, heparanase activity correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the extracellular matrix barrier. Similarly, heparanase activity was implicated in neovascularization, inflammation and autoimmunity, involving migration of vascular endothelial cells and activated cells of the immune system. The involvement of heparanase in inflammatory processes of the gastrointestinal tract has not been examined. Here, we utilized immunohistochemical analysis to investigate heparanase expression in acute and chronic inflammatory conditions. Heparanase expression was not detected in specimens derived from normal colon tissue. In contrast, strong heparanase staining was observed in Crohn's disease and ulcerative colitis, but not in infectious colitis. Interestingly, heparanase staining was primarily observed in epithelial rather than immune cells. Importantly, un-fractionated as well as low molecular weight heparin (enoxaparin), which exhibit a strong inhibitory activity towards heparanase, have proven efficacious in ulcerative colitis and Crohn's disease patients, suggesting that heparanase is actively involved in these pathologies and thus may be considered as a target for the development of anti-inflammatory therapies. The mammalian endoglycosidase heparanase is the predominant enzyme that degrades heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPG), the dominant proteoglycan in the extracellular matrix (ECM) and cell surfaces. 1-3 HSPG consist of a protein core to which HS side chains are covalently attached. These complex macromolecules are highly abundant in the ECM and are thought to play an important structural role, contributing to ECM integrity and insolubility. 4,5 Traditionally, heparanase activity was well correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the ECM barrier. 6-9 A proof-of-concept of this notion has recently been established by using a specific antiheparanase ribosyme and siRNA methodology, 10 clearly implicating heparanase activity as a critical requisite for metastatic spread. Similarly, heparanase was implicated in cell dissemination associated with inflammation and autoimmunity. [11][12][13] Furthermore, heparanase activity can liberate a variety of HSPG-bound biological mediators, including cytokines and chemokines such as interferon (IFN)-g, MIP-1b, RANTES and interleukins, thus contributing to the regulation of inflammation and other immune responses. 14 Heparanase expression by the gastrointestinal tract has been documented by employing immunostaining, RT-PCR and heparanase activity analy...

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Section: Discussionmentioning

confidence: 99%

Heparanase upregulation by colonic epithelium in inflammatory bowel disease

et al. 2007

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“…Heparanase was localized to tertiary granules of neutrophils (12,13) and mast cells (7) and was released upon tumor necrosis factor-␣ and calcium ionophore treatments, respectively. Heparanase release by degranulation has been implicated in diapedesis and extravasation of a number of immune cells, including neutrophils, macrophages, and lymphocytes (8,14,15), while heparanase inhibitors exhibited an anti-inflammatory activity (15). Cleavage of HS side chains by degranulated heparanase during inflammation may facilitate the passage of blood-borne normal and malignant cells into tissues by altering the composition and structural integrity of the subendothelial ECM (1,8,14).…”

mentioning

confidence: 99%

“…Heparanase release by degranulation has been implicated in diapedesis and extravasation of a number of immune cells, including neutrophils, macrophages, and lymphocytes (8,14,15), while heparanase inhibitors exhibited an anti-inflammatory activity (15). Cleavage of HS side chains by degranulated heparanase during inflammation may facilitate the passage of blood-borne normal and malignant cells into tissues by altering the composition and structural integrity of the subendothelial ECM (1,8,14). In addition, heparanase may facilitate the release of a multitude of HS-bound growth factors, cytokines and chemokines that would, in turn, amplify the immune reaction or activate the vascular endothelium (16,17).…”

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confidence: 99%

Heparanase Induces Endothelial Cell Migration via Protein Kinase B/Akt Activation

Gingis-Velitski¹,

Zetser²,

Flugelman

et al. 2004

Journal of Biological Chemistry

212

239

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Heparanase is a mammalian endoglycosidase that degrades heparan sulfate (HS) at specific intra-chain sites. Blood-borne neutrophils, macrophages, mast cells, and platelets exhibit heparanase activity that is thought to be stored in specific granules. The degranulated heparanase is implicated in extravasation of metastatic tumor cells and activated cells of the immune system. Degranulation and heparanase release in response to an inflammatory stimulus or platelet activation would facilitate cellular extravasation directly, by altering the composition and structural integrity of the extracellular matrix, or indirectly, by releasing HS-bound proinflammatory cytokines and chemokines. We hypothesized that in addition to such indirect effect, the released heparanase may also locally affect and activate neighboring cells such as endothelial cells. Here, we provide evidence that addition of the 65-kDa latent heparanase to endothelial cells enhances Akt signaling. Heparanase-mediated Akt phosphorylation was independent of its enzymatic activity or the presence of cell membrane HS proteoglycans and was augmented by heparin. Moreover, addition of heparanase stimulated phosphatidylinositol 3-kinasedependent endothelial cell migration and invasion. These results suggest, for the first time, that heparanase activates endothelial cells and elicits angiogenic responses directly. This effect appears to be mediated by as yet unidentified heparanase receptor.Heparanase is an endo-␤-D-glucuronidase capable of cleaving heparan sulfate (HS) 1 side chains at a limited number of sites, yielding HS fragments of still appreciable size (ϳ5-7 kDa) (1-3). Participating in extracellular matrix (ECM) degradation and remodeling, heparanase activity has been traditionally correlated with the metastatic potential of tumor-derived cells (4 -7). Similarly, heparanase has been shown to facilitate cell invasion associated with angiogenesis, autoimmunity, and inflammation (6 -9). Among the few cell types that express heparanase under normal physiological conditions, platelets possess a high heparanase activity and were used as a source for heparanase purification (2, 10). In fact, serum heparanase is mainly derived from activated platelets (11). Heparanase was localized to tertiary granules of neutrophils (12, 13) and mast cells (7) and was released upon tumor necrosis factor-␣ and calcium ionophore treatments, respectively. Heparanase release by degranulation has been implicated in diapedesis and extravasation of a number of immune cells, including neutrophils, macrophages, and lymphocytes (8, 14, 15), while heparanase inhibitors exhibited an anti-inflammatory activity (15). Cleavage of HS side chains by degranulated heparanase during inflammation may facilitate the passage of blood-borne normal and malignant cells into tissues by altering the composition and structural integrity of the subendothelial ECM (1,8,14). In addition, heparanase may facilitate the release of a multitude of HS-bound growth factors, cytokines and chemokines that would, in tu...

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“…Heparanase activity is associated with migration and invasion processes during pathological events such as tumor invasion and tumor-mediated neovascularization (24 -26). As well, heparanase has normal physiological functions in the migration and extravasation of a number of immune cells (27)(28)(29). Interestingly, heparanase can, in a manner not associated with its enzymatic activity, increase the adhesion of immune and cancer cells (29 -31).…”

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confidence: 99%

Two Heparanase Splicing Variants with Distinct Properties Are Necessary in Early Xenopus Development

Bertolesi

Michaiel

McFarlane

2008

Journal of Biological Chemistry

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Heparanase is an endoglycosidase that cleaves heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs) present in extracellular matrix and cell membranes. Although HSPGs have many functions during development, little is known of the role of the enzyme that degrades HS, heparanase. We cloned and characterized the expression of two heparanase splicing variants from Xenopus laevis and studied their function in early embryonic development. The heparanase gene (termed xHpa) spans over 15 kb and consists of at least 12 exons. The long heparanase (XHpaL) cDNA encodes a 531-amino acid protein, whereas the short splicing variant (XHpaS) results in a protein with the same open reading frame but missing 58 amino acids as a consequence of a skipped exon 4. Comparative studies of both isoforms using heterologous expression systems showed: 1) XHpaL is enzymatically active, whereas XHpaS is not; 2) XHpaL and XHpaS interact with heparin and HS; 3) both proteins traffic through the endoplasmic reticulum and Golgi apparatus, but XHpaL is secreted into the medium, whereas XHpaS remains associated with the membrane as a consequence of the loss of three glycosylation sites; 4) overexpression of XHpaS but not XHpaL increases cell adhesion of glioma cells to HS-coated surfaces; 5) XHpaL and XHpaS mRNA and protein levels vary as development progresses; 6) specific antisense knock-down of both XHpaL and XHpaS, but not XHpaL alone, results in failure of embryogenesis to proceed. Interestingly, rescue experiments suggest that the two heparanases regulate the same developmental processes, but via different mechanisms.Growth factors, cytokines, and extracellular matrix (ECM) 2 molecules are important in controlling embryonic development. Their activity can be regulated by proteoglycans, including heparan sulfate proteoglycans (HSPGs) and chondroitin sulfate proteoglycans, which are families of molecules found in the ECM, and in basement and cell membranes (1). The basic molecular structure of HSPGs consists of a core protein to which are attached many heparan sulfate (HS) glycosaminoglycan chains (2).HSPGs regulate development by controlling the migration, adhesion, and morphology of various cell types (3-5). For example, mutations in genes involved in HSPG synthesis have emerged from genetic screens that affect axon guidance and segment polarity in Drosophila (6 -8). Similarly, defects in gastrulation and aberrant axonal pathfinding were observed when HSPGs were either knocked down or degraded enzymatically during Xenopus laevis development (9 -12). HSPGs affect biological events by several different means. For example, the structural integrity and selective permeability of components of the ECM and basement membrane, such as laminin, fibronectin, or collagen IV, depend on interactions with HSPGs. HSPGs also interact with enzymes, growth factors, cytokines, and chemokines, sequestering them in the ECM as an inactive reservoir (5,13,14). These molecules are then released and become bioactive upon enzymatic degradation of ...

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Comparative analysis of the ability of leucocytes, endothelial cells and platelets to degrade the subendothelial basement membrane: Evidence for cytokine dependence and detection of a novel sulfatase

Cited by 75 publications

References 36 publications

Heparanase upregulation by colonic epithelium in inflammatory bowel disease

Heparanase upregulation by colonic epithelium in inflammatory bowel disease

Heparanase Induces Endothelial Cell Migration via Protein Kinase B/Akt Activation

Two Heparanase Splicing Variants with Distinct Properties Are Necessary in Early Xenopus Development

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