Cell surface expression and secretion of heparanase markedly promote tumor angiogenesis and metastasis

Goldshmidt, Orit; Zcharia, Eyal; Abramovitch, Rinat; Metzger, Shula; Aingorn, Helena; Friedmann, Yael; Schirrmacher, Volker; Mitrani, Eduardo; Vlodavsky, Israël

doi:10.1073/pnas.152070599

Cited by 157 publications

(164 citation statements)

References 44 publications

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“…Regulation at the post-translational level, namely heparanase processing, cellular localization and secretion, has also been implicated as major regulatory mechanisms. [26][27][28]42 Heparanase upregulation has been noted in several primary human tumors, including colon carcinoma by employing in situ hybridization and immunostaining. 31 Moreover, heparanase upregulation in colon carcinoma correlated with increased lymph vessel and vascular infiltration and, most importantly, with reduced postoperative survival rate, 43 suggesting that heparanase expression levels may be considered as an important diagnostic parameter.…”

Section: Discussionmentioning

confidence: 99%

Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Doviner

Maly

Kaplan³

et al. 2006

Modern Pathology

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Heparanase is a mammalian endo-b-D-glucuronidase that cleaves heparan sulfate side chains at a limited number of sites. Such enzymatic activity is thought to participate in degradation and remodeling of the extracellular matrix and to facilitate cell invasion associated with tumor metastasis, angiogenesis and inflammation. Traditionally, heparanase activity was well correlated with the metastatic potential of a large number of tumor-derived cell types. More recently, heparanase upregulation has been documented in an increasing number of primary human tumors, correlating with poor postoperative survival and increased tumor vascularity. Here, we employed antiheparanase 733 polyclonal antibody that preferentially recognizes the 50 kDa active heparanase subunit over the 65 kDa proenzyme, as well as anti-heparanase 92.4 monoclonal antibody that recognizes both the latent and the active enzyme, to follow heparanase expression, processing and localization throughout the adenoma-carcinoma transition of the colon epithelium. Normal (nondysplastic) mucosa of the large bowel near epithelial neoplasms, as well as areas of mild dysplasia in adenomas, exhibited a strong reactivity with antibody 733 that became even stronger in foci of moderate dysplasia. Interestingly, although reactivity with antibody 733 was markedly reduced in severe dysplasia and in colorectal carcinoma, response to antibody 92.4 exhibited the opposite trend and staining intensities increased in parallel with tumor stage, the highest being in carcinoma cells. Involvement of latent heparanase (detected by 92.4, but not by 733 antibody) in tumor progression was suggested by activation of the Akt/PKB signal transduction pathway upon heparanase overexpression or exogenous addition to HT29 human colon carcinoma cells. These results suggest that heparanase expression is induced during colon carcinogenesis, and that its processing, conformation and localization are tightly regulated during the course of colon adenoma-carcinoma progression. Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains of heparan sulfate proteoglycans. 1,2 Heparan sulfate proteoglycans consist of a protein core to which several heparan sulfate side chains are covalently attached. These complex macromolecules are highly abundant in the extracellular matrix and are thought to play an important structural role, contributing to extracellular matrix integrity and insolubility. 3 In addition, heparan sulfate side chains can bind to a variety of biological mediators such as growth factors, cytokines and chemokines, 4,5 thus functioning as a readily available reservoir that can be liberated upon local or systemic cues. Moreover, heparan sulfate proteoglycans on the cell surface participates directly in signal-transduction cascades by potentiating the interaction between certain growth factors and their receptors. 6-9 Heparan sulfate-degrading activity is thus expected to affect several fundamental aspects of cell behavior under normal and clinical settings. 1,2 Tr...

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Section: Discussionmentioning

confidence: 99%

Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Doviner

Maly

Kaplan³

et al. 2006

Modern Pathology

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“…Indeed, previous studies have suggested a role for heparanase in various pathophysiological conditions, including tumor metastasis (Escobar Galvis et al, 2007;Vlodavsky and Friedmann, 2001), experimental autoimmune disease (Lider et al, 1989), amyloidosis (Li et al, 2005) and delayed type hypersensitivity (DTH) reactions . A role for heparanase in tumour metastasis is supported by the strong correlation between levels of heparanase expression and metastatic potential of B16 melanoma (Vlodavsky et al, 1999) and T lymphoma (Goldshmidt et al, 2002b) cells. Further, it has been shown by RNA interference that suppression of heparanase expression ameliorates DTH reactions as well as reduces lung colonization of B16 melanoma cells (Edovitsky et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase

Waern

Jia

Pejler

et al. 2010

Molecular Immunology

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Heparanase is a heparan sulfate (HS) degrading endoglucuronidase that has been implicated in cell migration and inflammatory conditions. Here we used mice deficient of heparanase (Hpse -/-) to study the impact of heparanase on airway leukocytes. Normal numbers of macrophages and lymphocytes were present in bronchoalveolar lavage fluid of Hpse-/-mice, indicating that heparanase is not essential for proper homing of leukocytes to airways. While lymphocytes fromHpse -/-mice displayed normal morphology, Hpse -/-alveolar macrophages showed a striking, age-dependent appearance of granule-like structures in the cytoplasm.Transmission electron microscopy revealed that these structures corresponded to membrane-enclosed crystalline bodies that closely resembled the intracellular crystals known to be formed by the HS-binding protein Ym1, suggesting that heparanase deficiency is associated with intracellular Ym1 deposition. Indeed, applying immunocytochemistry, we found markedly higher levels of intracellular

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“…[21][22][23] Apart from its involvement in the egress of cells from the vasculature, heparanase is tightly involved in normal and pathological angiogenesis, primarily by means of releasing heparinbinding angiogenic factors sequestered by HS in the BM and ECM. 13,[24][25][26][27] In previous studies, we have demonstrated that human heparanase is localized primarily in a perinuclear pattern within lysosomes and late endosomes. 28,29 and occasionally may be surface associated and secreted.…”

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Human heparanase nuclear localization and enzymatic activity

Schubert¹,

Ilan²,

Shushy³

et al. 2004

Laboratory Investigation

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In previous studies, we have demonstrated that human heparanase (endo-b-D-glucuronidase) is localized primarily in a perinuclear pattern within lysosomes and late endosomes, and occasionally may be surface associated and secreted. The presence of two potential nuclear localization sequences in human heparanase, led us to investigate heparanase translocation into the nucleus and subsequent degradation of nuclear heparan sulfate. Applying cell fractionation, Western blot analysis, determination of heparanase activity and confocal microscopy, we identified heparanase within the nuclei of human glioma and breast carcinoma cells and estimated its amount to be about 7% of the cytosolic enzyme. Our results indicate that nuclear heparanase colocalizes with nuclear heparan sulfate and is enzymaticaly active. Moreover, following uptake of latent 65 kDa heparanase by cells that do not express the enzyme, an active 50 kDa heparanase was detected in the cell nucleus, capable of degrading both nuclear and extracellular matrix-derived heparan sulfate. Immunohistochemical examination of human squamous cell carcinoma specimens revealed a prominent granular staining of heparanase within the nuclei of the epithelial tumor cells vs no nuclear staining in the adjacent stromal cells. Taken together, it appears that heparanase is translocated into the cell nucleus where it may degrade the nuclear heparan sulfate and thereby affect nuclear functions that are thought to be regulated by heparan sulfate. Nuclear localization of heparanase suggests that the enzyme may fulfill nontraditional functions (ie, regulation of gene expression and signal transduction) apart of its well-documented involvement in cancer metastasis, angiogenesis and inflammation.

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Cell surface expression and secretion of heparanase markedly promote tumor angiogenesis and metastasis

Cited by 157 publications

References 44 publications

Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Accumulation of Ym1 and formation of intracellular crystalline bodies in alveolar macrophages lacking heparanase

Human heparanase nuclear localization and enzymatic activity

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