Heparanase expression in human colorectal cancer and its relationship to tumor angiogenesis, hematogenous metastasis, and prognosis

Sato, Tomohiro; Yamaguchi, Akio; Goi, Takanori; Hirono, Yasuo; Takeuchi, Kazuo; Katayama, Kanji; Matsukawa, Shigeru

doi:10.1002/jso.20097

Cited by 71 publications

(75 citation statements)

References 22 publications

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“…The residue dissolved in 500 ml of distilled water was dialyzed, and the product was isolated by evaporation under reduced pressure. Its 13 C NMR spectrum closely corresponded to the one reported in the literature (48), indicating an essentially complete conversion of the original IdoA2SO 3 residues into IdoA residues.…”

Section: -O-desulfated Heparinssupporting

confidence: 80%

“…Heparins were commercial preparations from pig mucosa (H-1 to H-3 from Laboratori Derivati Organici, Trino Vercellese, Italy, and H-6 from Hepar), from beef mucosa (H-4 and H-5, Laboratori Derivati Organci), and from beef lung (H-7, The Upjohn Co.). The corresponding contents of major sulfate groups, as evaluated by 13 C NMR spectroscopy (42) 21,600. Sample desalting was carried out by dialysis against water with 1000-Da cut-off tubes or by fractionation on a 2.5 ϫ 100-cm Sephadex G-25 column (Amersham Biosciences) using 10% ethanol in water as eluent and UV detection at 210 nm.…”

Section: Methodsmentioning

confidence: 99%

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Modulation of the Heparanase-inhibiting Activity of Heparin through Selective Desulfation, Graded N-Acetylation, and Glycol Splitting

Naggi

Casu

Perez

et al. 2005

Journal of Biological Chemistry

208

147

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Heparanase is an endo-␤-glucuronidase that cleaves heparan sulfate (HS) chains of heparan sulfate proteoglycans on cell surfaces and in the extracellular matrix (ECM). Heparanase, overexpressed by most cancer cells, facilitates extravasation of blood-borne tumor cells and causes release of growth factors sequestered by HS chains, thus accelerating tumor growth and metastasis. Inhibition of heparanase with HS mimics is a promising target for a novel strategy in cancer therapy. In this study, in vitro inhibition of recombinant heparanase was determined for heparin derivatives differing in degrees of 2-O-and 6-O-sulfation, N-acetylation, and glycol splitting of nonsulfated uronic acid residues. The contemporaneous presence of sulfate groups at O-2 of IdoA and at O-6 of GlcN was found to be non-essential for effective inhibition of heparanase activity provided that one of the two positions retains a high degree of sulfation. N-Desulfation/ N-acetylation involved a marked decrease in the inhibitory activity for degrees of N-acetylation higher than 50%, suggesting that at least one NSO 3 group per disaccharide unit is involved in interaction with the enzyme. On the other hand, glycol splitting of preexisting or of both preexisting and chemically generated nonsulfated uronic acids dramatically increased the heparanase-inhibiting activity irrespective of the degree of N-acetylation. Indeed N-acetylated heparins in their glycol-split forms inhibited heparanase as effectively as the corresponding N-sulfated derivatives. Whereas heparin and N-acetylheparins containing unmodified D-glucuronic acid residues inhibited heparanase by acting, at least in part, as substrates, their glycol-split derivatives were no more susceptible to cleavage by heparanase. Glycol-split N-acetylheparins did not release basic fibroblast growth factor from ECM and failed to stimulate its mitogenic activity. The combination of high inhibition of heparanase and low release/potentiation of ECM-bound growth factor indicates that N-acetylated, glycol-split heparins are potential antiangiogenic and antimetastatic agents that are more effective than their counterparts with unmodified backbones.

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Section: -O-desulfated Heparinssupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Modulation of the Heparanase-inhibiting Activity of Heparin through Selective Desulfation, Graded N-Acetylation, and Glycol Splitting

Naggi

Casu

Perez

et al. 2005

Journal of Biological Chemistry

208

147

View full text Add to dashboard Cite

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“…Prometastatic activities of HPSE have been observed in several human malignancies, including colorectal carcinoma, cervical cancer and multiple myeloma [35][36][37] . However, the relevance of the more recently discovered gene regulatory functions of nuclear HPSE 5,6 remains uninvestigated in melanoma progression and thus the motivation of our study.…”

Section: Discussionmentioning

confidence: 99%

Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity

et al. 2015

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Heparanase-1 (HPSE) plays a pivotal role in structural remodeling of the ECM and glycocalyx thus conferring protumorigenic, proangiogenic and prometastatic properties to many cancer entities. In addition to its extracellular function, recent studies suggest an intracellular activity of HPSE with a largely unknown significance during tumor progression. Therefore, we investigated the relevance of HPSE duality in malignant melanoma in vitro as well as in mouse melanoma models basing on the intradermal injection of transfected melanoma cells. In line with its extracellular action, HPSE-deficiency led to a reduced shedding of the glycocalyx accompanied by a reduced availability of VEGF affecting tumor growth and vascularization. In contrast, we measured an elevated expression of the protumorigenic factors pentraxin-3, tissue factor, TNF-and most prominently MMP-9 upon HPSE knockdown. In vivo, HPSE-deficiency was related to increased lymph node metastasis. While inhibition of its extracellular function heparin was unable to block the gene regulatory impact of HPSE we proposed an intracellular mechanism. Immunostainings revealed a counter-staining of HPSE and NF-B in the nucleus suggesting a close relationship between both proteins. This finding was further supported by the discovery of a direct charge-driven molecular interaction between HPSE and DNA by using atomic force microscopy and a co-precipitation approach. Our findings are novel and point towards a dual identity of HPSE in malignant melanoma with a protumorigenic extracellular activity and a tumor suppressive nuclear action. Identification of molecular strategies to shuttle extracellular HPSE into the nuclei of cancer cells envisions new therapeutic options. AbstractHeparanase-1 (HPSE) plays a pivotal role in structural remodeling of the ECM and glycocalyx thus conferring protumorigenic, proangiogenic and prometastatic properties to many cancer entities. In addition to its extracellular function, recent studies suggest an intracellular activity of HPSE with a largely unknown significance during tumor progression.Therefore, we investigated the relevance of HPSE duality in malignant melanoma in vitro as well as in mouse melanoma models basing on the intradermal injection of transfected melanoma cells. In line with its extracellular action, HPSE-deficiency led to a reduced shedding of the glycocalyx accompanied by a reduced availability of VEGF affecting tumor growth and vascularization. In contrast, we measured an elevated expression of the protumorigenic factors pentraxin-3, tissue factor, TNF-α and most prominently MMP-9 upon HPSE knockdown. In vivo, HPSE-deficiency was related to increased lymph node metastasis.While inhibition of its extracellular function heparin was unable to block the gene regulatory impact of HPSE we proposed an intracellular mechanism. Immunostainings revealed a counter-staining of HPSE and NF-κB in the nucleus suggesting a close relationship between both proteins. This finding was further supported by the discovery of a dir...

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“…Fractions (0.2 ml) were eluted with PBS and their radioactivity counted in a l-scintillation counter. Degradation fragments of heparan sulfate side chains generated by heparanase are eluted at 0.5oK av o0.8 (peak II, fractions [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Nearly intact heparan sulfate proteoglycans are eluted just after the Vo (K av o0.2, peak I, fractions 3-15).…”

Section: Heparanase Activity Assaymentioning

confidence: 99%

“…15 Since the cloning of the heparanase gene and the availability of specific molecular probes, heparanase upregulation was documented in an increasing number of primary human tumors. Heparanase upregulation correlated with reduced postoperative survival of pancreatic, 16 bladder, 17 gastric, 18 cervical 19 and colorectal 20 cancer patients. Similarly, heparanase upregulation correlated with increased lymph node and distant metastases, 17,18,[21][22][23][24][25] providing a strong clinical support for the prometastatic feature of heparanase.…”

mentioning

confidence: 94%

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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Heparanase expression in human colorectal cancer and its relationship to tumor angiogenesis, hematogenous metastasis, and prognosis

Abstract: These results indicated that Heparanase expression may be an important role in invasion and hematogenous metastasis, and may be a biologic marker of prognostic significance in colorectal cancer patients.

Cited by 71 publications

References 22 publications

Modulation of the Heparanase-inhibiting Activity of Heparin through Selective Desulfation, Graded N-Acetylation, and Glycol Splitting

Modulation of the Heparanase-inhibiting Activity of Heparin through Selective Desulfation, Graded N-Acetylation, and Glycol Splitting

Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity

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

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