Mammalian heparanase: what is the message?

Vreys, Veronique; Gourichon, David

doi:10.1111/j.1582-4934.2007.00039.x

Cited by 206 publications

(290 citation statements)

References 185 publications

(304 reference statements)

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“…Enzymatic degradation of HS leads to disassembly of the extracellular matrix (ECM) and correlates with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the ECM and basement membrane underlying epithelial and endothelial cells (1,2). Heparanase expression is induced in human cancer, most often associating with reduced patients' survival postoperation, increased tumor metastasis, and higher vessel density (3)(4)(5). In addition, heparanase up-regulation is associated with tumors larger in size (3,5).…”

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confidence: 99%

“…Heparanase expression is induced in human cancer, most often associating with reduced patients' survival postoperation, increased tumor metastasis, and higher vessel density (3)(4)(5). In addition, heparanase up-regulation is associated with tumors larger in size (3,5). Likewise, heparanase over-expression enhanced (6, 7), whereas local delivery of anti-heparanase siRNA inhibited (8), the growth of tumor xenografts.…”

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Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

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

106

140

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Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanaseneutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment.heparanase | lymphoma | neutralizing antibody | tumor growth | metastasis H eparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, releasing saccharide products with appreciable size (4-7 kDa) and biological potency. Enzymatic degradation of HS leads to disassembly of the extracellular matrix (ECM) and correlates with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the ECM and basement membrane underlying epithelial and endothelial cells (1, 2). Heparanase expression is induced in human cancer, most often associating with reduced patients' survival postoperation, increased tumor metastasis, and higher vessel density (3-5). In addition, heparanase up-regulation is associated with tumors larger in size (3, 5). Likewise, heparanase over-expression enhanced (6, 7), whereas local delivery of anti-heparanase siRNA inhibited (8), the growth of tumor xenografts. These results imply that heparanase function is not limited to tumor metastasis but is engaged in progression of the primary lesion, thus critically supporting the intimate involvement of heparanase in tumor progression and encouraging the development of heparanase inhibitors as anticancer therapeutics (9-12). As a consequence, heparanase inhibitors are currently evaluated in phase 1 clinical trials (13).Heparanase activity is similarly implicated in the progression of multiple myeloma (14-16), but its significan...

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confidence: 99%

mentioning

confidence: 99%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

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

106

140

View full text Add to dashboard Cite

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“…H eparanase is a mammalian endoglycosidase that degrades heparan sulfate (HS) at the cell surface and in the extracellular matrix (ECM) (1)(2)(3)(4)(5)(6)(7). Consequently, it facilitates migration of inflammatory and tumor cells, releases growth factors bound to HS in the ECM, and induces new blood vessel formation (angiogenesis) (3)(4)(5)(6)(7)(8).…”

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confidence: 99%

Alternatively splicedSpalaxheparanase inhibits extracellular matrix degradation, tumor growth, and metastasis

Nasser

Avivi²,

Shafat³

et al. 2009

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

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Heparanase is an endoglycosidase that degrades heparan sulfate (HS) at the cell surface and in the extracellular matrix. Heparanase is expressed mainly by cancer cells, and its expression is correlated with increased tumor aggressiveness, metastasis, and angiogenesis. Here, we report the cloning of a unique splice variant (splice 36) of heparanase from the subterranean blind mole rat (Spalax). This splice variant results from skipping part of exon 3, exons 4 and 5, and part of exon 6 and functions as a dominant negative to the wild-type enzyme. It inhibits HS degradation, suppresses glioma tumor growth, and decreases experimental B16 -BL6 lung colonization in a mouse model. Intriguingly, Spalax splice variant 7 of heparanase (which results from skipping of exon 7) is devoid of enzymatic activity, but unlike splice 36 it enhances tumor growth. Our results demonstrate that alternative splicing of heparanase regulates its enzymatic activity and might adapt the heparanase function to the fluctuating normoxic-hypoxic subterranean environment that Spalax experiences. Development of anticancer drugs designed to suppress tumor growth, angiogenesis, and metastasis is a major challenge, of which heparanase inhibition is a promising approach. We anticipate that the heparanase splicing model, evolved during 40 million years of Spalacid adaptation to underground life, would pave the way for the development of heparanase-based therapeutic modalities directed against angiogenesis, tumor growth, and metastasis.alternative splicing ͉ angiogenesis ͉ blind mole rat ͉ cancer ͉ heparan sulfate

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“…5,6 More recently, heparanase upregulation was documented in an increasing number of human carcinomas and hematological malignancies. 7,8 In many cases, heparanase induction correlated with increased tumor metastasis, vascular density, and shorter post-operative survival of cancer patients, thus providing a strong clinical support for the prometastatic and pro-angiogenic functions of the enzyme and encouraging the development of heparanase inhibitors such as anti-cancer drugs. [9][10][11][12] Heparanase expression by the gastrointestinal tract has been studied employing immunostaining, RT-PCR, and enzymatic activity analyses.…”

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Heparanase expression by Barrett's epithelium and during esophageal carcinoma progression

et al. 2009

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Enzymatic activity responsible for the cleavage of heparan sulfate, commonly known as heparanase, is abundant in tumor-derived cells. Heparanase cleaves heparan sulfate side chains, presumably at sites of low sulfation, thus facilitating structural alterations of the extracellular matrix and basement membrane underlying epithelial and endothelial cells. Traditionally, heparanase activity was correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of heparan sulfate cleavage and remodeling of the extracellular matrix barrier. More recently, heparanase upregulation was documented in an increasing number of human carcinomas and hematological malignancies, correlating with increased tumor metastasis, vascular density, and shorter post-operative survival of cancer patients. Although heparanase upregulation and its pro-malignant features are well documented, the instance of its induction in the course of tumor development was less investigated. Here, we used immunohistochemical analysis to investigate heparanase expression in normal esophagus, Barrett's esophagus without dysplasia, Barrett's esophagus with low-grade dysplasia, Barrett's esophagus with high-grade dysplasia, and adenocarcinoma of the esophagus. We report that heparanase expression is already induced in Barrett's epithelium without dysplasia, and is further increased during progression through distinct pathological stages, namely, low-grade dysplasia, highgrade dysplasia, and adenocarcinoma. Notably, heparanase induction correlated with increased cell proliferation index revealed by Ki-67 staining. These findings suggest that heparanase function is not limited to the process of tumor metastasis, but rather is engaged at the early stages of esophagus carcinoma initiation and progression. Modern Pathology ( Keywords: heparanase; Barrett's epithelium; esophageal; adenocarcinoma; staining; localization Heparanase is an endo-b-D-glucuronidase, the predominant enzyme that degrades heparan sulfate side chains of heparan sulfate proteoglycans. 1,2 These complex macromolecules are highly abundant in the extracellular matrix and are thought to have an important structural role, contributing to extracellular matrix integrity and insolubility. 3,4 Traditionally, heparanase activity was correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of heparan sulfate cleavage and remodeling of the extracellular matrix barrier. 1,2 A proof-of-concept to this notion has been established by using specific anti-heparanase ribozyme and siRNA methodologies, clearly implicating heparanase-mediated heparan sulfate cleavage as a critical requisite for metastatic spread. 5 Similarly, heparanase activity was implicated in cell dissemination associated with inflammation and angiogenesis. 5,6 More recently, heparanase upregulation was documented in an increasing number of human carcinomas and hematological malignancies. 7,8 In many cases, heparanase ind...

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Mammalian heparanase: what is the message?

Cited by 206 publications

References 185 publications

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Alternatively splicedSpalaxheparanase inhibits extracellular matrix degradation, tumor growth, and metastasis

Heparanase expression by Barrett's epithelium and during esophageal carcinoma progression

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