Heparanase: a key enzyme involved in cell invasion

Parish, Christopher R.; Freeman, Craig; Hulett, Mark D.

doi:10.1016/s0304-419x(01)00017-8

Cited by 336 publications

(481 citation statements)

References 42 publications

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“…Thus, a key aspect of tumor cell invasion is likely the cleavage of heparan sulfate molecules by heparanase, a supposition that is now confirmed from investigations of in vitro human metastatic cancer cell lines. 9 Ascertaining the role of heparanase in in vivo metastasis was stymied by the heterogeneity of the tissue. In our study, direct RT-PCR from bulk tissue showed that almost all of the matching normal gastric tissue had detectable heparanase expression.…”

Section: Discussionmentioning

confidence: 99%

Positive association of heparanase expression with tumor invasion and lymphatic metastasis in gastric carcinoma

Wang

Jiang

et al. 2005

Modern Pathology

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Tumor invasion and metastasis are the most common causes of death in gastric carcinoma. Human heparanase influences tumor invasiveness and angiogenesis. Analysis of its expression in gastric carcinoma has been hindered by our inability to procure pure cancer cells from heterogeneous tissue. In the present study, we analyzed heparanase expression in human primary and metastatic gastric carcinoma cells as well as in paired normal gastric epithelial cells by laser capture microdissection coupled with reverse transcriptionpolymerase chain reaction (RT-PCR). Tumor tissues, metastatic lymph nodes, and apparently uninvolved normal gastric tissues were collected from 30 patients who had undergone gastrectomy with radical lymph node dissection for gastric carcinoma without preoperative treatment. Bulk tissues and laser capture microdissected cell groups were separately subjected to RT-PCR analysis with heparanase-specific primers. For bulk tissues, heparanase-specific transcripts were detectable in all primary tumor tissues, metastatic lymph nodes, and almost all matching normal tissues. RT-PCR analysis after laser capture microdissection showed no detectable heparanase expression in matching normal epithelial cell groups. Of the laser capture microdissected primary gastric carcinoma cells, 47% (14/30) were heparanase positive. Expression was closely associated with greater tumor invasiveness, including Borrmann gross type and depth of wall infiltration. For metastatic cell groups dissected from lymph nodes, 95% showed clear heparanase expression. Furthermore, the extent of lymphatic spread was directly correlated to heparanase expression at the primary site. In conclusion, laser capture microdissection coupled with RT-PCR is a reliable approach for molecular analysis of heparanase expression in gastric carcinoma. Heparanase may facilitate invasion and metastasis of gastric carcinoma cells. Keywords: gastric carcinoma; laser capture microdissection; lymphatic metastasis; heparanase expression It is generally accepted that the invasion of the basement membrane and extracellular matrix is one of the critical steps for cancer cell metastasis. 1 Heparan sulfate proteoglycans, composed of a protein core covalently linked to heparan sulfate side-chains, represent a principal component of the extracellular matrix and, in particular, basement membranes. Cell surface heparan sulfate can also serve as coreceptors, along with the other cell surface molecules, to form functional receptor complexes that facilitate signal transduction. 2 Furthermore, heparan sulfate chains bind a large number of bioactive molecules and regulate their availability and function. These include growth factors, chemokines, cytokines, and enzymes that are essential for angiogenesis, cell adhesion, and locomotion. 3 Accordingly, enzymatic degradation of heparan sulfate may play a critical role in cancer cell invasion and metastasis. Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of heparan sulfate proteoglycans at a limited number ...

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Section: Discussionmentioning

confidence: 99%

Positive association of heparanase expression with tumor invasion and lymphatic metastasis in gastric carcinoma

Wang

Jiang

et al. 2005

Modern Pathology

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“…By far, the strongest reactivity with antibody 92.4 was observed in the deep growing edge of the carcinoma (Figure 1e, arrowheads, Table 1; P50.05 compared to carcinoma at a more superficial level), in agreement with the proinvasive function of the heparanase enzyme. 2,15,30,31,35 In cell clusters, heparanase was noted to assume both diffuse cytoplasmic and membrane-like localization (Figure 1f, arrows), whereas invading single carcinoma cells exhibited mostly membrane-like localization of heparanase (Figure 1f, arrowheads).…”

Section: Expression and Localization Of Heparanase As Evident By Antmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

“…[6][7][8][9] Heparan sulfate-degrading activity is thus expected to affect several fundamental aspects of cell behavior under normal and clinical settings. 1,2 Traditionally, heparanase activity was implicated in cellular invasion associated with angiogenesis, inflammation and cancer metastasis. [10][11][12][13][14] Recently, this notion gained further support by employing siRNA and ribozyme technologies, clearly depicting heparanase-mediated heparan sulfate cleavage and extracellular matrix remodeling as critical requisites for metastatic spread.…”

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confidence: 99%

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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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“…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.…”

mentioning

confidence: 99%

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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Heparanase: a key enzyme involved in cell invasion

Cited by 336 publications

References 42 publications

Positive association of heparanase expression with tumor invasion and lymphatic metastasis in gastric carcinoma

Positive association of heparanase expression with tumor invasion and lymphatic metastasis in gastric carcinoma

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

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

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