Heparanase expression is a prognostic indicator for postoperative survival in pancreatic adenocarcinoma

Rohloff, J.; Zinke, Jan; Schoppmeyer, Konrad; Tannapfel, Andrea; Witzigmann, Helmut; Mössner, Joachim; Wittekind, Christian; Caca, Karel

doi:10.1038/sj.bjc.6600232

Cited by 112 publications

(111 citation statements)

References 29 publications

(32 reference statements)

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“…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: 79%

“…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%

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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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confidence: 79%

Section: Heparanase Activity Assaymentioning

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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“…Consequently, as the protein is synthesized and subsequently secreted into the medium, the Hpa levels within and outside the cells may be different at particular times. Additionally, though distributed in the stromal cells, Hpa protein expression is predominately found to occur in tumor cells (5)(6)(7)(8)(9)(10)(11). Consequently, detecting the Hpa protein levels inside the cell should more accurately reflect the amount of Hpa present in the cell.…”

Section: Discussionmentioning

confidence: 99%

“…Up-regulation of Hpa has been demonstrated in a number of primary human cancers and correlates with reduced postoperative survival in bladder (1), stomach (2), pancreas (3), colorectal (4) and gallbladder cancers (5). In addition, high levels of Hpa are expressed in patients with lymph nodes and distant metastasis (4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia activates heparanase expression in an NF-κB dependent manner

Wang

Pan²,

Meng³

et al. 2009

Oncol Rep

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Abstract. Hypoxia was shown to increase tumor cell invasion into the extracellular matrix in vitro. This result suggests that heparanase (Hpa), one of the key enzymes involved in tumor invasion and metastasis, may be regulated by hypoxia. RT-PCR, Western blot and Matrigel invasive assays were used to study the regulation of Hpa under hypoxia in human pancreatic MIA PaCa-2 cancer cells. Compared with those in normoxia (20% O 2 ), Hpa mRNA, protein and enzymatic activity levels, were up-regulated by a reduction in the oxygen level (1% O 2 ). Invasion by tumor cells into the extracellular matrix was found to be significantly enhanced. A reduction in Hpa protein levels was observed when nuclear factor κB (NF-κB) activation was blocked by pyrrolidine dithiocarbamate. The levels of Hpa were also reduced when Hpa was inhibited by an Hpa-specific antisense oligonucleotide. The MMP-9 mRNA, protein and gelatinase B activity levels in supernatants decreased significantly when Hpa was inhibited. We conclude that up-regulation of Hpa by hypoxia is NF-κB-dependent in MIA PaCa-2 cells and inhibition of Hpa reduces MMP-9 activity. This reduction in MMP-9 activity may be an important mechanism in tumor metastasis. IntroductionHeparanase (Hpa) is an endo-ß-glucuronidase that cleaves the heparin sulfate (HS) side-chain. This enzymatic reaction not only enhances tumor cell invasion and migration, but also releases important HS-binding cytokines relevant to angiogenesis, wound healing and tumor growth. Up-regulation of Hpa has been demonstrated in a number of primary human cancers and correlates with reduced postoperative survival in bladder (1), stomach (2), pancreas (3), colorectal (4) and gallbladder cancers (5). In addition, high levels of Hpa are expressed in patients with lymph nodes and distant metastasis (4-7).In solid tumors, cells are constantly exposed to chronic or acute hypoxia (8). In vitro studies have reported that tumor cells exposed to hypoxia exhibit an increased ability to invade the extracellular matrix (ECM) (9,10). Consequently, understanding the regulation and mutual relationship of degrading enzymes in hypoxic conditions is particularly important. It has been shown that high level of heparanase molecules may serve some species to adapt to severe hypoxic environment in spalax blind subterrance mole rat (11). In addition, a recent study showed that heparanase gene expression was increased in the brain tissue of rats subjected to repeated hypoxic exposures (12). Hpa activity was shown to be up-regulated by hypoxia in ovarian OC-MZ-6 cancer cell (13). However, information describing the mechanism of the regulation of Hpa and the relationship between degrading enzymes and hypoxia remains unresolved.In this study, we have characterized the regulation of Hpa in hypoxia using the human pancreatic cancer cell line MIA PaCa-2. The results showed that Hpa mRNA, protein and enzymatic activity levels were up-regulated by hypoxia, which is closely related to enhanced tumor cell invasion. Furthermore, up-regulation of Hpa ...

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“…Heparanase activity is correlated with cancer metastasis and angiogenesis, and the heparanase protein is up-regulated in essentially all types of human cancer, namely carcinomas, sarcomas, and hematological malignancies (1)(2)(3). Increased heparanase levels are often associated with increased tumor metastasis, higher microvessel density, and reduced postoperative patient survival (3)(4)(5)(6)(7), thus critically supporting the intimate involvement of heparanase in tumor progression.…”

mentioning

confidence: 99%

Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence

Riaz

Ilan²,

Vlodavsky³

et al. 2013

Journal of Biological Chemistry

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Background: Heparanase levels are associated with tumor metastasis. Latent heparanase induces the prosurvival PI3K-AKT pathway via uncharacterized mechanisms. Results: AKT activation by heparanase involved PI3K p110␣, RAS, RICTOR, a PP2-sensitive kinase, FAK or PYK2, and ␤1 or ␤3 integrin-mediated adhesion. Conclusion:The heparanase receptor(s) intimately cooperates with integrins during induction of the PI3K-AKT pathway. Significance: Key steps in the heparanase-PI3K-AKT axis were identified.

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Heparanase expression is a prognostic indicator for postoperative survival in pancreatic adenocarcinoma

Cited by 112 publications

References 29 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

Hypoxia activates heparanase expression in an NF-κB dependent manner

Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence

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