Heparanase Levels Are Elevated in the Plasma of Pediatric Cancer Patients and Correlate with Response to Anticancer Treatment

Shafat, Itay; Barak, Asher; Postovsky, Sergey; Elhasid, Ronit; Ilan, Neta; Vlodavsky, Israël; Arush, M. Weyl Ben

doi:10.1593/neo.07673

Cited by 38 publications

(31 citation statements)

References 39 publications

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“…The occurrence of active heparanase extracellularly is further supported by the establishment of an ELISA method which preferentially recognizes the active 50 kDa enzyme vs. the latent 65 kDa protein [114]. Applying this method it was demonstrated that heparanase levels are elevated in the plasma of pediatric cancer patients, correlating with their response to anti-cancer treatments [115]. Likewise, elevated levels of heparanase were measured in the urine of bladder cancer patients, associating with disease progression [116].…”

Section: Post-transcriptional Regulation Biosynthesis Trafficking mentioning

confidence: 99%

The heparanase system and tumor metastasis: is heparanase the seed and soil?

Arvatz

Shafat

Levy-Adam

et al. 2011

Cancer Metastasis Rev

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101

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Tumor metastasis, the leading cause of cancer patients' death, is still insufficiently understood. While concepts and mechanisms of tumor metastasis are evolving, it is widely accepted that cancer metastasis is accompanied by orchestrated proteolytic activity executed by array of proteases. While matrix metalloproteinases (MMPs) attracted much attention, other proteases constitute the tumor milieu, of which a large family consists of cysteine proteases named cathepsins. Like MMPs, some cathepsins are often upregulated in cancer and, once secreted or localized to the cell surface, can degrade components of the extracellular matrix. In addition, cathepsin L is held responsible for processing and activation of heparanase, an endo-β-glucuronidase capable of cleaving heparan sulfate side chains of heparan sulfate proteoglycans, activity that is strongly implicated in cell dissemination associated with tumor metastasis, angiogenesis, and inflammation. In this review, we discuss recent progress in heparanase research focusing on heparanase-related molecules namely, cathepsin L and heparanase 2 (Hpa2), a heparanase homolog.

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Section: Post-transcriptional Regulation Biosynthesis Trafficking mentioning

confidence: 99%

The heparanase system and tumor metastasis: is heparanase the seed and soil?

Arvatz

Shafat

Levy-Adam

et al. 2011

Cancer Metastasis Rev

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101

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“…Using an ELISA method, 21 it was found that the level of active heparanase (GS3 8+50 kDa) in plasma drawn in sodium citrate was 500±29 pg/mL (0.0085 μM). 22 When heparanase, factor VIIa and factor X were incubated (15 min, 37°C) with pooled normal human plasma from five healthy donors, followed by the addition of a chromogenic substrate for factor Xa, a 7-to 8-fold increase in factor Xa levels was obtained compared to levels in plasma incubated in the absence of heparanase (Figure 2). In this condition the coagulation was mainly dependent on the concentration of endogenous TF, as described previously.…”

Section: Heparanase In Human Plasmamentioning

confidence: 99%

Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII

Nadir¹,

Brenner²,

Fux³

et al. 2010

Haematologica

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BackgroundHeparanase is an endo-β-D-glucuronidase dominantly involved in tumor metastasis and angiogenesis. Recently, we demonstrated that heparanase is involved in the regulation of the hemostatic system. Our hypothesis was that heparanase is directly involved in activation of the coagulation cascade. Design and MethodsActivated factor X and thrombin were studied using chromogenic assays, immunoblotting and thromboelastography. Heparanase levels were measured by enzyme-linked immunosorbent assay. A potential direct interaction between tissue factor and heparanase was studied by coimmunoprecipitation and far-western assays. ResultsInterestingly, addition of heparanase to tissue factor and activated factor VII resulted in a 3-to 4-fold increase in activation of the coagulation cascade as shown by increased activated factor X and thrombin production. Culture medium of human embryonic kidney 293 cells overexpressing heparanase and its derivatives increased activated factor X levels in a non-enzymatic manner. When heparanase was added to pooled normal plasma, a 7-to 8-fold increase in activated factor X level was observed. Subsequently, we searched for clinical data supporting this newly identified role of heparanase. Plasma samples from 35 patients with acute leukemia at presentation and 20 healthy donors were studied for heparanase and activated factor X levels. A strong positive correlation was found between plasma heparanase and activated factor X levels (r=0.735, P=0.001). Unfractionated heparin and an inhibitor of activated factor X abolished the effect of heparanase, while tissue factor pathway inhibitor and tissue factor pathway inhibitor-2 only attenuated the procoagulant effect. Using co-immunoprecipitation and farwestern analyses it was shown that heparanase interacts directly with tissue factor. ConclusionsOverall, our results support the notion that heparanase is a potential modulator of blood hemostasis, and suggest a novel mechanism by which heparanase increases the generation of activated factor X in the presence of tissue factor and activated factor VII.Key words: heparanase, coagulation cascade, tissue factor, Xa level.Citation: Nadir Y, Brenner B, Fux L, Shafat I, Attias J, and Vlodavsky I. Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII. Haematologica 2010;95(11):1927-1934. doi:10.3324/haematol.2010 Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII

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“…Heparanase upregulation was noted in an increasing number of primary human cancers, correlating with reduced postoperative survival of cancer patients (5,9). Elevated levels of heparanase were detected in the urine and plasma of patients with aggressive metastatic disease (11). Recently, we cloned a splice variant of human heparanase lacking exon 5 whose function has yet to be unraveled (12).…”

mentioning

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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Heparanase Levels Are Elevated in the Plasma of Pediatric Cancer Patients and Correlate with Response to Anticancer Treatment

Cited by 38 publications

References 39 publications

The heparanase system and tumor metastasis: is heparanase the seed and soil?

The heparanase system and tumor metastasis: is heparanase the seed and soil?

Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII

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

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