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Batool T.,Uppsala University | Fang J.,Uppsala University | Fang J.,GlycoNovo Technologies Co. | Barash U.,Cancer and Vascular Biology Research Center Rappaport | And 3 more authors.
FEBS Open Bio | Year: 2017

Heparan sulfate (HS) mediates the activity of various growth factors including TGF-β. Heparanase is an endo-glucuronidase that specifically cleaves and modifies HS structure. In this study, we examined the effect of heparanase expression on TGF-β1-dependent signaling activities. We found that overexpression of heparanase in human tumor cells (i.e., Fadu pharyngeal carcinoma, MCF7 breast carcinoma) attenuated TGF-β1-stimulated Smad phosphorylation and led to a slower cell proliferation. TGF-β1-stimulated Akt and Erk phosphorylation was also affected in the heparanase overexpression cells. This effect involved the enzymatic activity of heparanase, as overexpression of mutant inactive heparanase did not affect TGF-β1 signaling activity. Analysis of HS isolated from Fadu cells revealed an increase in sulfation of the HS that had a rapid turnover in cells overexpressing heparanase. It appears that the structural alterations of HS affect the ability of TGF-β1 to signal via its receptors and elicit a growth response. Given that heparanase expression promotes tumor growth in most cancers, this finding highlights a crosstalk between heparanase, HS, and TGF-β1 function in tumorigenesis. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.


Vlodavsky I.,Cancer and Vascular Biology Research Center Rappaport | Ilan N.,Cancer and Vascular Biology Research Center Rappaport | Zunino F.,Fondazione IRCCS Instituto Nazionale Dei Tumori
Biochemical Pharmacology | Year: 2014

Heparanase has generated substantial interest as therapeutic target for antitumor therapy, because its activity is implicated in malignant behavior of cancer cells and in tumor progression. Increased heparanase expression was found in numerous tumor types and correlates with poor prognosis. Heparanase, an endoglucuronidase responsible for heparan sulfate cleavage, regulates the structure and function of heparan sulfate proteoglycans, leading to disassembly of the extracellular matrix. The action of heparanase is involved in multiple regulatory events related, among other effects, to augmented bioavailability of growth factors and cytokines. Inhibitors of heparanase suppress tumor growth, angiogenesis and metastasis by modulating growth factor-mediated signaling, ECM barrier function and cell interactions in the tumor microenvironment. Therefore, targeting heparanase has potential implications for anti-tumor, anti-angiogenic and anti-inflammatory therapies. Current approaches for heparanase inhibition include development of chemically modified heparins, small molecule inhibitors and neutralizing antibodies. The available evidence supports the emerging utility of heparanase inhibition as a promising antitumor strategy, specifically in rational combination with other agents. The recent studies with compounds designed to block heparanase (e.g., modified heparins) provide a rational basis for their therapeutic application and optimization. © 2014 Elsevier Inc.


Jendresen C.B.,University of Oslo | Cui H.,Uppsala University | Zhang X.,Uppsala University | Vlodavsky I.,Cancer and Vascular Biology Research Center Rappaport | And 2 more authors.
Journal of Biological Chemistry | Year: 2015

Background: Heparan sulfate colocalizes with amyloid-β in senile plaques of Alzheimer disease. Results: Overexpression of the heparan sulfate-degrading enzyme (heparanase) lowers the amyloid burden in a transgenic mouse model of Alzheimer disease. Conclusion: Heparan sulfate modulates amyloid-β deposition. Significance: We present the first direct in vivo proof that heparan sulfate actively participates in senile plaque formation. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.


PubMed | Fondazione IRCCS Instituto Nazionale dei Tumori and Cancer and Vascular Biology Research Center Rappaport
Type: Journal Article | Journal: Biochemical pharmacology | Year: 2014

Heparanase has generated substantial interest as therapeutic target for antitumor therapy, because its activity is implicated in malignant behavior of cancer cells and in tumor progression. Increased heparanase expression was found in numerous tumor types and correlates with poor prognosis. Heparanase, an endoglucuronidase responsible for heparan sulfate cleavage, regulates the structure and function of heparan sulfate proteoglycans, leading to disassembly of the extracellular matrix. The action of heparanase is involved in multiple regulatory events related, among other effects, to augmented bioavailability of growth factors and cytokines. Inhibitors of heparanase suppress tumor growth, angiogenesis and metastasis by modulating growth factor-mediated signaling, ECM barrier function and cell interactions in the tumor microenvironment. Therefore, targeting heparanase has potential implications for anti-tumor, anti-angiogenic and anti-inflammatory therapies. Current approaches for heparanase inhibition include development of chemically modified heparins, small molecule inhibitors and neutralizing antibodies. The available evidence supports the emerging utility of heparanase inhibition as a promising antitumor strategy, specifically in rational combination with other agents. The recent studies with compounds designed to block heparanase (e.g., modified heparins) provide a rational basis for their therapeutic application and optimization.


Cui H.,Uppsala University | Tan Y.-X.,Uppsala University | Tan Y.-X.,Beijing Institute of Transfusion Medicine | Osterholm C.,Karolinska Institutet | And 5 more authors.
Oncotarget | Year: 2016

Heparanase is an endo-glucuronidase that specifically cleaves heparan sulfate (HS) and heparin polysaccharides. The enzyme is expressed at low levels in normaltissues, but is often upregulated under pathological conditions such as cancer and inflammation. Normal human platelets express exceptionally high levels of heparanase, but the functional consequences of this feature remain unknown. We investigated functional roles of heparanase by comparing the properties of platelets expressing high (Hpa-tg) or low (Ctr) levels of heparanase. Upon activation, Hpa-tg platelets exhibited a much stronger adhesion activity as compared to Ctr platelets, likely contributing to a higher thrombotic activity in a carotid thrombosis model. Furthermore, we found concomitant upregulated expression of both heparanase and CD62P (P-selectin) upon activation of mouse and human platelets. As platelets play important roles in tumor metastasis, these findings indicate contribution of the platelet heparanase to hyper-thrombotic conditions often seen in patients with metastatic cancer.


PubMed | Karolinska Institutet, Uppsala University and Cancer and Vascular Biology Research Center Rappaport
Type: Journal Article | Journal: Oncotarget | Year: 2016

Heparanase is an endo-glucuronidase that specifically cleaves heparan sulfate (HS) and heparin polysaccharides. The enzyme is expressed at low levels in normal tissues, but is often upregulated under pathological conditions such as cancer and inflammation. Normal human platelets express exceptionally high levels of heparanase, but the functional consequences of this feature remain unknown. We investigated functional roles of heparanase by comparing the properties of platelets expressing high (Hpa-tg) or low (Ctr) levels of heparanase. Upon activation, Hpa-tg platelets exhibited a much stronger adhesion activity as compared to Ctr platelets, likely contributing to a higher thrombotic activity in a carotid thrombosis model. Furthermore, we found concomitant upregulated expression of both heparanase and CD62P (P-selectin) upon activation of mouse and human platelets. As platelets play important roles in tumor metastasis, these findings indicate contribution of the platelet heparanase to hyper-thrombotic conditions often seen in patients with metastatic cancer.

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