Involvement of Heparanase in the Pathogenesis of Mesothelioma: Basic Aspects and Clinical Applications

Barash, Uri; Lapidot, Moshe; Zohar, Yaniv; Loomis, Cynthia A.; Moreira, André L.; Feld, Sari; Goparaju, Chandra; Yang, Haining; Hammond, Edward; Zhang, Gan‐Lin; Li, Jin Ping; Ilan, Neta; Nagler, Arnon; Pass, Harvey I.; Vlodavsky, Israël

doi:10.1093/jnci/djy032

Cited by 43 publications

(51 citation statements)

References 45 publications

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“…Clinically, heparanase levels in patients' pleural effusions could distinguish between malignant and benign effusions, and heparanase H-score above 90 was associated with reduced patient survival. Given these preclinical and clinical data, heparanase appears to be an important mediator of mesothelioma, and heparanase inhibitors are worthy of investigation as a new therapeutic modality in mesothelioma clinical trials [114].…”

Section: Involvement Of Heparanase In the Pathogenesis Of Mesotheliommentioning

confidence: 99%

Forty Years of Basic and Translational Heparanase Research

Vlodavsky

Ilan

Sanderson

2020

Advances in Experimental Medicine and Biology

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Section: Involvement Of Heparanase In the Pathogenesis Of Mesotheliommentioning

confidence: 99%

Forty Years of Basic and Translational Heparanase Research

Vlodavsky

Ilan

Sanderson

2020

Advances in Experimental Medicine and Biology

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“…It inhibits the pro-inflammatory enzyme heparanase (Dredge et al, 2011) and has been demonstrated to suppress IL-6 in inflammatory (pancreatitis) and viral (Ross River virus) animal models in a process thought to be driven by elevated levels of heparanase , Supramaniam et al, 2018. Moreover, it blocks the heparanase-dependent invasion of macrophages into tumours in mouse cancer models (Ostapoff et al, 2013;Boyango et al, 2014;Barash et al, 2018). In the context of viral infection, the invasion of monocytes and macrophages into the lungs is associated with severe COVID-19 disease (Merad and Martin, 2020), representing an immunopathology which may be heparanase-dependent and potentially responsive to agents such as pixatimod.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 By Disrupting The Spike-ACE2 interaction

Mycroft-West

Gandhi

et al. 2020

Preprint

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A major global effort is currently ongoing to search for therapeutics and vaccines to treat or prevent infection by the SARS-CoV-2 virus. Repurposing existing entities is one attractive approach. The heparan sulfate mimetic pixatimod is a clinical-stage synthetic sulfated compound that is a potent inhibitor of the glycosidase heparanase, and has known anti-cancer, anti-inflammatory and also antiviral properties. Here we show that pixatimod binds directly to the SARS-CoV-2 spike protein S1 receptor binding domain (RBD) and alters its conformation. Notably, this site overlaps with the known ACE2 binding site in the S1 RBD. We find that pixatimod inhibits binding of recombinant S1 RBD to Vero cells which express the ACE2 receptor. Moreover, in assays with three different isolates of live SARS-CoV-2 virus we show that pixatimod effectively inhibits viral infection of Vero cells. Importantly, its potency is well within its safe therapeutic dose range. These data provide evidence that pixatimod is a potent antiviral agent against SARS-CoV-2. Together with its other known activities this provides a strong rationale for its clinical investigation as a new multimodal therapeutic for the current COVID-19 pandemic.

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“…The cells were cultured in DMEM medium (Biological Industries, Israel) supplemented with 10% fetal calf serum and antibiotics. Cells were infected with heparanase or heparanase shRNAs constructs (GIPZ lentiviral shRNA; Waltham, MA), selected with puromycin (Sigma; 5 μg/ml), expanded and pooled . CD24 gene construct was purchased from Origene Technologies (Rockville, MD), and transfected into the glioma cells utilizing X‐tremeGENE transfection reagent (Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…A second set of TMAs contained high‐grade glioma (HGG, 102 cases), low‐grade glioma (LGG, 80 cases), and nonmalignant control brain tissue has been described elsewhere . TMAs were subjected to immunostaining applying antiheparanase (antibody 733) and anti‐CD24 (Novus Biologicals; Littleton, CO) antibodies, essentially as described …”

Section: Methodsmentioning

confidence: 99%

“…Numerous clinical association studies have consistently demonstrated that upregulated heparanase expression correlates with enhanced metastasis and poor prognosis, thus confirming the prometastatic function of heparanase and encouraging the development of heparanase inhibitors as antitumor therapeutics . More recent studies provided compelling evidence that tie heparanase with all steps of tumor formation including tumor initiation, growth, metastasis and chemoresistance . While the prometastatic function of heparanase is a direct consequence of its enzymatic activity and remodeling of the ECM underlying epithelial and endothelial cells, the molecular mechanisms underlying the capacity of heparanase to promote tumor initiation, growth and chemoresistance are still incompletely understood.…”

Section: Introductionmentioning

confidence: 95%

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Heparanase promotes glioma progression via enhancing CD24 expression

Barash

Spyrou

Liu

et al. 2019

Intl Journal of Cancer

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Heparanase is an endo-β-D-glucuronidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans. Compelling evidence tie heparanase levels with all steps of tumor formation including tumor initiation, growth, metastasis and chemo-resistance, likely involving augmentation of signaling pathways and gene transcription. In order to reveal the molecular mechanism(s) underlying the protumorigenic properties of heparanase, we established an inducible (Tet-on) system in U87 human glioma cells and applied gene array methodology in order to identify genes associated with heparanase induction. We found that CD24, a mucin-like cell adhesion protein, is consistently upregulated by heparanase and by heparanase splice variant devoid of enzymatic activity, whereas heparanase gene silencing was associated with decreased CD24 expression. This finding was further substantiated by a similar pattern of heparanase and CD24 immunostaining in glioma patients (Pearson's correlation; R = 0.66, p = 0.00001). Noteworthy, overexpression of CD24 stimulated glioma cell migration, invasion, colony formation in soft agar and tumor growth in mice suggesting that CD24 functions promote tumor growth. Likewise, anti-CD24 neutralizing monoclonal antibody attenuated glioma tumor growth, and a similar inhibition was observed in mice treated with a neutralizing mAb directed against L1 cell adhesion molecule (L1CAM), a ligand for CD24. Importantly, significant shorter patient survival was found in heparanase-high/CD24-high tumors vs. heparanase-high/CD24-low tumors for both high-grade and low-grade glioma (p = 0.02). Our results thus uncover a novel heparanase-CD24-L1CAM axis that plays a significant role in glioma tumorigenesis.

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Involvement of Heparanase in the Pathogenesis of Mesothelioma: Basic Aspects and Clinical Applications

Cited by 43 publications

References 45 publications

Forty Years of Basic and Translational Heparanase Research

Forty Years of Basic and Translational Heparanase Research

Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 By Disrupting The Spike-ACE2 interaction

Heparanase promotes glioma progression via enhancing CD24 expression

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