Heparanase and Heparanase-2: Function, Regulation, Signaling, and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: 20 May 2026 | Viewed by 1319

Special Issue Editors


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Guest Editor
Rappaport Faculty of Medicine, Technion Integrated Cancer Center (TICC), Technion—Israel Institute of Technology, Haifa 31096, Israel
Interests: heparanase; tumor microenvironment; extracellular matrix; tumor progression; metastasis
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Guest Editor
SciLifeLab Uppsala, The Biomedical Center, Department of Medical Biochemistry and Microbiology, University of Uppsala, 75237 Uppsala, Sweden
Interests: heparanase; tumor microenvironment

Special Issue Information

Dear Colleagues,

Heparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions extracellularly to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM-bound factors, augmenting, among other effects, gene transcription, autophagy, exosome formation, and heparan sulfate (HS) turnover. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor–host crosstalk and priming the tumor microenvironment to better support tumor growth, metastasis, and chemoresistance. The emerging premise is that heparanase, expressed by tumor cells, immune cells, endothelial cells, and other cells of the tumor microenvironment, is a key regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients, and a valid target for therapy. So far, however, anti-heparanase-based therapy has not been implemented in the clinic. Unlike heparanase, heparanase-2 (Hpa2), a close homolog of heparanase (Hpa1), does not undergo proteolytic processing and hence lacks intrinsic HS-degrading activity, the hallmark of heparanase. Hpa2 retains the capacity to bind heparin/HS and exhibits an even higher affinity for HS than heparanase, thus competing for HS binding and inhibiting heparanase enzymatic activity. It appears that Hpa2 functions as a natural inhibitor of Hpa1, regulates the expression of selected genes that maintain tissue hemostasis and normal function, and plays a protective role against cancer and inflammation, together emphasizing the significance of maintaining a proper Hpa1/Hpa2 ratio. 

We warmly invite researchers in this field to submit their work to this Special Issue. Both original research articles and comprehensive reviews are welcome.

Prof. Dr. Israël Vlodavsky
Prof. Dr. Jin-Ping Li
Guest Editors

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Keywords

  • heparanase (Hpa1)
  • heparanase-2 (Hpa2)
  • tumor microenvironment
  • extracellular matrix
  • tumor progression
  • tumor suppression
  • metastatic niche
  • glycocalyx
  • immune cells
  • inflammation

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Published Papers (1 paper)

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Research

17 pages, 3777 KB  
Article
Heparanase-Neutralizing Monoclonal Antibody (mAb A54) Attenuates Tumor Growth and Metastasis
by Uri Barash, Malik Farhoud, Maali Odeh, Eliezer Huberman, Liang Wu and Israel Vlodavsky
Cells 2025, 14(17), 1379; https://doi.org/10.3390/cells14171379 - 4 Sep 2025
Viewed by 864
Abstract
Heparanase is the only human enzyme responsible for heparan sulfate (HS) breakdown, an activity that remodels the extracellular matrix (ECM) and strongly drives cancer metastasis and angiogenesis. Compelling evidence implies that heparanase promotes essentially all aspects of the tumorigenic process, namely, tumor initiation, [...] Read more.
Heparanase is the only human enzyme responsible for heparan sulfate (HS) breakdown, an activity that remodels the extracellular matrix (ECM) and strongly drives cancer metastasis and angiogenesis. Compelling evidence implies that heparanase promotes essentially all aspects of the tumorigenic process, namely, tumor initiation, vascularization, growth, metastasis, and chemoresistance. A key mechanism by which heparanase accelerates cancer progression is by enabling the release and bioavailability of HS-bound growth factors, chemokines, and cytokines, residing in the tumor microenvironment and supporting tumor growth and metastasis. The currently available heparanase inhibitors are mostly HS/heparin-like compounds that lack specificity and exert multiple off-target side effects. To date, only four such compounds have progressed to clinical trials, and none have been approved for clinical use. We have generated and characterized an anti-heparanase monoclonal antibody (A54 mAb) that specifically inhibits heparanase enzymatic activity (ECM degradation assay) and cellular uptake. Importantly, A54 mAb attenuates xenograft tumor growth and metastasis (myeloma, glioma, pancreatic, and breast carcinomas) primarily when administered (syngeneic or immunocompromised mice) in combination with conventional anti-cancer drugs. Co-crystallization of the A54 Fab fragment and the heparanase enzyme revealed that the interaction between the two proteins takes place adjacent to the enzyme HS/heparin binding domain II (HBDII; Pro271-Ala276), likely hindering heparanase from interacting with HS substrates via steric occlusion of the active site cleft. Collectively, we have generated and characterized a novel mAb that specifically neutralizes heparanase enzymatic activity and attenuates its pro-tumorigenic effects in preclinical models, paving the way for its clinical examination against cancer, inflammation, and other diseases. Full article
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