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Semin Thromb Hemost 2021; 47(03): 240-253
DOI: 10.1055/s-0041-1725066
Review Article

Biology of the Heparanase–Heparan Sulfate Axis and Its Role in Disease Pathogenesis

Israel Vlodavsky
1   Technion Integrated Cancer Center (TICC), Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
,
Uri Barash
1   Technion Integrated Cancer Center (TICC), Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
,
Hien M. Nguyen
2   Department of Chemistry, Wayne State University, Detroit, Michigan
,
Shi-Ming Yang
3   Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China
,
Neta Ilan
1   Technion Integrated Cancer Center (TICC), Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
› Author Affiliations Funding This study was generously supported by research grants awarded to R.S. and I.V. by the National Institutes of Health (CA211752) and the United States-Israel Binational Science Foundation (BSF). It was also supported by grants from the Israel Science Foundation (grant 601/14; 1021/19), the ISF-NSFC joint research program (grant no. 2572/16 awarded to I.V. and S-M.Y.), the National Institutes of Health (R01GM098285 awarded to H.M.N.), and the Israel Cancer Research Fund (ICRF, awarded to I.V.). I.V. is a research professor of the ICRF. We gratefully acknowledge the continuous support and advice provided by Dr. Ralph D. Sanderson (UAB Comprehensive Cancer Center).
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Abstract

Cell surface proteoglycans are important constituents of the glycocalyx and participate in cell–cell and cell–extracellular matrix (ECM) interactions, enzyme activation and inhibition, and multiple signaling routes, thereby regulating cell proliferation, survival, adhesion, migration, and differentiation. Heparanase, the sole mammalian heparan sulfate degrading endoglycosidase, acts as an “activator” of HS proteoglycans, thus regulating tissue hemostasis. Heparanase is a multifaceted enzyme that together with heparan sulfate, primarily syndecan-1, drives signal transduction, immune cell activation, exosome formation, autophagy, and gene transcription via enzymatic and nonenzymatic activities. An important feature is the ability of heparanase to stimulate syndecan-1 shedding, thereby impacting cell behavior both locally and distally from its cell of origin. Heparanase releases a myriad of HS-bound growth factors, cytokines, and chemokines that are sequestered by heparan sulfate in the glycocalyx and ECM. Collectively, the heparan sulfate–heparanase axis plays pivotal roles in creating a permissive environment for cell proliferation, differentiation, and function, often resulting in the pathogenesis of diseases such as cancer, inflammation, endotheliitis, kidney dysfunction, tissue fibrosis, and viral infection.

Keywords

heparanase - syndecan - glycocalyx - signal transduction - exosomes

Authors' Contributions

I.V. and N.I. designed and wrote the review. U.B., H.M.N., and S-M.Y. contributed some sections and revised the review.




Publication History

Article published online:
01 April 2021

© 2021. Thieme. All rights reserved.

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