Heparanase and the hallmarks of cancer
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ournal of Translational Medicine Open Access
REVIEW
Heparanase and the hallmarks of cancer Krishnath M. Jayatilleke and Mark D. Hulett*
Abstract Heparanase is the only mammalian enzyme that cleaves heparan sulphate, an important component of the extracellular matrix. This leads to the remodelling of the extracellular matrix, whilst liberating growth factors and cytokines bound to heparan sulphate. This in turn promotes both physiological and pathological processes such as angiogenesis, immune cell migration, inflammation, wound healing and metastasis. Furthermore, heparanase exhibits non-enzymatic actions in cell signalling and in regulating gene expression. Cancer is underpinned by key characteristic features that promote malignant growth and disease progression, collectively termed the ‘hallmarks of cancer’. Essentially, all cancers examined to date have been reported to overexpress heparanase, leading to enhanced tumour growth and metastasis with concomitant poor patient survival. With its multiple roles within the tumour microenvironment, heparanase has been demonstrated to regulate each of these hallmark features, in turn highlighting the need for heparanase-targeted therapies. However, recent discoveries which demonstrated that heparanase can also regulate vital anti-tumour mechanisms have cast doubt on this approach. This review will explore the myriad ways by which heparanase functions as a key regulator of the hallmarks of cancer and will highlight its role as a major component within the tumour microenvironment. The dual role of heparanase within the tumour microenvironment, however, emphasises the need for further investigation into defining its precise mechanism of action in different cancer settings. Keywords: Heparanase, Cancer, Hallmarks of cancer, Extracellular matrix, Tumour microenvironment Background The common defining feature of all cancers is the loss of cellular regulation mechanisms through genetic changes leading to uncontrolled cell division, resulting in either benign or malignant neoplasms. A number of common characteristic features termed the ‘hallmarks of cancer’ were first described by Hanahan and Weinberg [1]. Six hallmarks were initially proposed as sustaining proliferative signalling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis and activating invasion and metastasis. These are now accompanied by four additional ‘enabling characteristics’ and ‘emerging hallmarks’, namely genome instability and mutation, tumour-promoting inflammation,
*Correspondence: [email protected] Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Plenty Road & Kingsbury Drive, Melbourne, VIC 3086, Australia
reprogramming energy metabolism and avoiding immune destruction [2]. The extracellular matrix (ECM) is essential for tissue integrity and homeostasis. Heparan sulphate (HS) is an important component of the ECM by contributing to maintenance of its structural integrity and regulatory
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