Heparanase and the hallmarks of cancer

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.

The feedback regulator Nord controls Dpp/BMP signaling via extracellular interaction with Dally in theDrosophilawing

“…human; https://www.uniprot.org/uniprot/Q8TB73). Heparin is a variant of HS polysaccharides, which are ubiquitously present in all tissue types as a major component of HSPGs (Hammond et al, 2014; Nakato and Li, 2016; Xie and Li, 2019; Jayatilleke and Hulett, 2020). In the developing wing disc, Dally and Dally-like, members of the glypican family of HSPGs, regulate both the Dpp/BMP and Wg/Wnt signaling pathways by acting as co-receptors (Nakato and Li, 2016; Mii and Takada, 2020).…”

“…Extracellular regulation of HSPG, such as shedding of membrane-localized HSPGs from the cell surface, and digestion and/or modification of HS chains, is tightly regulated during development and homeostasis, and its misregulation has been recognized as a hallmark of cancer (Hammond et al, 2014; Nakato and Li, 2016; Xie and Li, 2019; Jayatilleke and Hulett, 2020). Matrix metallopeptidase 9 cleaves a transmembrane form HSPG syndecan-1 from the cell membrane, facilitating tumor growth, metastasis and angiogenesis (Yang et al, 2007; Purushothaman et al, 2008).…”

“…Nevertheless, the molecular mechanisms by which NDNF modulates multiple signaling pathways remain unclear. Intriguingly, it has been shown that HSPGs play essential roles in these biological processes (Purushothaman et al, 2008; Hammond et al, 2014; Jayatilleke and Hulett, 2020). For instance, mutations in heparan sulfate 6-O-sulfotransferase-1 and anosimin-1 are found in CHH patients (Tornberg et al, 2011; Hu et al, 2013; Neocleous et al, 2020).…”

Dissociation of DNA damage sensing by endoglycosidase HPSE

“…With this exploration of various cellular responses to genotoxic stress, we demonstrate that HPSE serves as a key intersection between the detection and effector phases of signal transduction in the regulation of cell cycle and DNA damage responses. HPSE non-enzymatic activity in particular has been implicated in an array of cellular pathways, yet the mechanism of these roles remains unclear ( Coombe and Gandhi, 2019 ; Jayatilleke and Hulett, 2020 ). Our recent study established that HPSE displays an inhibitory role over type I interferon and downstream responses ( Agelidis et al, 2021 ).…”

A Pro-Tumorigenic Effect of Heparanase 2 (Hpa2) in Thyroid Carcinoma Involves Its Localization to the Nuclear Membrane

“…Heparanase also cleaves HSPGs on the cell surface (i.e., syndecans), affecting their ability to function as co-receptors in signaling pathways (4). This, and other mechanisms utilized by heparanase to promote tumorigenesis (5)(6)(7)(8)(9), have turned this enzyme into a promising drug target and heparanase inhibitors are currently being evaluated in clinical trials as anti-cancer drugs (10,11). Elevated levels of heparanase were documented in an increasing number of human carcinomas and hematological malignancies, often associating with increased tumor metastasis and shorter survival rates (5)(6)(7)(8)(9).…”