Heparanase as a molecular target of cancer chemotherapy

Abstract

Cancer cells require the ability to degrade the extracellular matrix (ECM) in order to turn into invasive and metastatic cancer cells. Many proteases and glycosidases are essential in the process of dissolving the components of the ECM. An endo-β β β β-D-glucuronidase, heparanase, is capable of specifically degrading one of the ECM components, heparan sulfate, and this activity is associated with the metastatic potential of tumor cells. Since heparanase mRNA is overexpressed in many human tumors (e.g., hepatomas, head and neck tumors, and esophageal carcinomas), the mechanisms regulating the activity of heparanase should be clarified; considering the possible role of heparanase in cancer, the development of heparanase inhibitors would appear to be advantageous. This review will focus on recent findings that have contributed to the characterization of heparanase and to the elucidation of the transcriptional regulation of heparanase mRNA expression, as well as the development of heparanase inhibitors. tudies of the biological function of extracellular matrix (ECM) molecules have revealed the central role of heparan sulfate proteoglycans (HSPGs) in many biological events, such as early embryogenesis and angiogenesis.1, 2) Heparan sulfate (HS) chains, consisting of strongly anionic linear polysaccharides, are structurally heterogeneous and bind a diverse repertoire of proteins under physiological conditions. Cell surface HS provides cells with a mechanism to snare a wide variety of extracellular effectors. These cell surface HSPGs modulate the activity of a wide variety of HS-binding proteins, acting as coreceptors with signaling receptors and directly as endocytosis receptors.3) As co-receptors, they potentiate the activity of sparse ligands by enhancing the formation of ligand-receptor complexes. In addition, intracellular signaling and endocytosis are augmented when HSPGs interact with soluble ligands. 1-3)HS/HSPG is known to interact with various molecules, 3) such as growth factors (e.g., fibroblast growth factors), cytokines (e.g., interleukin-2), ECM proteins (e.g., collagens), factors involved in blood coagulation (e.g., heparin cofactor II), and other proteins such as β-amyloid proteins and matrix metalloproteinase-7.1, 2, 4) Since HS chains are very similar among organisms as diverse as insects, mollusks, and mammals, the conservation of HS binding to extracellular proteins suggests that the association of these proteins with HS is conserved and functionally relevant. Because of the important and pleiotropic roles of HSPGs in cell physiology, the cleavage of HSPGs is likely to alter the integrity and functional state of tissues and to provide a mechanism by which cells can respond rapidly to changes in the extracellular environment. HS/HSPG carbohydrate chains are cleaved either by lyases (eliminative cleavage) or hydrolases (hydrolytic cleavage). These cleaving enzymes are therefore in part responsible for the modulation of the biological functions of HS/HSPGs-binding proteins. The enzymatic degradation o...

RECK-Mediated Suppression of Tumor Cell Invasion Is Regulated by Glycosylation in Human Tumor Cell Lines

“…The proteases (e.g., MMPs) and glycosidases (e.g., heparanase) play key roles in the normal physiology of connective tissue during development, morphogenesis, and wound healing, but their unregulated activity has been implicated in numerous disease processes including arthritis, tumor cell metastasis, and atherosclerosis (1)(2)(3)(4)9). Two important mechanisms regulating the activity of MMPs are (a) the binding of MMPs to a family of homologous proteins referred as the TIMPs and (b) the inhibition of both the enzymatic activity of MMPs and of their secretion into the extracellular space by RECK.…”

“…Due to the capacity of degradative enzymes such as proteases and glycosidases to degrade extracellular matrix (ECM) proteins, they are important components of this process (1)(2)(3)(4)(5). Among these enzymes, matrix metalloproteinases (MMP) have been the focus of much anticancer research (6).…”

Heparan sulphate synthetic and editing enzymes in ovarian cancer

“…Alternatively, the fine structure of HS can be modified by endosulphatases that specifically remove 6-O-sulphate groups from HS-S-domains (Morimoto-Tomita et al, 2002;Viviano et al, 2004). This has functional consequences as, in quails, QSULF-1, the avian homologue of mammalian SULFs, has dual regulatory functions as a negative regulator of FGF signalling and a positive regulator of Wnt signalling (Ai et al, 2003;Wang et al, 2004) Heparanase mRNA expression has been investigated in a wide variety of human tumours (reviewed in Simizu et al, 2004). Kodama et al (2003) examined heparanase RNA expression by RT -PCR in five borderline and 31 malignant epithelial ovarian tumours.…”

Involvement of Disulfide Bond Formation in the Activation of Heparanase

“…The antimetastatic effects of heparanase inhibitors have been reported in vitro and in vivo (8,40,42,47,48). In addition, our findings suggest that inhibitors of the formation of the disulfide bond may be developed into effective therapeutic agents for the treatment of heparanaseoverexpressing cancers.…”

“…Because heparan sulfate chains tightly bind to a diverse repertoire of proteins under physiologic conditions, the enzymatic cleavage of heparan sulfate by heparanase is likely to be involved in several biological phenomena, including cancer metastasis and angiogenesis (5)(6)(7)(8).…”