Heparanase as a Target in Cancer Therapy

Abstract

Heparanase is the unique and specific functional endoglycosidase capable of cleaving heparan sulfate (HS) chains. It exerts its enzymatic activity catalyzing the cleavage of the β (1,4)-glycosidic bond between glucuronic acid and glucosamine residue. HS cleavage results in remodelling of the extracellular matrix as well as in regulating the release of many HS-linked molecules such as growth factors, cytokines and enzymes involved in inflammation, wound healing and tumour invasion. A pro-metastatic and pro-angiogenic role for this enzyme has been widely demonstrated in many primary human tumours since high levels of heparanase correlate with lymph node and distant metastasis, elevated micro vessel density and reduced survival of cancer patients. Recently, data have been reported that heparanase regulates heparan sulfate proteoglycan syndecan-1 and promotes its shedding from the cell surface. Shed syndecan-1 in turn controls tumour growth, metastasis and neo-angiogenesis mainly by promoting growth-factor signaling in the tumour milieu. Considering that, once inactivated, there are no other molecules capable of performing the same function, it is evident how this enzyme may be an effective and attractive drug target. Several heparanase inhibitors have been developed and some of them have undergone clinical trials showing efficacy against tumours. In this mini-review we will discuss current knowledge of heparanase involvement in cancer as well as its targeted inhibition as a promising therapeutic option in tumour treatment.

Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma

“…Synthesis of the HS chain continues with chain elongation, followed by a series of enzymatic modifications, including deacetylation, epimerization, and sulfation, which result in broad diversity in the HS structure and lead to a varying capacity to bind molecules, such as growth factors, cytokines, chemokines, enzymes, matrix proteins, and numerous cell surface receptors [11]. In addition, several post-synthetic changes can occur at the cell surface and affect HS structure and function: i) fragmentation of HS by heparanase into oligosaccharides of different lengths, regulating the release of HS-bound ligands [12]; ii) selective removal of the 6-O-sulfate groups from HS chains by the two isoforms of extracellular endosulfatases, SULF1 and SULF2; and iii) shedding of the core protein ectodomain with the HS chains from the cell surface by sheddases. The shed syndecans may act as competitive inhibitors for membrane HSPGs or alter growth factor gradients in the neighborhood of the cell [13].…”

The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics

“…We will not cover in detail the work describing the importance of heparanase in these processes but will instead refer the interested reader to the excellent reviews that have already summarized this data (5, 6, 66). Rather, we will highlight one of the areas of research that has recently increased our understanding of heparanase functioning at the cellular level: namely its role in promoting epithelial–mesenchymal transition (EMT).…”

“…These functions are modulated by proteins that are released into the ECM to modify its constituent molecules. Three important proteins within this category are heparanase (4–6), Sulf1, and Sulf2 (7, 8), which are released by a variety of cells to modify the structure of HS and thereby alter the function of the ECM.…”

Impact of heparanase on renal fibrosis

“…In the last years, a number of HPSE inhibitors have been developed and some of them have entered clinical trials for cancer [48–50]. They include heparan sulfate mimetics, heparin-derived compounds, or other oligosaccharides that compete with the heparan sulfate chain for binding to heparanase [49].…”