Role of heparanase in tumor progression: Molecular aspects and therapeutic options

Heparanase (HPSE) is an endoglycosidase that catalyses the cutting of the side chains of heparan-sulphate proteoglycans (HS), thus determining the remodelling of the extracellular matrix and basement membranes, as well as promoting the release of different HS-related molecules as growth factors, cytokines and enzymes. Ever since the HPSE was identified in the late 1980s, several experimental studies have shown that its overexpression was instrumental in increasing tumor growth, metastatic dissemination, angiogenesis and inflammation. More recently, HPSE involvment has also been demonstrated in mediating tumor-host crosstalk, in inducing gene transcription, in the activation of signaling pathways and in the formation of exosomes and in autophagy. All of these activities (enzymatic and non-enzymatic) together make heparanase a multifunctional molecule that increases the aggressiveness and chemo-resistance of tumor cells. Conversely, heparanase gene-silencing or tumor treatment with compounds that inhibit heparanase activity have been shown to significantly attenuate tumor progression in different animal models of tumorigenesis, further emphasizing the therapeutic potential of anti-heparanase therapy for several types of neoplasms. This review focuses on present knowledge and recent development in the study of heparanase in cancer progression as well as on novel mechanisms by which heparanase regulates tumor metastasis and chemo-resistance. Moreover, recent advances in strategies for its inhibition as a potential therapeutic option will be discussed.