Send Orders for Reprints to reprints@benthamscience.net Current Cancer Drug Targets, 2014, 14, 1-8 1 1568-0096/14 $58.00+.00 © 2014 Bentham Science Publishers Heparanase as a Target in Cancer Therapy Valentina Masola 1 , Maria Francesca Secchi 1 , Giovanni Gambaro 2 and Maurizio Onisto 1, * 1 Department of Biomedical Science, University of Padova, Padova, Italy; 2 Division of Nephrology and Dialysis, Columbus-Gemelli Hospital Catholic University, School of Medicine, Rome, Italy 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  (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. Keywords: Angiogenesis, cancer, extracellular matrix, heparanase, heparanase inhibitors, heparan sulfate, metastasis. 1. INTRODUCTION The ability to metastasize is the feature that makes the malignant tumour cells so difficult to eradicate surgically or to eliminate by means of radio-chemotherapy and is the leading cause of death in cancer patients. The process by which cancer cells grow by infiltrating the surrounding normal tissues is referred to as tumour invasiveness. Initially, this process affects the same type of tissue from which the tumour has taken origin, but subsequently extends to adjacent tissues including the connective tissue from which, via the lymph-vascular system, metastatic dissemination may begin. Therefore, metastases are the end result of a complex series of events of interaction in the cell - extracellular environment. The invasive-metastatic process comprises several phases or steps: a) loss of adhesion between tumour cells and local invasion of the extracellular matrix (ECM) and stromal cell layers b) intravasation into the vascular system c) survival at turbulent transport through the vessels d) arrest at a distant organ level and extravasation e) adaptation to survive in the new microenvironment and metastatic colonization [1]. A successful tumour spreading also requires neo- angiogenesis since, in order to grow, cancerous cells need nutrients and oxygen together with the removal of metabolic waste. These necessities may be supplied by a new network *Address correspondence to this author at the Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy; Tel: +39 049 8276093; Fax: +39 049 8276097; E-mail: maurizio.onisto@unipd.it of blood vessels that penetrates into the cancerous mass. Moreover, these vessels sustain cancer-cell dissemination leading to metastasis. Heparanase (HPSE), an enzyme that cleaves within heparan sulphate (HS) chains, has been demonstrated to be particularly crucial in cancer progression and metastasis. Its over-expression in an increasing number of primary human tumours provides strong evidence for its pro-invasive and pro-angiogenic features. Heparanase promotes cancer progression not only by means of its activity that enables tumour cells to break through the ECM, but also by the release of many HS-linked molecules such as growth factors, cytokines and enzymes [2]. Some aspects of the role of heparanase in cancer and inflammation as well as its possible pharmacological inhibition as a strategy for relieving such disorders have been the subject of several recent review articles [3-5]. In this review we report an update of the present knowledge on the involvement of heparanase in cancer progression by incorporating recent advances with the latest information on strategies for its inhibition. 2. HEPARANASE 2.1. Molecular Properties, Processing and Localization The principal components of ECM are proteins and glycosaminoglycans (GAGs). HS is a GAG composed of linear repeating disaccharide units consisting of an uronic acid (glucuronic acid or iduronic acid) and a D-glucosamine.