Heparanase as a Target in Cancer Therapy
Valentina Masola, Maria Francesca Secchi, Giovanni Gambaro and Maurizio OnistoAffiliation:
Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
AbstractHeparanase 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.
Angiogenesis, cancer, extracellular matrix, heparanase, heparanase inhibitors, heparan sulfate, metastasis.
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