Abstract
Heparanase has been viewed as a promising anti-cancer drug target for almost two decades, but no anti-heparanase therapy has yet reached the clinic. This endoglycosidase is highly expressed in a variety of malignancies, and its high expression is associated with greater tumor size, more metastases, and a poor prognosis. It was first described as an enzyme cleaving heparan sulfate chains of proteoglycans located in extracellular matrices and on cell surfaces, but this is not its only function. It is a multi-functional protein with activities that are enzymatic and non-enzymatic and which take place both outside of the cell and intracellularly. Knowledge of the crystal structure of heparanase has assisted the interpretation of earlier structure-function studies as well as in the design of potential anti-heparanase agents. This review re-examines the various functions of heparanase in light of the structural data. The functions of the heparanase variant, T5, and structure and functions of heparanase-2 are also examined as these heparanase related, but non-enzymatic, proteins are likely to influence the in vivo efficacy of anti-heparanase drugs. The anti-heparanase drugs currently under development predominately focus on inhibiting the enzymatic activity of heparanase, which, in the absence of inhibitors with high clinical efficacy, prompts a discussion of whether this is the best approach. The diversity of outcomes attributed to heparanase and the difficulties of unequivocally determining which of these are due to its enzymatic activity is also discussed and leads us to the conclusion that heparanase is a valid, but challenging drug target for cancer.
Highlights
Heparanase is a heparin/heparan sulfate (HS) specific endo-β-D glucuronidase
A study using a series of structurally defined oligosaccharides ranging in size from penta- to nona-saccharides where the heparanase cleavage products were examined by electrospray ionization mass spectrometry (ESI-MS), revealed that heparanase most favors cleaving the linkage of a glucuronic acid linked to 6O-sulfated glucosamine that may be N-sulfated or N-acetylated [34, 35]
Most interestingly it inhibited the transcription and mRNA levels of the proangiogenic proteins, FGF1, FGF2, vascular endothelial growth factor (VEGF), and the metalloproteinase MMP-9 as well as heparanase itself [117]. Whether this effect was dependent upon heparanase was not determined. It is apparent from the analysis described here that heparanase is not a straight-forward anti-cancer drug target despite the wealth of evidence to indicate it contributes to tumor growth, tumor cell migration, metastasis formation, and chemoresistance
Summary
Heparanase has been viewed as a promising anti-cancer drug target for almost two decades, but no anti-heparanase therapy has yet reached the clinic. This endoglycosidase is highly expressed in a variety of malignancies, and its high expression is associated with greater tumor size, more metastases, and a poor prognosis. It was first described as an enzyme cleaving heparan sulfate chains of proteoglycans located in extracellular matrices and on cell surfaces, but this is not its only function.
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