Heparan sulfate proteoglycans (HSPGs) are primary components at the interface between virtually every eukaryotic cell and its extracellular matrix. HSPGs not only provide a storage depot for
heparin-binding molecules in the cell microenvironment, but also decisively regulate their accessibility, function and mode of action. As such, they are intimately involved in modulating cell invasion and signaling loops that are critical for
tumor growth,
inflammation and kidney function. In a series of studies performed since the cloning of the human
heparanase gene, we and others have demonstrated that
heparanase, the sole
heparan sulfate degrading
endoglycosidase, is causally involved in
cancer progression,
inflammation and
diabetic nephropathy and hence is a valid target for drug development.
Heparanase is causally involved in
inflammation and accelerates colon
tumorigenesis associated with
inflammatory bowel disease. Notably,
heparanase stimulates macrophage activation, while macrophages induce production and activation of latent
heparanase contributed by the colon epithelium, together generating a vicious cycle that powers
colitis and the associated
tumorigenesis.
Heparanase also plays a decisive role in the pathogenesis of
diabetic nephropathy, degrading
heparan sulfate in the glomerular basement membrane and ultimately leading to
proteinuria and kidney dysfunction. Notably, clinically relevant doses of ionizing radiation (IR) upregulate
heparanase expression and thereby augment the metastatic potential of
pancreatic carcinoma. Thus, combining
radiotherapy with
heparanase inhibition is an effective strategy to prevent
tumor resistance and dissemination in IR-treated
pancreatic cancer patients. Also, accumulating evidence indicate that
peptides derived from human
heparanase elicit a potent anti-
tumor immune response, suggesting that
heparanase represents a promising target
antigen for immunotherapeutic approaches against a broad variety of tumours.
Oligosaccharide-based compounds that inhibit
heparanase enzymatic activity were developed, aiming primarily at halting
tumor growth,
metastasis and angiogenesis. Some of these compounds are being evaluated in clinical trials, targeting both the
tumor and tumor microenvironment.