Significance of heparanase in cancer and inflammation

Abstract

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.

Fig. 1

Predicted model of the active heparanase heterodimer showing the 50 + 8 kDa heparanase subunits, TIM-barrel and C-terminus domains, active site (Glu₂₂₅ & E₃₄₃, Red), and heparin binding domains (sites A and B). Right: Predicted structure of the C-terminus domain

Fig. 2

Overall survival curves of patients with salivary gland tumors according to heparanase immunostaining levels. Right: Immunohistochemical staining of heparanase in patients with salivary gland tumors. Formalin-fixed paraffin-embedded sections of salivary gland tumors were subjected to immunostaining of heparanase, applying anti-heparanase pAb 733. Staining was graded as 0 (negative), 1 (weak) and 2 (strong). Left: Kaplan-Meier analysis showed poor survival of patients with positive (score 1 & 2) heparanase expression, compared with patients who were diagnosed as heparanase-negative (score 0). After 300 months (25 years) of follow-up, 0% of heparanase-positive patients survived compared with 70% of patients with no detectable heparanase expression. [Reproduced from Ben-Izhak et al., (2006) Neoplasia8, 879–884]

Fig. 3

Heparanase expression in acute and chronic phases of UC. Tissue specimens derived from normal colon tissue (left), UC patients in acute (middle) and chronic (right) phases of the disease were stained with anti-heparanase antibody (reddish staining). Photographs are representative of control (n = 29) and UC (n = 10) samples (original magnification, ×200). [Reproduced from Lerner et al., (2011) J Clin Invest 121:1709–1721]

Fig. 4

A model of heparanase-driven vicious cycle that may power chronic inflammation and the associated tumorigenesis. Increased levels of TNFα secreted by activated macrophages induce heparanase expression in the epithelial compartment via Egr1-dependent mechanism. Secreted latent heparanase is processed into its active form by cathepsin (supplied by the macrophages), and in turn sensitizes macrophages to further activation (i.e., in case of colitis by luminal flora) thus preventing inflammation resolution, switching macrophage responses to the chronic inflammation pattern and creating tumor-inducing inflammatory environment. In addition, heparanase promotes tumor progression via stimulation of angiogenesis, release of ECM-bound growth factors and bioactive HS fragments, and removal of extracellular barriers for invasion. [Reproduced in part from Lerner et al., (2011) J Clin Invest 121:1709–1721]