Heparanase regulation of cancer, autophagy and inflammation: new mechanisms and targets for therapy

Abstract

Because of its impact on multiple biological pathways, heparanase has emerged as a major regulator of cancer, inflammation and other disease processes. Heparanase accomplishes this by degrading heparan sulfate which regulates the abundance and location of heparin-binding growth factors thereby influencing multiple signaling pathways that control gene expression, syndecan shedding and cell behavior. In addition, heparanase can act via nonenzymatic mechanisms that directly activate signaling at the cell surface. Clinical trials testing heparanase inhibitors as anticancer therapeutics are showing early signs of efficacy in patients further emphasizing the biological importance of this enzyme. This review focuses on recent developments in the field of heparanase regulation of cancer and inflammation, including the impact of heparanase on exosomes and autophagy, and novel mechanisms whereby heparanase regulates tumor metastasis, angiogenesis and chemoresistance. In addition, the ongoing development of heparanase inhibitors and their potential for treating cancer and inflammation are discussed.

Keywords: angiogenesis; autophagy; cancer; exosomes; heparan sulfate; heparanase; heparanase inhibitors; inflammation; metastasis; proteoglycan.

Figure 1

A schematic model of heparanase trafficking and function in autophagy. Once secreted (1), heparanase rapidly interacts with cell membrane HSPGs such as syndecans (SDC) (2), followed by a rapid endocytosis of the heparanase-HSPG complex (3). Conversion of endosomes to lysosomes (4) results in heparanase processing and activation (5). Typically, heparanase appears at perinuclear lysosomal vesicles (5). Lysosomal heparanase regulates the basal level of autophagy and resides within autophagosomes (HPSE-low). Cancer cells that exhibit high content of heparanase (HPSE-high) are endowed with increased autophagy (6) that promotes tumor growth and chemo resistance. Enhanced autophagy by heparanase is associated with reduced p70 S6-kinase phosphorylation levels and accumulation of mTOR1 at peri-nuclear areas (7) vs. more diffused distribution in control (HPSE-low) cells. Function of heparanase within the cell encourages the development of new class of inhibitors that will prevent heparanase uptake and lysosomal accumulation (8).

Figure 2

Heparanase activates a signaling mechanism that drives both tumor cell invasion and angiogenesis. (Left Panel) Myeloma cells express syndecan-1 on their cell surface composed of a core protein (green) and heparan sulfate chains (brown). Upregulation of heparanase (HPSE) expression by myeloma cells leads to trimming of syndecan-1 heparan sulfate chains, shortening their length and allowing increased access of proteases to the exposed syndecan-1 core protein. One such protease is MMP-9, a syndecan-1 sheddase whose expression is upregulated when heparanase is expressed by myeloma cells. MMP-9 cleaves the syndecan-1 core protein and the proteoglycan is shed from the cell surface. (Center Panel) Shedding of syndecan-1 exposes a cryptic domain within the juxtamembrane region of the core protein (green). Within this cryptic domain are amino acid sequences that bind to clustered VLA-4 (blue) and VEGFR2 (red) on the surface of myeloma cells or endothelial cells. (Right Panel) The coupling of VLA-4 and VEGFR2 receptors by shed syndecans activates VEGFR2 signaling that stimulates both cell invasion and endothelial tube formation. This signaling mechanism is inhibited by Roneparstat, a heparanase inhibitor that diminishes syndecan-1 shedding, or by synstatin peptides, peptide mimics of the syndecan-1 core protein that competitively inhibit binding of either VLA-4 or VEGFR-2 to shed syndecan-1.