The heparanase/syndecan-1 axis in cancer: mechanisms and therapies

Abstract

Heparanase is an endoglucuronidase that cleaves heparan sulfate chains of proteoglycans. In many malignancies, high heparanase expression and activity correlate with an aggressive tumour phenotype. A major consequence of heparanase action in cancer is a robust up-regulation of growth factor expression and increased shedding of syndecan-1 (a transmembrane heparan sulfate proteoglycan). Substantial evidence indicates that heparanase and syndecan-1 work together to drive growth factor signalling and regulate cell behaviours that enhance tumour growth, dissemination, angiogenesis and osteolysis. Preclinical and clinical studies have demonstrated that therapies targeting the heparanase/syndecan-1 axis hold promise for blocking the aggressive behaviour of cancer.

Figure 1

Schematic model of syndecan-1 structure – Syndecan-1 core protein consists of three major domains, 1) a long extracellular domain that bears the heparan sulfate (HS) and chondroitin sulfate (CS) chains at distinct sites, 2) a short transmembrane domain, and 3) a cytoplasmic domain that is highly conserved among different syndecans.

Figure 2

Model of the heparanase/syndecan-1 axis in cancer – The model shows the series of molecular events triggered by heparanase in tumor cells that establishes the heparanase/syndecan-1 axis. When heparanase is elevated in tumors the following events occur, (1) Levels of active ERK (P-ERK) are elevated in the cells. (2) P-ERK up-regulates the cellular expression of VEGF and MMP-9. HGF is also elevated in these cells but via signaling pathways that are independent of P-ERK. (3) With the increase in heparanase expression, syndecan-1 levels in the nucleus are diminished leading to an increase in the levels of acetylated histone H3. This facilitates the transcription of MMP-9 and VEGF. (4) Due to heparanase activity, the HS chains of syndecan-1 (SDC-1) on the cell surface are trimmed leading to enhanced cleavage of the core protein by MMP-9 which is now present in abundance. (5) The heparan sulfate chains of the shed syndecan-1 bind and complex with growth factors including HGF and VEGF whose expression is also stimulated by the expression of heparanase. (6) Shed syndecan-1 bearing the growth factors binds to extracellular matrix proteins (e.g., fibronectin, collagens) and sequesters these growth factors in the tumor microenvironment as well as at distal sites. (7) Shed syndecan-1 binding potentiates the signaling of the bound growth factors. This results in a strong, sustained downstream signaling in the host cells (e.g., stromal cells, endothelial cells), priming the microenvironment to support aggressive tumor growth.