Heparanase Enhances Syndecan-1 Shedding

Abstract

When shed from the cell surface, the heparan sulfate proteoglycan syndecan-1 can facilitate the growth, angiogenesis, and metastasis of tumors. Here we report that tumor cell expression of heparanase, an enzyme known to be a potent promoter of tumor progression and metastasis, regulates both the level and location of syndecan-1 within the tumor microenvironment by enhancing its synthesis and subsequent shedding from the tumor cell surface. Heparanase regulation of syndecan-1 is detected in both human myeloma and breast cancer cell lines. This regulation requires the presence of active enzyme, because mutated forms of heparanase lacking heparan sulfate-degrading activity failed to influence syndecan-1 expression or shedding. Removal of heparan sulfate from the cell surface using bacterial heparitinase dramatically accelerated syndecan-1 shedding, suggesting that the effects of heparanase on syndecan-1 expression by tumor cells may be due, at least in part, to enzymatic removal or reduction in the size of heparan sulfate chains. Animals bearing tumors formed from cells expressing high levels of heparanase or animals transgenic for heparanase expression exhibited elevated levels of serum syndecan-1 as compared with controls, indicating that heparanase regulation of syndecan-1 expression and shedding can occur in vivo and impact cancer progression and perhaps other pathological states. These results reveal a new mechanism by which heparanase promotes an aggressive tumor phenotype and suggests that heparanase and syndecan-1 act synergistically to fine tune the tumor microenvironment and ensure robust tumor growth.

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

“…We previously demonstrated that heparanase enhances syndecan-1 shedding in both myeloma and breast cancer cells and that elevated levels of syndecan-1 in the myeloma tumor microenvironment drives tumor angiogenesis, metastasis and growth (7,36,37). In addition to enhancing syndecan-1 shedding, elevation of heparanase diminishes localization of syndecan-1 in the nucleus (21).…”

Heparanase Plays a Dual Role in Driving Hepatocyte Growth Factor (HGF) Signaling by Enhancing HGF Expression and Activity

“…Heparan sulfate chains from the shed syndecan-1 were removed by addition of 5 milliunits/ml heparinase III (Seikagaku, Kogyo, Japan) at 37°C for 2 h. Levels of shed syndecan-1 were determined by ELISA as described previously (4). Experiments also included depletion of heparin-binding growth factors such as HGF from the conditioned media by incubating overnight at 4°C with 25 l of heparin immobilized on agarose (MP Biomedicals, Solon, OH).…”

“…In addition to its enzymatic glycosidase activity, various nonenzymatic roles of heparanase such as enhancement of AKT signaling have also been described (2). In multiple myeloma, data from in vitro and in vivo models coupled with analysis of clinical samples have identified heparanase as a promoter of tumor angiogenesis, growth, and metastasis (3)(4)(5)(6)(7). Together these findings indicate that heparanase is a key regulator of myeloma progression.…”

“…Many of the pro-tumorigenic effects of heparanase in myeloma have been traced to heparanase-stimulated up-regulation of syndecan-1 expression and shedding (2,4). Syndecan-1, a heparan sulfate proteoglycan, is expressed on most myeloma tumor cells and is a critical determinant of myeloma cell survival and growth (8).…”

Syndecan as a Messenger to Link Diabetes and Cancer

“…It has been identifi ed that syndecan-1 can be shed by heparanase from the cell surface (Yang et al, 2007) via stimulation of ERK that leads to MMP-9, a syndecan-1 sheddase, expression (Purushothaman et al, 2008). A more recent study indicated that heparanase also regulates levels of syndecan-1 in the nucleus (Chen and Sanderson, 2009).…”