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

Abstract

Hepatocyte growth factor (HGF) is a heparin-binding cytokine that enhances growth, motility, and angiogenesis of many tumor types, including multiple myeloma where it is often highly expressed. However, little is known regarding what controls HGF level and activity in these tumors. Evaluation of bone marrow biopsies from myeloma patients revealed a strong positive correlation between the levels of HGF and heparanase, an endoglucuronidase known to promote aggressive tumor behavior. In vitro, addition of recombinant heparanase to myeloma cells or transfection of myeloma cell lines with the cDNA for heparanase significantly increased tumor cell expression and secretion of biologically active HGF. Shed syndecan-1, whose levels in myeloma are also enhanced by heparanase expression, binds to secreted HGF. This syndecan-1-HGF complex is active as shown by its ability to stimulate paracrine signaling via c-Met, the cell surface receptor for HGF. Surprisingly, heparanase enzyme activity was not required for up-regulation of HGF expression by the tumor cells. This is in contrast to the heparanase-mediated enhanced syndecan-1 shedding, which does require activity of the enzyme. This suggests that two different functional domains within the heparanase enzyme (the enzyme active site and a separate site) contribute to events leading to enhanced HGF signaling. These findings demonstrate a novel mechanism driving the HGF pathway whereby heparanase stimulates an increase in both HGF expression and syndecan-1 shedding to enhance HGF signaling. This work also provides further mechanistic insight into the dynamic role of heparanase in driving aggressive tumor progression.Heparanase, an endo-␤-D-glucuronidase capable of cleaving intact heparan sulfate chains from proteoglycans, is up-regulated in a wide variety of human cancers and has been associated with promoting an array of cellular events leading to enhanced tumor progression (1). 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 (3-7). 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). Heparanase stimulates the synthesis and shedding of syndecan-1 via increased expression of two sheddases, MMP-9 and uPA 3 (7). Syndecan-1 remains biologically active after it is shed from cells and can control the localization and availability of many heparin-binding growth factors (9). Using in vivo models of myeloma, our laboratory has demonstrated t...

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

“…This dramatic increase in the level of histone acetylation in tumors formed by HPSE-high cells correlates with increased tumor cell expression of MMP-9, VEGF, HGF, and RANKL, four proteins that promote the aggressive phenotype of myeloma tumors (9,26). Importantly, the correlation between high heparanase expression and elevated levels of HGF and RANKL has also been demonstrated in bone marrow biopsies of myeloma patients (8,9), indicating that our data from laboratory models of myeloma parallel clinical observations.…”

Angiogenesis and Multiple Myeloma

“…A relationship between HGF and syndecan-1 levels has also been observed with BM angiogenesis [12]. Heparanase is involved in syndecan-1 shedding through the upregulation of MMP-9 and in HGF expression and activity [88,89], enhancing the pro-angiogenic properties of myeloma cells. Moreover, recent data suggest that heparanase expressed by myeloma cells upregulates VEGF production.…”

Mesenchymal stem cells expressing osteoprotegerin variants inhibit osteolysis in a murine model of multiple myeloma

“…Early studies showed that subcutaneous injection of CAG Hep cells resulted in bone-specific growth of myeloma cells, enhanced by syndecan-1. 26,42 Studies determined that syndecan-1 not only is an important molecule involved in myeloma cell growth and survival but also exerted a role in tumor angiogenesis because tumors with low syndecan-1 expression developed poor vasculature due to decreased VEGF. 43 Other studies have shown that overexpression of heparanase in CAG cells promoted local and systemic bone destruction through secretion of RANKL and enhanced the expression and activity of the degree of osteolytic damage, cohorts of mice from untreated and indicated treatment groups were euthanized, and tibia (A) and spine (B) were subjected to micro-CT analysis.…”