Pre-clinical and clinical significance of heparanase in Ewing’s sarcoma

Abstract

Heparanase is an endoglycosidase that specifically cleaves heparan sulphate side chains of heparan sulphate proteoglycans, activity that is strongly implicated in cell migration and invasion associated with tumour metastasis, angiogenesis and inflammation. Heparanase up-regulation was documented in an increasing number of human carcinomas, correlating with reduced post-operative survival rate and enhanced tumour angiogenesis. Expression and significance of heparanase in human sarcomas has not been so far reported. Here, we applied the Ewing’s sarcoma cell line TC71 and demonstrated a potent inhibition of cell invasion in vitro and tumour xenograft growth in vivo upon treatment with a specific inhibitor of heparanase enzymatic activity (compound SST0001, non-anticoagulant N-acetylated, glycol split heparin). Next, we examined heparanase expression and cellular localization by immunostaining of a cohort of 69 patients diagnosed with Ewing’s sarcoma. Heparanase staining was noted in all patients. Notably, heparanase staining intensity correlated with increased tumour size (P = 0.04) and with patients’ age (P = 0.03), two prognostic factors associated with a worse outcome. Our study indicates that heparanase expression is induced in Ewing’s sarcoma and associates with poor prognosis. Moreover, it encourages the inclusion of heparanase inhibitors (i.e. SST0001) in newly developed therapeutic modalities directed against Ewing’s sarcoma and likely other malignancies.

Overexpression of heparanase in ovarian cancer and its clinical significance

“…This result is consistent with previous studies reporting that HPSE had direct and indirect effects on tumor invasion (21)(22)(23). The direct effect of HPSE on cell invasion was that HPSE uniquely degrades heparan sulfate proteoglycans in extracellular matrix (HPSG), causes the degradation of heparin, destroys the extracellular matrix and basement membrane, and eventually promotes the tumor cell invasion.…”

The heparanase system and tumor metastasis: is heparanase the seed and soil?

“…In contrast with the ubiquitous expression of cathepsin L, heparanase activity is restricted, under normal conditions, to the placenta and skin tissues and to blood-borne cells such as platelets, neutrophils, monocytes, mast cells and T lymphocytes while epithelial cells exhibit low or undetectable levels of heparanase [42][43][44]. Heparanase expression is induced in all major types of human cancer namely carcinomas, sarcomas and hematological malignancies [44][45][46][47]. Increased heparanase levels are most often associated with reduced patients' survival post operation, increased tumor metastasis and higher microvessel density [44,47,48], thus critically supporting the intimate involvement of heparanase in tumor progression and encouraging the development of heparanase inhibitors as anti-cancer therapeutics [48][49][50][51][52][53][54][55][56].…”

Heparanase enhances myeloma progression via CXCL10 downregulation

“…In addition, heparanase up regulation in primary human tumors correlates in some cases with tumors larger in size and with enhanced micro vessel density 3, 5 . Likewise, cells engineered to over-express heparanase are endowed with more rapid expansion of tumor xenografts 1, 2, 6-8 , while heparanase inhibitors attenuate tumor growth in pre-clinical settings 9-12 . The molecular mechanism exerted by heparanase to promote tumor development is incompletely understood and likely combines enzymatic activity-dependent and -independent aspects.…”