Heparanase induces VEGF C and facilitates tumor lymphangiogenesis

Abstract

Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains, a class of glycosaminoglycans abundantly present in the extracellular matrix and on the cell surface. Heparanase activity is strongly implicated in tumor angiogenesis and metastasis attributed to remodeling of the subepithelial and subendothelial basement membranes. We hypothesized that similar to its proangiogenic capacity, heparanase is also engaged in lymphangiogenesis and utilized the D2-40 monoclonal antibody to study lymphangiogenesis in tumor specimens obtained from 65 head and neck carcinoma patients. Lymphatic density was analyzed for association with clinical parameters and heparanase staining. We provide evidence that lymphatic vessel density (LVD) correlates with head and neck lymph node metastasis (N-stage, p 5 0.007) and inversely correlates with tumor cell differentiation (p 5 0.007). Notably, heparanase staining correlated with LVD (p 5 0.04) and, moreover, with VEGF C levels (p 5 0.01). We further demonstrate that heparanase overexpression by epidermoid, breast, melanoma and prostate carcinoma cells induces a 3-to 5-fold elevation in VEGF C expression in vitro and facilitates tumor xenograft lymphangiogenesis in vivo, whereas heparanase gene silencing was associated with decreased VEGF C levels. These findings suggest that heparanase plays a unique dual role in tumor metastasis, facilitating tumor cell invasiveness and inducing VEGF C expression, thereby increasing the density of lymphatic vessels that mobilize metastatic cells. ' 2008 Wiley-Liss, Inc.Key words: heparanase; head and neck carcinoma; lymphatic vessels; VEGF C; D2-40Heparanase is an endo-b-glucuronidase that cleaves heparan sulfate (HS) side chains of HS proteoglycans (HSPG). Heparanase activity has long been correlated with cell invasion associated with cancer metastasis, a consequence of structural modification that loosens the extracellular matrix (ECM) barrier. 1,2 This notion gained further support by employing siRNA and ribozyme technologies, 3,4 clearly depicting heparanase-mediated HS cleavage and ECM remodeling as critical requisites for inflammation, tumor angiogenesis and tumor metastasis. More recently, heparanase upregulation was documented in an increasing number of human carcinomas and hematological malignancies. [5][6][7] In many cases, heparanase induction correlated with increased tumor metastasis, vascular density and shorter postoperative survival rate, thus providing a strong clinical support for the prometastatic function of the enzyme. 5,6 These studies depict compelling evidence for the clinical relevance of the enzyme, making it an attractive target for the development of anticancer drugs. 5,[8][9][10][11][12] The role that heparanase plays in the primary tumor is less well understood, but likely involves angiogenic aspects. Elevation of microvessel density correlated with heparanase induction in solid 13-17 and hematological 18 malignancies and was also evident in tumor xenografts produced by cells overexpressing hepar...

Significance of heparanase in metastatic lymph nodes of cervical squamous cell cancer

“…Although experimental studies that identify the function of HPA in promoting the secretion of VEGF are poorly reported, melanoma, breast and prostate cancer cells with overexpression of HPA cause the level of VEGF-C to increase by 3-5 times, and promote angiogenesis of transplant tumors. Conversely, the silencing of HPA genes reduces the VEGF-C level (32). The present study revealed that the expression level of HPA in primary lesions of cervical cancer patients with LN metastasis was notably higher than that in non-metastatic cases, which supports the hypothesis that HPA promotes LN metastasis from the point of view of clinicopathology.…”

Influence of Heparanase and VEGF-C mRNA Expressions in Lung Cancer

“…The clinical analyses suggested that heparanase facilitates tumor lymphangiogenesis which is mediated, possibly, by VEGF-C gene induction [9]. We also found that heparanase and VEGF-C mRNA expression did not correlate with the pathological type and grade of the tumor (P>0.05); it contradicts the view of correlation between tumor metastasis and pathological type or degree of differentiation.…”

CD147 overexpression allows an accurate discrimination of bladder cancer patients’ prognosis

“…Previous studies have demonstrated that overexpression of heparanase in human tumours, including bladder cancer, facilitates their invasive activity [16]; heparanase and VEGF-C (vascular endothelial growth factor-C, a lymphatic molecular player) co-expression is related with the occurrence of lymphangiogenesis [17].…”