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 = 0.007) and inversely correlates with
tumor cell differentiation (p = 0.007). Notably,
heparanase staining correlated with LVD (p = 0.04) and, moreover, with
VEGF C levels (p = 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.