Heparan sulfate proteoglycans are integral components of the extracellular matrix that surrounds all mammalian cells. In addition to providing structural integrity, they act as a storage depot for a variety of
heparan sulfate (HS)-
binding proteins, including
growth factors and
chemokines.
Heparanase is a matrix-degrading
enzyme that cleaves
heparan sulfate side chains from the core
proteoglycans, thus liberating such HS-
binding proteins, as well as potentially contributing to extracellular matrix degradation. Here, we report that
heparanase mRNA and
protein expression are increased in the neoplastic stages progressively unfolding in a mouse model of multistage pancreatic islet
carcinogenesis. Notably,
heparanase is delivered to the neoplastic lesions in large part by infiltrating Gr1+/Mac1+ innate immune cells. A sulfated
oligosaccharide mimetic of
heparan sulfate,
PI-88, was used to inhibit simultaneously both
heparanase activity and HS effector functions.
PI-88 had significant effects at distinct stages of
tumorigenesis, producing a reduction in the number of early progenitor lesions and an impairment of
tumor growth at later stages. These responses were associated with decreased cell proliferation, increased apoptosis, impaired angiogenesis, and a substantive reduction in the number of invasive
carcinomas. In addition, we show that the reduction in
tumor angiogenesis is correlated with a reduced association of
VEGF-A with its receptor VEGF-R2 on the
tumor endothelium, implicating
heparanase in the mobilization of matrix-associated
VEGF. These data encourage clinical applications of inhibitors such as
PI-88 for the many human
cancers where
heparanase expression is elevated or mobilization of HS-binding regulatory factors is implicated.