Despite great strides toward diagnosis and
therapy,
breast cancer remains a most threatening disease in its incidence, morbidity and mortality; therefore, additional knowledge regarding the molecular mechanisms contributing to
breast cancer progression, as well as new targets for
drug discovery are highly needed.
Heparanase is the predominant
enzyme involved in cleavage of
heparan sulfate, the main
polysaccharide component of the extracellular matrix. Experimental and clinical data indicate that
heparanase plays important roles in
cancer metastasis and angiogenesis. In
breast carcinoma patients,
heparanase expression correlates with the metastatic potential of the
tumor. The present study was undertaken to investigate the role of
heparanase in local growth and angiogenesis of primary
breast tumors. MCF-7
breast carcinoma cells were stable transfected with the human
heparanase (H-hpa)
cDNA, or empty vector (mock), and injected into the mammary pad of nude mice. MRI was applied to monitor progression of
tumor growth and angiogenesis. We demonstrate that
tumors produced by cells overexpressing
heparanase grew faster and were 7-fold larger than
tumors produced by mock transfected cells. This enhanced growth was accompanied by increased
tumor vascularization and a higher degree of vessel maturation. Histological examination ascribed the differences in
tumor growth to
heparanase-stimulated cell proliferation and survival. In-vitro experiments reinforced
heparanase role as a survival factor under stress conditions. Moreover, H-hpa
tumor cells infiltrate into the adjacent stroma, promoting formation of highly vascularized fibrous bands. Our results emphasize the significance and clarify the involvement of
heparanase in primary
breast cancer progression by generating a supportive microenvironment that promotes
tumor growth, angiogenesis and survival.