Involvement of Heparanase in Breast Carcinoma Progression
Abstract
Cellular localization of heparanase was found to be a major determinant of its pro-metastic and pro- angiogenic properties. While normally, the human enzyme is localized mostly in late endosomes and lysosomes, both the cellular content and secretion of heparanase were stimulated by estrogen. Estrogen may thus promote breast cancer progression through stimulation of heparanase transcription and secretion. Processing and activation of latent heparanase by MDA-435 breast carcinoma cells was inhibited by maspin, but not by BBI (Bowman-Birk inhibitor). BBI was applied to increase the yield of active heparanase, since it efficiently inhibited degradation of the enzyme by cellular proteases. Primary tumors produced by MCF-7 breast carcinoma cells over-expressing a secreted form of heparanase, elicited a potent angiogenic response and grew faster than tumors produced by MCF-7 cells expressing the intracellular enzyme. Mammary glands of pregnant transgenic mice over-expressing heparanase exhibited a massive branching of ducts, hyperplasia and basement membrane (BM) disruption, associated with intense neovascularization of the mammary tissue. we applied a ribozyme targeting approach to suppress heparanase expression in MDA-435 breast carcinoma cells. A pronounced inhibition of heparanase activity and BM invasion was obtained. We identified lead species of heparin and laminaran sulfate that efficiently inhibit the enzyme. Our results further emphasize the involvement of heparanase in breast carcinoma progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2002
- Accession Number
- ADA407484
Entities
People
- Israel Vlodavsky
- Tamar Peretz
- Yael Friedmann