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Hypoxia Increases Heparanase-Dependent Tumor Cell Invasion, Which Can Be Inhibited by Antiheparanase Antibodies

¹ University of Manchester Gynaecological Oncology Laboratory, St. Mary’s Hospital, Manchester, United Kingdom; ² Manchester Institute of Nephrology and Transplantation, Manchester Royal Infirmary, Manchester, United Kingdom; and ³ University of Manchester Department of Medical Oncology, Christie Hospital, Manchester, United Kingdom

The ß-endoglucuronidase heparanase plays an important role in tumor invasion, a process that is significantly enhanced by hypoxia. We have used a strategy of stable transfection with antisense to derive ovarian carcinoma cell lines that express different levels of heparanase and used these to demonstrate that invasion correlates with heparanase activity. Secreted heparanase activity was increased by reduction, hypoxia, and growth of cells under reduced oxygen (1%) augmented heparanase activity and invasion, both of which are inhibited by treatment with antiheparanase antibodies. This is the first demonstration that heparanase activity may be regulated by microenvironmental redox conditions, which influence invasion, and that invasion can be blocked with specific heparanase-neutralizing antibodies.

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