Involvement of Heparanase and Extracellular Matrix-Bound Fibroblast Growth Factor in Tumor Progression

The pluripotent angiogenic factor, basic fibroblast growth factor (bFGF) was extracted from the extracellular matrix (ECM) produced by cultured endothelial cells (EC) and was identified in epithelial and endothelial basement membranes of the rat fetus, bovine cornea and human blood vessels. Despite the ubiquitous presence of bFGF in normal tissues, EC proliferation in these tissues is usually very low with turnover time measured in years. This raises the question of how these heparin-binding growth factors are prevented from acting on the vascular endothelium and in response to what signals they become available for stimulation of EC proliferation. Our studies demonstrate that bFGF binds specifically to heparan sulfate (HS) and heparin-like molecules in the ECM and cell surfaces, as indicated by its displacement by heparin, HS, or HS-degrading enzymes, but not by unrelated GAGs or GAG degrading enzymes. Heparanase activity expressed by intact cells (i.e. platelets, mast cells, neutrophils, lymphoma cells) was found to degrade the ECM-HS and to release active bFGF from ECM and basement membranes of bovine cornea. Elevated levels of heparanase were detected in highly metastatic tumor cells and in tumor biopsies of cancer patients. Moreover, treatment of experimental animals with heparanase inhibitors (i.e. non-anticoagulant species of heparin) markedly reduced the incidence of lung metastasis induced by B16 melanoma, Lewis lung carcinoma and mammary adenocarcinoma. Our results indicate that heparanase mediated degradation of HSPG is involved in cell invasion and release of ECM-resident angiogenic factors, both critical events in tumor progression. Heparanase inhibiting molecules are therefore expected to have a significant anticancerous effect. We propose that restriction of bFGF bioavailability due to its lack of a signal peptide and sequestration by HS, as well as local regulation of its release in the vicinity of EC, provides a novel mechanism for regulation of capillary blood vessel growth in processes such as wound repair, inflammation and tumor development.