Mammalian heparanase: Gene cloning, expression and function in tumor progression and metastasis

Heparan sulfate proteoglycans interact with many extracellular matrix const ituents, growth factors and enzymes. Degradation of heparan sulfate by endo glycosidic heparanase cleavage affects a variety of biological processes. W e have purified a 50-kDa heparanase from human hepatoma and placenta, and n ow report cloning of the cDNA and gene encoding this enzyme. Expression of the cloned cDNA in insect and mammalian cells yielded 65-kDa and 50-kDa rec ombinant heparanase proteins. The 50-kDa enzyme represents an N-terminally processed enzyme, at least 100-fold more active than the 65-kDa form. The h eparanase mRNA and protein are preferentially expressed in metastatic cell lines and specimens of human breast, colon and liver carcinomas. Low metast atic murine T-lymphoma and melanoma cells transfected with the heparanase c DNA acquired a highly metastatic phenotype in vivo, reflected by a massive liver and lung colonization. This represents the first cloned mammalian hep aranase, to our knowledge, and provides direct evidence for its role in tum or metastasis. Cloning of the heparanase gene enables the development of sp ecific molecular probes for early detection and treatment of cancer metasta sis and autoimmune disorders.