Heparan sulfate proteoglycans interact with many extracellular matrix constituents, growth factors and enzymes. Degradation of heparan sulfate by endoglycosidic
heparanase cleavage affects a variety of biological processes. We have purified
a 50-kDa heparanase from human hepatoma and placenta, and now 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 recombinant heparanase
proteins. The 50-kDa enzyme represents an N-terminally processed enzyme, at
least 100-fold more active than the 65-kDa form. The heparanase mRNA and protein
are preferentially expressed in metastatic cell lines and specimens of human
breast, colon and liver carcinomas. Low metastatic murine T-lymphoma and melanoma
cells transfected with the heparanase cDNA acquired a highly metastatic phenotype
in vivo, reflected by a massive liver and lung colonization. This represents
the first cloned mammalian heparanase, to our knowledge, and provides direct
evidence for its role in tumor metastasis. Cloning of the heparanase gene
enables the development of specific molecular probes for early detection and
treatment of cancer metastasis and autoimmune disorders.
