Heparanases and tumor metastasis.
The successful penetration of endothelial basement membranes is an important process in the formation of hematogenous tumor metastases. Heparan sulfate (HS) proteoglycan is a major constituent of endothelial basement membranes, and we have found that HS-degradative activities of metastatic B16 melanoma sublines correlate with their lung-colonizing potentials. The melanoma HS-degrading enzyme is a unique endo-beta-D-glucuronidase (heparanase) that cleaves HS at specific intrachain sites and is detectable in a variety of cultured human malignant melanomas. The treatment of B16 melanoma cells with heparanase inhibitors that have few other biological activities, such as N-acetylated N-desulfated heparin, results in significant reductions in the numbers of experimental lung metastases in syngeneic mice, indicating that heparanase plays an important role in melanoma metastasis. HS-degrading endoglycosidases are not tumor-specific and have been found in several normal tissues and cells. There are at least three types of endo-beta-D-glucuronidases based on their substrate specificities. Melanoma heparanase, an Mr approximately 96,000 enzyme with specificity for beta-D-glucuronosyl-N-acetylglucosaminyl linkages in HS, is different from platelet and mastocytoma endoglucuronidases. Elevated levels of heparanase have been detected in sera from metastatic tumor-bearing animals and malignant melanoma patients, and a correlation exists between serum heparanase activity and extent of metastases. The results suggest that heparanase is potentially a useful marker for tumor metastasis.
Nakajima
M
M
Department of Tumor Biology, University of Texas M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Irimura
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T
Nicolson
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D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis*; D005966:Glucuronidase; D006026:Glycoside Hydrolases / Q000032:analysis* / Q000037:antagonists & inhibitors; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000556:secondary; D051379:Mice; D009362:Neoplasm Metastasis / Q000201:enzymology*; D000099175:Heparanase
D014408:Biomarkers, Tumor; D005966:Glucuronidase; D006026:Glycoside Hydrolases; D006497:Heparan Sulfate; D000099175:Heparanase