S-9-3 Heparanase Expression in Metastatic Tumors
Motowo Nakajima Tsukuba Research Institute, Novartis Pharma K.K. Ibaraki, Japan


@ Heparan sulfate proteoglycans (HSPGs) are important components of both cell surfaces and extracellular matrices. HSPGs are involved in the regulation of cell growth, migration and differentiation, thus important in morphogenesis, development, and tissue repair. HSPGs are also major components of the basement membrane and function as a barrier against cationic molecules and macromolecules. Furthermore HSPGs protect type IV collagen matrix in the basement membrane from proteolytic attack and serve as storage of variety of cytokines and growth factors, such as bFGF, VEGF, KGF, INF- and TGF-.

@ Heparan sulfate is specifically cleaved by heparanase, an endo--D-glucuronidase, which has been detected in a variety of normal and tumor cells at various levels. In the process of tumor metastasis hematogenous metastatic cells confront endothelial basement membranes and degrade HSPGs. Degradation of HS by heparanase results in not only destruction of the basement membrane but also enhancement of tumor cell migration and growth, which is caused by cytokines and growth factors released from HSPGs. Angiogenesis could be also induced by angiogenic factors released from the basement membrane. HS fragments has a role to suppress T cell immunofunction. Thus, heparanase activity appears to be necessary for metastatic tumor cells to accomplish colony formation in distant organ sites.

@ In fact a good correlation between heparanase activity and metastatic potential was first observed in murine B16 melanoma sublines (Science 220:661, 1983) followed by many reports of the similar observations using different tumor cell lines. After more than 15 years of the research human heparanase was finally purified from SV40-transformed lung fibroblast cell line WI38-VA13 as a 50 kDa single peptide with high N-glycosylations, and its cDNA encoding a 543 amino acid proenzyme was cloned from the cDNA library of the same cells (J. Biol. Chem. 274:24153, 1999).

@ To assess the effect of heparanase expression on metastatic phenotypes, heparanase was transduced in human A375M melanoma cells. Although the heparanase transfectants and mock control cells did not show any significant differences in the characteristics of cell growth and adhesion to various ECM components, the heparanase transfectants obtained significantly higher invasiveness in vitro and higher metastatic potential in vivo.

@ Immunohistological and in situ hybridization studies of 40 resected bladder cancer specimens revealed that heparanase expression is higher in muscular invasive and lymph-node metastatic cancers than superficial or non metastatic cancers. The microvessel formation was significantly associated with high heparanase expression. The cancer-specific and over-all survival rates of patients with the expression of heparanase were significantly lower than those of patients without heparanase expression. Therefore, the expression of heparanase could be a new prognostic factor of bladder cancer.