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-β and TGF-β.
Heparan sulfate is specifically cleaved by heparanase, an endo-β-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.
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