No abstract

Emerging evidence indicates that tumor-associated proteolytic remodeling of bone matrix may underlie the capacity of tumor cells to colonize and survive in the bone microenvironment. Of particular importance, urokinase-type plasminogen activator (uPA) has been shown to correlate with human prostate cancer (PC) metastasis. The importance of this protease may be related to its ability to initiate a proteolytic cascade, leading to the activation of multiple proteases and growth factors. Previously, we showed that maspin, a serine protease inhibitor, specifically inhibits PC-associated uPA and PC cell invasion and motility in vitro. In this article, we showed that maspin-expressing transfectant cells derived from PC cell line DU145 were inhibited in in vitro extracellular matrix and collagen degradation assays. To test the effect of tumor-associated maspin on PC-induced bone matrix remodeling and tumor growth, we injected the maspin-transfected DU145 cells into human fetal bone fragments, which were previously implanted in immunodeficient mice. These studies showed that maspin expression decreased tumor growth, reduced osteolysis, and decreased angiogenesis. Furthermore, the maspin-expressing tumors contained significant fibrosis and collagen staining, and exhibited a more glandular organization. These data represent evidence that maspin inhibits PC-induced bone matrix remodeling and induces PC glandular redifferentiation. These results support our current working hypothesis that maspin exerts its tumor suppressive role, at least in part, by blocking the pericellular uPA system and suggest that maspin may offer an opportunity to improve therapeutic intervention of bone metastasis.A ndrogen deprivation therapy has been the mainstay of treatment of metastatic prostate cancer (PC) for Ͼ50 years. Usually, this therapy produces tremendous tumor shrinkage and significant clinical improvement. However, the duration of response is limited and disease always recurs. Cytotoxic chemotherapy is commonly added, although this approach offers little chance for meaningful, long-term survival. Thus, new approaches are needed. The skeleton is the major target organ of metastasis in patients with PC, and bone metastasis is associated with poor survival. Can bone-targeted therapy improve survival? In a recent clinical trial (1), a therapeutic, bone-seeking radioisotope was added to standard chemotherapy in patients showing an initial chemotherapeutic response. Survival was prolonged in the patients receiving the bone-seeking radioisotope compared with those receiving chemotherapy alone, suggesting that targeting skeletal metastases is a promising approach in PC treatment.Clinicians have traditionally classified bone metastases as either osteolytic or osteoblastic (2). However, tumor deposits in bone usually contain both bone formation and bone degradation (3-8). A ''vicious cycle'' is created whereby metastatic tumor stimulates bone turnover and bone turnover promotes local tumor growth. To date, various molecules have been implicated ...