Metastasis to the bone is a major clinical complication in patients with prostate cancer (PC). However, therapeutic options for treatment of PC bone metastasis are limited. Gelatinases are members of the matrix metalloproteinase (MMP) family and have been shown to play a key role in PC metastasis. Herein, we investigated the effect of SB-3CT, a covalent mechanism-based MMP inhibitor with high selectivity for gelatinases, in an experimental model of PC bone metastases. Intraperitoneal (i.p.) treatment with SB-3CT (50 mg/kg) inhibited intraosseous growth of human PC3 cells within the marrow of human fetal femur fragments previously implanted in SCID mice, as demonstrated by histomorphometry and Ki-67 immunohistochemistry. The anti-osteolytic effect of SB-3CT was confirmed by radiographic images. Treatment with SB-3CT also reduced intratumoral vascular density and bone degradation in the PC3 bone tumors. A direct inhibition of bone marrow endothelial cell invasion and tubule formation in Matrigel by SB-3CT in vitro was also demonstrated. The use of the highly selective gelatinase inhibitors holds the promise of effective intervention of metastases of PC to the bone. ' 2005 Wiley-Liss, Inc.Key words: matrix metalloproteinases; endothelium; MMP-2; MMP-9; gelatinase inhibitor PC is the second leading cause of cancer death in males in the United States. 1 Bone metastasis represents a major clinical complication of PC and is usually associated with pain, fractures and other life-impairing conditions. 2 In spite of the extent of this complication, the therapeutic options for the treatment of PC bone metastasis are very limited and are mostly palliative in nature. Therefore, new approaches to treat PC bone metastasis are urgently needed.Members of the matrix metalloproteinase (MMP) family of zincdependent endopeptidases, in particular gelatinases A and B, also known as MMP-2 and MMP-9, have been associated with the development of bone metastasis by PC cells. 3-8 Therefore, MMPs constitute an attractive target for intervention in PC bone metastasis. A limited number of preclinical studies reported the ability of synthetic MMP inhibitors to inhibit primary and metastatic PC growth in animal models. 9-11 We previously reported that administration of the broad-spectrum MMP inhibitor batimastat (BB-94) reduced tumor burden and bone degradation by human PC3 cells growing within human bone in severe combined immunodeficiency (SCID) mice. 8 These studies demonstrated the potential benefit of targeting MMP activity in PC bone metastasis. In spite of the success of broad-spectrum MMP inhibitors in preclinical studies, these inhibitors failed to demonstrate therapeutic efficacy in clinical trials in patients with advanced cancer, and also produced undesired side effects. [12][13][14] Lack of selectivity has been considered one of the main reasons for the disappointing performance of broad-spectrum MMP inhibitors in clinical trials. 12,14 Thus, targeting of specific and relevant MMPs in cancer progression remains an important goal.A...

The tyrosine kinase receptor c-kit and its ligand stem cell factor (SCF) have not been explored in prostate cancer (PC) bone metastasis. Herein, we found that three human PC cell lines and bone marrow stromal cells express a membrane-bound SCF isoform and release a soluble SCF. Bone marrow stromal cells revealed strong expression of c-kit, whereas PC cells showed very low levels of the receptor or did not express it all. Using an experimental model of PC bone metastasis, we found that intraosseous bone tumors formed by otherwise c-kit-negative PC3 cells strongly expressed c-kit, as demonstrated using immunohistochemical and Western blot analyses. Subcutaneous PC3 tumors were, however, c-kit-negative. Both bone and subcutaneous PC3 tumors were positive for SCF. Immunohistochemical analysis of human specimens revealed that the expression frequency of c-kit in epithelial cells was of 5% in benign prostatic hyperplasia, 14% in primary PC, and 40% in PC bone metastases, suggesting an overall trend of increased c-kit expression in clinical PC progression. Stem cell factor expression frequency was more than 80% in all the cases. Our data suggest that the bone microenvironment up-regulates c-kit expression on PC cells, favoring their intraosseous expansion.

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