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• W3136515517 abstract "1612 In prostate cancer, androgen-blockade strategies are commonly used to treat osteoblastic bone metastases, but responses to these therapies are of short duration, and eventually tumor progression occurs. The mechanism for androgen-independent progression in bone is not clear. We established two prostate cancer xenografts (MDA PCa 118a and MDA PCa 118b) from an osteoblastic bone metastasis in a man with castration-resistant prostate cancer. These xenografts are androgen-receptor negative and can grow in castrated as well as intact male mice. Also, these cells induce a robust osteoblastic reaction in bone and in the subcutis of immunodeficient mice. We found that these cells display a pattern of gene expression similar to that of the osteolytic prostate cancer cell line PC3, in that both MDA PCa 118 and PC3 express bone morphogenetic proteins, Wnts, and endothelin-1 as well as the Wnt inhibitor dickkopf-1 and the osteoclast-activating factor parathyroid hormone-related peptide, suggesting that other factors are involved in MDA PCa 118-induced osteogenesis. In a gene array analysis, we identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells of mildly blastic (MDA PCa 2b) or lytic (PC3) phenotypes and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. We also found that the MDA PCa 118-induced osteoblast proliferation was blocked by FGF9 antibody. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Findings were confirmed by RT-PCR analysis of RNA obtained by laser capture microdissection of normal prostate epithelial cells and prostate cancer epithelial cells derived from two bone metastases Collectively, these results suggest that FGF9 contributes to MDA PCa 118-induced osteogenesis and may participate in the osteoblastic progression of prostate cancer in bone. MDA PCa 118 is the first human prostate cancer xenograft that does not express androgen receptor, yet it induces strong osteogenic response both in bone and the subcutis of immunodeficient mice. These observations suggest that androgen receptor-null cells contribute to the castration-resistant osteoblastic progression of prostate cancer and imply that targeting these cells will be critical in the treatment of prostate cancer bone metastases. In addition, this new osteogenic xenograft will be an important preclinical model for therapy testing." @default.
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• W3136515517 date "2008-05-01" @default.
• W3136515517 modified "2023-09-25" @default.
• W3136515517 title "Androgen receptor-negative human prostate cancer cells induce osteogenesis through FGF9-mediated mechanisms" @default.
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