Prostate cancer (PCa) is invariably fatal once bone metastasis occurs. A characteristic of prostate cancer bone metastasis is the striking osteoblastic phenotype. Understanding the mechanisms that lead to the osteoblastic progression of prostate cancer in bone will enable us to prevent, predict, and treat bone metastasis. Towards this goal, we have developed a strategy to identify the prostate cancer """"""""Metastasis Proteome,"""""""" protein factors that are involved in prostate cancer bone metastasis, by a combination of protein purification and Proteomics approaches. To ensure that the findings are clinically relevant, we have used disease-relevant samples, i.e., bone marrow supernatant from prostate cancer patients with or without bone metastasis, in our study. We have isolated a novel bone metastasis factor, MDA-BF-1, from the bone marrow supernatants of prostate cancer patients with bone metastasis. Several lines of evidence suggest that MDA-BF-1 is a paracrine factor that is secreted by the metastatic prostate cancer cells and mediates osteoblast proliferation in prostate cancer bone metastasis. First, Western blot showed that MDA-BF-1 is only present in the bone marrow supernatant of prostate cancer patients with bone metastasis but not in those without bone metastasis. Second, immunohistochemical analysis showed that MDA-BF-1 is not expressed in normal prostate epithelial cells and is only produced by the metastatic prostate cancer cells. Third, a bone-derived cell line with osteoblastic features (MDA PCa 2b) produces a high amount of MDA-BF-1, while a bone-derived cell line with osteolytic features (PC-3) does not. Fourth, recombinant MDA-BF-1 induced osteoblast but not prostate cancer cell proliferation in vitro. Fifth, preliminary studies showed that expression of MDA-BF-1 in the osteolytic PCa cell line PC-3 generated an osteoblastic response in vivo when these cells were injected into bone. In contrast, MDA-BF-1 does not affect PC-3 cell growth in vivo when the cells were injected subcutaneously. These observations provide strong evidence that MDA-BF-1 has osteoblast stimulating activity and may be a major player in the osteoblastic progression of prostate cancer in bone. We thus hypothesize that MDA-BF-1 is a prostate cancer cell-osteoblast interacting factor that mediates osteoblastic progression of prostate cancer in bone. To test this hypothesis, we propose to:
Aim 1. Elucidate the effects of MDA-BF-1 on osteoblast/PCa cell interactions in vivo in an osseous PCa animal model;
Aim 2. Investigate the mechanism of MDA-BF-1-mediated osteoblast proliferation and differentiation;
and Aim 3. Purify, identify, and clone the receptor for MDA-BF-1 (BF1-receptor). ? ?
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