CELLULAR AND MOLECULAR BASIS OF PROSTATE METASTASIS TO BONE

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The long-term goal of this research is to understand the mechanism(s) of metastasis of prostate cancer to bone. What is the cellular and molecular basis of the osteotropism of prostate cancer in humans? The bone morphogenetic proteins (BMPs) are prime candidates to play a role in prostate metastases and propensity to invade bone. The metastases of prostate to bone is characterized by osteosclerotic lesions and stimulation of osteoblast function. Current work has demonstrated both mRNA and protein for BMPs 4 and 7 in rat and human prostate. Very recently BMP-4 type I receptors were identified in osteoblasts. We will examine the hypothesis that BMP-4 acts on prostate in an autocrine manner via BMP-4 receptors. We will then investigate the hypothesis that metastatic prostate carcinoma over expresses BMP-4 receptor. A novel BMP type I receptor has been identified by PCR-based cloning strategy. We will determine the role of this putative receptor by functional assays. One of us has identified endothelin-1 gene and the protein in osseous metastases in human prostate cancer. Another investigator has identified a novel Bone and Prostate derived Growth Factor-1 (BPGF-1) and confers the metastatic phenotype to human LNCap cells. The specific aims of this proposal are: 1. Identification and characterization of BMP-4 and BMP-7 in rat and human prostate cancer. Examine the hypothesis that the BMP receptors are over-expressed in metastatic prostate carcinoma. 2. Determine the function of endothelin-1 in molecular physiology of osteoblastic response to prostate cancer and translate findings to clinical data as a marker of therapeutic response. 3. Investigate the role of BPGF-1 in bone metastases and translate findings to clinical data set as a biomarker of therapeutic response and intervention.