We have recently contributed to major achievements in modeling human prostate cancer in mice. Global assessment of molecular changes in these models have led to identification of key gene functions implicated in human prostate cancer and its metastases. Two such functions are the focus of this proposal. These molecules, both secretory and commonly referred to as bone matrix proteins, are: osteopontin (OPN), an RGD-containing glycosylated phosphoprotein, and osteogenic protein-1 (OP-1 or BMP-7), a member of the TGF-p superfamily. Since prostate cancer has the propensity to metastasize to bone and to induce bone lesions, and both of these proteins are believed to be involved, in osteoblast differentiation and bone formation, these molecules constitute an important, but yet an understudied area of research in the biology of prostate cancer. In preliminary experiments we find that OPN expression, prominent in prostatic preneoplastic lesions of a mouse model, continues to increase with progression to invasive adenocarcinoma, and cells overexpressing OPN are enriched in the metastatic deposits. Additional data collected to date indicate that OPN upregulation may be a factor in proliferation, motility, invasion, and most remarkably in the ability of the human prostate cancer cells to intravasate blood vessels. We find that BMP-7 expression continues to increase with the growth of the prostate cancer in our mouse model, it can modulate growth, motility and invasion properties of human prostatic epithelial cells, and it can induce epithelial-mesenchymal transition to a prostate cancer cell line. We implicate BMP receptor signaling differences with the observed differential biological responses induced. The stated goals of this application are two-fold. First to refine our metastatic prostate cancer model by incorporating the capability of either to monitor the tumor growth and site-specific metastases by in vivo bioluminescense, or to isolate cancer cells from primary tumor and organspecific metastases. Second is to define the molecular/cellular parameters by which OPN or BMP-7 may positively influence prostate cancer progression and metastases. A series of interconnected and parallel studies using the mouse model and cancer cells derived from it, human prostate cancer cell lines, and osteoblasts and precursors are outlined to obtain insight into how OPN and BMP-7 may contribute to prostate cancer progression and to the mechanism of prostate cancer-mediated osteogenesis.
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