Metastases are present in the bone of approximately 90% patients with advanced CaP and are responsible for most the morbidity associated with this disease. CaP usually causes dysregulation of the homeostatic processes which normally maintain the balance between bone lysis and bone formation, leading to an overall osteoblastic response in the bone. The mechanisms by which CaP disrupts bone metabolism are not yet understood. However, we and others have recently identified a number of factors with two critical characteristics which may implicate them in the interaction between CaP and bone: they are expressed by CaP cells, and they have been shown to be involved in the homeostasis of normal bone. Our preliminary data show that CaP cells express Osteoprotegerin (OPG), osteoprotegerin ligand (RANKL), endothelin-1 (ET-1), and the prostate-associated proteases prostate and TMPRSS2. OPG and RANKL are directly involved in osteoclastogenesis, while ET-1 has been shown to stimulate osteoblast proliferation. We have four hypothesis and five specific aims. We hypothesize that: 1. Expression of OPG and RANKL by CaP cells disrupts the regulation of bone remodeling at metastatic sites. 2. Expression of ET-1 by CaP cells is involved in stimulation of the osteoblastic reaction. 3. RANKL mediates the stimulation of the osteoclastogenesis cascade initiated by IGF-1 and IGF-2. 4. Prostate and TMPRSS2 play roles in bone resorption and activation of latent growth factors from the bone extracellular matrix.
Our specific aims will allow testing of the above hypotheses: 1. We will determine whether the expression of OPG and RANKL by CaP cell lines and xenografts interferes with the normal with the normal process by bone remodeling, 2. We will investigate in vitro and in vivo the role of ET-1 in the development of metastases in CaP. 3. We will investigate the signal transduction pathways involved in effects of ET-1 on CaP and bone cells. 4. We will investigate the effects of prostase, TMPRSS2 and other newly discovered prostate cancer-associated proteases on bone resorption in collaboration with Projects III and I, respectively. 5. We will investigate the potential role of IGF in the regulation of OPG and RANKL in collaboration with Project IV. The studies proposed will lead to enhanced understanding of the dysregulation of bone remodeling which accompanies CaP bone metastasis, and have the potential to identify new targets and pathways for therapeutic intervention.
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