of the project) A unique feature of CaP is that approximately 85% of disseminated disease are located in the bone, specifically to those bones with a significant red marrow component. Ninety-five percent of these bone lesions are solely osteoblastic (i.e., bone formation) from a radiographic perspective whereas other adenocarcinomas produce mainly osteolytic lesions (i.e., bone degradation). Despite contributing significantly to the morbidity/ mortality of this disease, the biological characteristics of CaP bone metastasis have not been well studied. Hypotheses: 1. CaP cells release factors that initiate and regulate bone remodeling (i.e. osteoclastic and osteoblastic processes) as an essential part of their establishment in the bone. 2. Enzymatically active PSA and hK2 within the bone environment contribute to the phenomenology of the unique osteoblastic response observed in CaP bone metastasis. 3. Human CaP cells do not establish themselves in the bone of athymic/SCID mice because murine bone lacks factors necessary for implantation and for growth of human CaP cells.
Specific Aims : 1. Determine whether CaP cell lines and freshly harvested CaP cells (from primary, soft tissue metastases and bone metastases) augment or replace the role of osteoclasts in producing the critical ?pitting? of bone as the initial process in bone remodeling. 2. Assess the effects of PTHrP and its fragments on development of bone metastases in vivo. 3. Compare the expression of BMP4 and 7 in metastatic CaP to expression in normal prostate cells and demonstrate in vitro that BMPs expressed by CaP stimulate osteoblast activity. 4. Over-express or abrogate the activity of PSA, hK2, and single chain uPA (scuPA) in LNCaP cells by transfection and determine the effects on CaP invasiveness in vitro and in vivo. 5. Develop a human model of bone metastasis in SCID mice by implanting human bone subcutaneously, and subsequently injecting CaP cell lines and fresh CaP cells orthotopically. 6. Use the SCID-hu bone system, to determine whether there is osteoclast-like activity and osteoblastic activity biochemically, microscopically and radiographically.
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