Molecular mechanisms of osteoblastic bone metastasis: Role of endothelin-1

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Osteoblastic metastases represent a significant clinical problem for patients with cancer. They occur almost always in prostate cancer and frequently in other common malignancies such as breast cancer. The pathophysiology underlying osteoblastic metastases is unknown due to lack of a reproducible animal model of this disease. During this Program Project, we have developed an in vivo model of osteoblastic bone metastases which is reproducible and allows investigation into the pathophysiology of this disease. The human tumor cells which cause osteoblastic metastases in this model produce large amounts of endothelin-1 (ET-1), a stimulator of osteoblast growth, which recently has been linked to prostate cancer osteoblastic metastases. This project will characterize the new model, critically test the role of ET-1 in the genesis of osteoblastic metastases and identify other factors responsible for osteoblastic lesions. The following hypotheses will be tested: 1) The human breast cancer cell line, ZR-75-1, mediates osteoblastic metastases by the secretion of a soluble factor or factors which locally stimulate osteoblast proliferation and new bone formation. 2) Tumor- produced ET-1 is a local mediator of osteoblastic metastases caused by prostate and breast cancer. Blocking the effects of tumor-produced ET-1 or decreasing its production will inhibit the development and progression of osteoblastic bone metastases. 3) The relative ratio of tumor-produced osteoblast-stimulating factors to osteoclast-stimulating factors in a given tumor will determine the tumor phenotype in bone. 4) The bone microenvironment enhances tumor production of ET-1 and other osteoblast-stimulating factors, relative to non bone sites. The following specific aims are proposed: 1) To investigate the role of ET-1 in osteoblastic metastasis. The effect of ET-1 on new bone formation will be studied in vitro and in vivo and the relative importance of endothelin receptor A(ETA) and receptor B (ETB) in mediating the effects of endothelin on osteoblast function and osteoblastic bone metastases will be investigated. 2) To determine if tumor production of osteoblastic factors is induced in the bone microenvironment compared with nonbone sites. Molecular techniques will be applied to the bone metastases model to determine which osteoblast-stimulating factors are produced by the ZR-75-1 cells in the bone microenvironment and if ET-1 is the predominant factor. The aim will also determine if tumor production of osteoblast-stimulating factors are enhanced in the bone microenvironment relative to nonbone sites.