PTHRP AS AN AUTOCRINE MEDIATOR OF BONE METASTASIS WITH PROSTATE CANCER
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Prostate carcinoma is unique since it metastasizes to bone and stimulates osteoblastic activity with a resultant increase in bone formation. Bone involvement occurs in the majority of patients with metastatic prostate carcinoma; however, the mechanism for the increased bone formation is not known. Bone stimulatory factors such as the bone morphogenetic proteins (BMPs) are secreted by prostate cancer cells, but the regulatory factors controlling their expression are unknown. One candidate which may be responsible for alterations in bone remodeling in prostate carcinoma is the tumor-derived factor, parathyroid hormone-related protein (PTHrP). PTHrP acts as an autocrine or paracrine factor and is a potent mediator of bone remodeling via its interaction with the parathyroid hormone receptor on osteoblasts. Prostate carcinoma cells produce and secrete PTHrP in vitro and in vivo. Furthermore, we have preliminary evidence that prostate carcinoma cells have receptors for PTHrP. These findings suggest an autocrine role for PTHrP in prostate cancer cells. The studies described here will lead to new information regarding the role of PTHrP in prostate carcinoma/bone interactions. The hypothesis for this proposal is that prostate tumor cells produce PTHrP which acts in an autocrine manner to induce the production of proteins responsible for stimulating bone formation. Three specific aims will be utilized to test this hypothesis: 1) the ability of PTHrP to act in an autocrine mechanism in prostate carcinoma cells will be established using techniques of radioimmunoassay, receptor binding assays, immunohistochemistry and in situ hybridization, 2) the effects of PTHrP on the induction of bone stimulating factors, such as the bone morphogenetic proteins, from prostate tumor cells will be determined using northern blot analysis and an in vitro bone mineralization model, and 3) the ability of PTHrP to induce bone stimulatory activity will be confirmed in an in vitro and in vivo model of prostate carcinoma. These studies will provide critical information regarding the regulation of bone metabolism in prostate metastasis and enhance our understanding of prostate carcinoma at the cellular level. This information will be clinically useful in designing preventive and treatment strategies for bone disorders associated with metastatic prostate carcinoma.
