PROSTATE CANCER, BONE METASTASIS, AND METALLOPROTEINASES

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DESCRIPTION: (Adapted from the investigator's abstract) Metastasis of prostate cancer to bone causes increased turnover of bone matrix and is frequently accompanied by pain and pathological fractures. Radiologically, prostate cancer metastases are "blastic," however, on a biochemical level, they are both lytic and blastic. The cellular and biochemical mechanisms underlying the enhanced turnover of bone matrix associated with metastatic cancer are unknown. The "SCID-human model of prostate cancer metastasis to bone," recently developed in our laboratory, mimics clinical disease on several levels: prostate cancer cells home to human bone implanted in SCID mice, they grow more rapidly in bone as compared to other tissue environments, and there is rapid turnover of bone matrix. In this and other models, we found that prostate cancer cells growing in bone produce and/or secrete matrix metalloproteinases (MMPs) including MMP-2, MMP-9 and MT1-MMP. These proteinases are enzymatically competent to degrade bone matrix, and they normally participate in several of the steps of bone matrix metabolism. For example, osteoblasts use MMPs to digest nonmineralized bone matrix, and this leads to recruitment of osteoclasts and enhanced osteoclastic degradation of mineralized matrix. We hypothesize that prostate cancer cells degrade nonmineralized matrix in a fashion similar to osteoblasts and that production of MMP-2, MMP-9, and MT1-MMP by metastatic prostate cancer cells may contribute to the enhanced bone matrix turnover associated with metastatic disease. Using the in vivo SCID-human system and an in vitro bone organ culture model, we will test the hypothesis that: (1) the bone environment induces an upregulation of MMP-2, MMP-9 and MT1-MMP expression in prostate cancer cells and an increase in MMP-2, MMP-9 secretion and activity; (2) there is MMP activity at the interface between prostate cancer cells and the nonmineralized bone matrix; and (3) MMP production/secretion by prostate cancer cells in the bone environment leads to tumor cell proliferation, and migration of tumor cells to endosteal surfaces; degradation of nonmineralized bone matrix; recruitment of osteoclasts; and enhanced osteoclast activity and degradation of mineralized matrix. These experiments will take advantage of our model systems and a variety of prostate cancer cells that produce a spectrum of response in bone ranging from primarily osteolytic to primarily osteoblastic. The results of these studies may lead to new therapeutic strategies aimed at interrupting the interactions between prostate cancer cells and bone.