Background: The major cause of death from prostate cancer is metastases that are resistant to conventional therapies such as androgen ablation and cytotoxic chemotherapy. The design of effective new therapies against human prostate cancer bone metastasis requires a better understanding of the process at the systemic, cellular, and molecular levels. The outcome of metastasis depends on multiple continuous interactions between unique subpopulations of tumor cells and specific host factors, including the organ microenvironment, as exemplified by angiogenesis. Hypotheses and Specific Aims: These data suggest the hypothesis that the progressive growth and metastasis of prostate cancer are dependent on the induction of organ-specific angiogenesis associated with an imbalance between the pro-angiogenic molecules, such as interleukin (IL)-8 and ant- angiogenic molecules, such as interferon (IFN)-beta. Restoration of the balance, therefore, should inhibit angiogenesis and lead to tumor regression. To test this hypothesis, we shall use a nude mouse orthotopic model to select non-metastatic and metastatic cells from different human prostate cancers and to isolate and culture endothelial cells from different organs (bone, lung, and skin). We shall determine the metastatic genotypes and phenotypes of the variant cells and determine the mechanisms that regulate bone-specific angiogenesis. We shall determine the role of IL-8 in the progressive growth and metastasis of human prostate cancer and whether shall determine the role of IL-8 in the progressive growth and metastasis of human prostate cancer and whether the organ microenvironment regulates expression of IL-8. Recent data showed that neoplastic angiogenesis is associated with a decrease in tissue levels of IFN (alpha and beta), so we shall therefore determine whether chronic systemic administration of IFN inhibits angiogenesis of primary prostate cancer and bone metastases and whether the combination of IFN and chemotherapy can eradicate prostate cancer metastases. Finally, in preparation for clinical trials using low-dose IFN, we shall determine whether the expression levels of metastasis/angiogenesis-regulating genes in the prostate cancers of individual patients validate the experimental data and can serve as a surrogate marker for anti-angiogenic therapy. Significance: Understanding the process of prostate cancer angiogenesis and bone metastasis on the systemic, cellular, and molecular levels will be invaluable in designing new effective therapy.
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