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Androgenic Regulation of White Adipose Tissue-Prostate Cancer Interactions

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Annual rept. 1 May 2012-30 Apr 2013

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Prostate cancer PCa cells are initially sensitive to hormonal manipulation, and androgen-deprivation therapy ADT generally reverses androgen receptor AR dependent growth and proliferation. ADT is one of the main treatment modalities in the clinical management of PCa, but ADT is only palliative, and PCa eventually progresses to an androgen-insensitive stage, i.e., castrate-resistant PCa CRPC, after a median of 12 20 months. Progression to CRPC is a dynamic process that is incompletely understood as yet. Potential mechanisms contributing to the development of CRPC include selective growth of a preexisting hormone-insensitive population of cancer cells as a result of suppression by androgen ablation of the androgen-dependent cell population activation of oncogenes inactivation of tumor suppression genes and interaction between cancer cells and tumor-associated stroma and tumorassociated macrophages. The object of this research project is to investigate the effect of castration on epididymal white adipose tissue WAT, ventral prostate VP tissue, and adipose stromal cells ASCs from male Glipr1 WT and Glipr1 KO mice. We are testing our hypothesis that the biologic activity of WAT is affected by castration and that although the acute effects of castration e.g., GLIPR1 induction may suppress cancer-promoting adipokines, long-term ADT results in monocyte infiltration and the generation of WAT-associated macrophages WAMs. WAMs, in turn, produce cytokines and promote the growth and survival of growth factor expressing ASCs, which enter the systemic circulation and promote PCa progression. An important note is that the prostate, an androgen target organ, is significantly affected by castration and also produces cytokines and cytokine receptors that may, in concert with WAT-derived cytokines, contribute to the progression of already established local tumors. We also hypothesize that Glipr1GLIPR1 protein regulates castration-induced WAMs and ASCs.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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