Prostate cancer (PRCA) is estimated to be the most frequently diagnosed cancer in the United States. This year nearly 200,000 new cases of prostate cancer will be recorded in the United States alone. It will be fatal for another 3 1,500 men. Despite its huge societal impact, the etiology of prostatic carcinoma is poorly understood. This lack of understanding of how prostate cancer progresses is in part due to a lack of appropriate models. We have developed a new prostate cancer progression model based on a modified hormonal carcinogenesis protocol established by Noble. We propose implanting 25 mg Testosterone (T) and 2.5 mg estradiol-17b within silastic tubing under the skin of nude mice hosts to stimulate cancer progression in benign human prostatic epithelial cells (BPH-1) and recombine with mouse urogenital mesenchyme (mUGM). BPH-1 does not undergo malignant transformation without the presence of UGM. Our objectives of this proposal are to 1) develop and characterize a new model for prostate cancer progression, 2) determine which steroid receptors within the mesenchyme are responsible for tumor progression, and 3) to evaluate the effects of antiestrogens (ICI182,780) or antiandrogens (flutamide) on progression of the disease in this model. We will use the techniques of tissue recombination and xenografting under changing hormonal milieus to develop a new prostate cancer model. This model will merge 2 highly desired aspects of all cancer models 1) use of human epithelial cells, and 2) mouse genetics. Characterization of this model will be performed using immunohistochemical methods for known normal and pathologic prostatic markers, proliferation and apoptotic markers, and steroid receptors. We will determine how hormonal cues mediate their affects in a paracrine fashion in prostate cancer. We propose using steroid receptor deficient mice to evaluate which receptors within the mesenchyme are necessary and sufficient to prevent malignant transformation of the prostatic epithelium. Additionally, we will use antiestrogens and/or antiandrogens to determine which steroid is necessary for prostate cancer progression. Such models are pertinent to the problem of human prostate cancer as they will allow us to examine the processes of carcinogenesis and tumor progression in human prostatic epithelial cells in vivo.
| Ricke, William A; Ishii, Kenichiro; Ricke, Emily A et al. (2006) Steroid hormones stimulate human prostate cancer progression and metastasis. Int J Cancer 118:2123-31 |
| Cunha, Gerald R; Ricke, Will; Thomson, Axel et al. (2004) Hormonal, cellular, and molecular regulation of normal and neoplastic prostatic development. J Steroid Biochem Mol Biol 92:221-36 |
