Steroid hormones stimulate human prostate cancer progression and metastasis

Authors

  • William A. Ricke,

    1. Department of Anatomy, University of California, San Francisco, CA
    Current affiliation:
    1. Departments of Urology, Pathology and Laboratory Medicine, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642
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  • Kenichiro Ishii,

    1. Department of Urologic Surgery, Vanderbilt University Medical Center, A1302, Medical Center North, Nashville, TN
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  • Emily A. Ricke,

    1. Department of Anatomy, University of California, San Francisco, CA
    Current affiliation:
    1. Departments of Urology, Pathology and Laboratory Medicine, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642
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  • Jeff Simko,

    1. Department of Anatomic Pathology, University of California, San Francisco, CA
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  • Yuzhuo Wang,

    1. Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
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  • Simon W. Hayward,

    1. Department of Urologic Surgery, Vanderbilt University Medical Center, A1302, Medical Center North, Nashville, TN
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  • Gerald R. Cunha

    Corresponding author
    1. Department of Anatomy, University of California, San Francisco, CA
    • Department of Anatomy, 513 Parnassus Ave., University of California, San Francisco, CA 94143, USA
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    • Fax: +415-502-2270.


Abstract

Tissue recombinants (TRs) composed of mouse urogenital mesenchyme (mUGM) plus an immortalized nontumorigenic human prostatic epithelial cell line (BPH-1) were grown under the kidney capsule of male athymic nude mice under different hormonal conditions. The objectives were to determine temporal plasma concentrations of testosterone (T) and estradiol-17β (E2) that elicit progression of nontumorigenic human prostatic epithelial cells in vivo. Second, to determine whether mUGM+BPH-1 TRs in [T+E2]-treated hosts could progress to metastases. Control mouse hosts received no exogenous hormonal support, whereas treated mice received Silastic implants containing T and E2 for 1–4 months. Plasma from hormonally treated mice contained significantly higher (p < 0.01) concentrations of T at 1 month (11.7 vs. 0.9 ng/ml). Plasma levels of E2 in steroid implanted mice were significantly higher (p <0.05) at 2 months (104.5 vs. 25.6 ng/l) and 4 months (122.8 vs. 19.2 pg/ml). Wet weights of mUGM+BPH-1 TRs from [T+E2]-implanted mice were significantly larger (p < 0.001) than those from untreated hosts. Untreated mUGM+BPH-1 TRs contained a well organized differentiated epithelium surrounded by smooth muscle stroma similar to developing prostate. In [T+E2]-implanted mice, mUGM+BPH-1 TRs formed carcinomas that contained a fibrous connective tissue stroma permeating the tumor; smooth muscle when present was associated with vasculature. Renal lymph nodes collected from [T+E2]-treated mice, but not untreated mice, contained metastatic carcinoma cells. Moreover, metastases could be observed at distant sites including lung and liver. Epithelial cells isolated from untreated mUGM+BPH-1 TRs exhibited benign histology and formed small nontumorigenic grafts when subsequently transplanted into athymic nude mice. In contrast, epithelial cells isolated from mUGM+BPH-1 tumors of [T+E2]-treated hosts formed large tumors that grew independent of stromal and hormonal support and developed lymph node metastases. We conclude that [T+E2]-treatment promotes prostatic cancer progression in mUGM + BPH-1 TRs. Use of mUGM in this system will allow future studies to utilize the power of mouse genetics to identify paracrine factors involved in human prostatic carcinogenesis. © 2005 Wiley-Liss, Inc.

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