title: Steroid hormones stimulate human prostate cancer progression and metastasis.
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-17beta (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.
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94143, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Ricke
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ishii
authors.forename: Emily A
authors.initials: EA
authors.lastname: Ricke
authors.forename: Jeff
authors.initials: J
authors.lastname: Simko
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Cunha
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000502:physiology; D004958:Estradiol / Q000502:physiology*; D006801:Humans; D008297:Male; D008648:Mesoderm; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D013739:Testosterone / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: D013739:Testosterone; D004958:Estradiol