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-17b (E 2 ) that elicit progression of nontumorigenic human prostatic epithelial cells in vivo. Second, to determine whether mUGM1BPH-1 TRs in [T1E 2 ]-treated hosts could progress to metastases. Control mouse hosts received no exogenous hormonal support, whereas treated mice received Silastic implants containing T and E 2 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 E 2 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 mUGM1BPH-1 TRs from [T1E 2 ]-implanted mice were significantly larger (p < 0.001) than those from untreated hosts. Untreated mUGM1BPH-1 TRs contained a well organized differentiated epithelium surrounded by smooth muscle stroma similar to developing prostate. In [T1E 2 ]-implanted mice, mUGM1BPH-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 [T1E 2 ]-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 mUGM1BPH-1 TRs exhibited benign histology and formed small nontumorigenic grafts when subsequently transplanted into athymic nude mice. In contrast, epithelial cells isolated from mUGM1BPH-1 tumors of [T1E 2 ]-treated hosts formed large tumors that grew independent of stromal and hormonal support and developed lymph node metastases. We conclude that [T1E 2 ]-treatment promotes prostatic cancer progression in mUGM 1 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.Key words: prostate; hormonal carcinogenesis; apoptosis; stromalepithelial interactions Prostate cancer (PRCA) has been detected in over 230,000 men in the United States in 2004. Many of these patients will undergo treatment to halt or slow PRCA progression. Many more will be diagnosed with advanced PRCA for which there is no cure. Moreover, this year more than 30,000 men will die of this disease. Goals of early detection, surgery, hormone therapy and chemoprevention are to decrease morbidity and mortality and increase life span. To achieve these goals, useful models of human PRCA progression must be developed.Sex steroids are known to play important roles in prostatic carcinogenesis. In men and dogs, levels of serum androgens decrease with age, where...

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

“…In prostatic carcinoma, the tumor stroma is constituted mainly of fibroblastic and myofibroblastic cells (Cunha et al, 2003), suggesting that cell-transition changes have occurred in both the stroma and the epithelium during tumorigenesis. Earlier tissue recombination studies by Thompson et al (1993) have indicated that prostatic tumorigenesis indeed requires changes in both the stroma and the epithelium, a notion supported by the results of Cunha and co-workers (Olumi et al, 1999;Wang et al, 2001;Cunha et al, 2003;Ricke et al, 2006). Thus, prostate cancer-associated fibroblasts could promote tumor transformation of the epithelial BPH-1 cells that are immortalized with SV40 Tag (Olumi et al, 1999;Wang et al, 2001).…”

“…Thus, prostate cancer-associated fibroblasts could promote tumor transformation of the epithelial BPH-1 cells that are immortalized with SV40 Tag (Olumi et al, 1999;Wang et al, 2001). Similarly, urogenital mesenchymes from rat and mouse could also elicite tumor transformation in BPH-1 cells in the presence of testosterone and 17b-estradiol (E2) (Wang et al, 2001;Ricke et al, 2006). However, cancer-associated fibroblasts in a castrated host and urogenital mesenchyme from testicular feminized mice (a mouse without functional AR) were unable to promote tumor transformation from BPH-1 cells (Ricke WA, personal communication).…”

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

“…It is noteworthy that although the prostate is exquisitely sensitive to androgens, administration of high doses of T alone in this model is insufficient to drive tumorigenesis. Instead, estrogens are required to act in synergy with androgens to induce tumor formation [38], mediated through estrogen receptor a expressed in the stromal cells [23]. Both of these approaches highlight the active role played by stroma in the process of tumorigenesis in the prostate.…”

“…However, the ''initiation events'' were the basis for their selection as the epithelial source for these studies, since this instability facilitates induction of malignancy in response to CAFs and/or hormonal carcinogenesis; normal epithelial cells from primary specimens are not susceptible to carcinogenesis using these assays [13,38]. While there are key differences between BPH-1 cells and primary epithelial cells, including the methylation of the CD133, with silencing of up to 50% of BPH-1 cells [39], our data are supported by several previous studies in mice [4] and in primary human cells [3] showing that basal cells are a cell of origin of prostate cancer.…”

The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer

“…The nutritional uptake and blood supply from surrounding and endothelial cells are very important in PCa cell growth and invasion [7,71]. The inflammatory cells also infiltrate the prostate and can cause prostatitis, which can alter PCa cell growth and metastasis.…”