Induction at high incidence of ductal prostate adenocarcinomas in NBL/Cr and Sprague-Dawley Hsd:SD rats treated with a combination of testosterone and estradiol-17β or diethylstilbestrol

Ishii

et al. 2005

Intl Journal of Cancer

115

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...

mentioning

confidence: 56%

Steroid hormones stimulate human prostate cancer progression and metastasis

Ishii

et al. 2005

Intl Journal of Cancer

115

The American Journal of Pathology

“…Alternatively, a subset of cells may be particularly susceptible to redox injury, whereas others may be totally resistant to development of carcinoma. In this context, previous studies 20,21 have suggested that carcinoma develops from periurethral ducts of the LP in the NBL rat model. It is important to note that we now also find evidence of OS/NS damage in these ducts.…”

Section: Discussionmentioning

confidence: 88%

“…19 Exposure of NBL rats to treatment with a combination of testosterone (T) and 17␤-estradiol (E2) for 16 weeks induces dysplasia accompanied by inflammation selectively in the lateral prostates (LPs), and longer exposure of these steroids induces a high incidence of adenocarcinomas in the LP. 20,21 However, neither of these lesions are induced in the ventral prostates (VPs) of all treated animals. 20 -24 Using the NBL experimental model, our current results provide evidence that this steroid treatment selectively causes major disruptive effects in the OS/NS of the LP that affects damage to DNA, protein, and lipids.…”

mentioning

confidence: 99%

Sex Hormones Induce Direct Epithelial and Inflammation-Mediated Oxidative/Nitrosative Stress That Favors Prostatic Carcinogenesis in the Noble Rat

Tam

Leav

2007

Oxidative and nitrosative stress have been implicated in prostate carcinogenesis, but the cause(s) of redox imbalance in the gland remains poorly defined. We and others have reported that administration of testosterone plus 17␤-estradiol to Noble rats for 16 weeks induces dysplasia and stromal inflammation of the lateral prostate (LP) but not the ventral prostate. Here, using laser capture microdissected specimens, we found that the combined hormone regimen increased the expression of mRNA of specific members of NAD(P)H oxidase (NOX-1, NOX-2, and NOX4), nitric-oxide synthase [NOS; inducible NOS and endothelial NOS], and cyclooxygenase (COX-2) in the LP epithelium and/or its adjacent inflammatory stroma. Accompanying these changes was the accumulation of 8-hydroxy-2-deoxyguanosine, 4-hydroxynonenal protein adducts, and nitrotyrosine, primarily in the LP epithelium, suggesting that NOX, NOS, and COX may mediate hormone-induced oxidative/nitrosative stress in epithelium. We concluded that the oxidative/ nitrosative damage resulting from the testosterone-plus-17␤-estradiol treatment is not solely derived from stromal inflammatory lesions but likely also originates from the epithelium per se. In this context, the upregulation of COX-2 from epithelium represents a potential mechanism by which the hormone-initiated epithelium might induce inflammatory responses. Thus , we link alterations in the hormonal milieu with oxidative/nitrosative/inflammatory damage to the prostate epithelium that promotes carcinogenesis. (Am J Pathol 2007, 171

Reproductive Toxicology

“…The E capsules produce serum levels of ˜ 75 pg/ml in rats which, although elevated for males, is not considered pharmacologic (79). These T+E capsule for 16 weeks produce PIN in the dorsolateral prostates at 100% incidence in Noble rats (4) but only 33% incidence in Sprague-Dawley rats (80). At 28 weeks of age, the prostates were examined for hyperplasia, inflammation and PIN, the presumed precursor lesion of prostate cancer.…”

Section: Neonatal Exposure To Low-dose Estradiol and Bisphenol Amentioning

confidence: 99%

Developmental estrogen exposures predispose to prostate carcinogenesis with aging☆

Prins

Birch

Tang

et al. 2007

208

162

Prostate morphogenesis occurs in utero in humans and during the perinatal period in rodents. While largely driven by androgens, there is compelling evidence for a permanent influence of estrogens on prostatic development. If estrogenic exposures are abnormally high during the critical developmental period, permanent alterations in prostate morphology and function are observed, a process referred to as developmental estrogenization. Using the neonatal rodent as an animal model, it has been shown that early exposure to high doses of estradiol results in an increased incidence of prostatic lesions with aging which include hyperplasia, inflammatory cell infiltration and prostatic intraepithelial neoplasia or PIN, believed to be the precursor lesion for prostatic adenocarcinoma. The present review summarizes research performed in our laboratory to characterize developmental estrogenization and identify the molecular pathways involved in mediating this response. Furthermore, recent studies performed with low-dose estradiol exposures during development as well as exposures to environmentally relevant doses of the endocrine disruptor bisphenol A show increased susceptibility to PIN lesions with aging following additional adult exposure to estradiol. Gene methylation analysis revealed a potential epigenetic basis for the estrogen imprinting of the prostate gland. Taken together, our results suggest that a full range of estrogenic exposures during the postnatal critical period -from environmentally relevant bisphenol A exposure to low-dose and pharmacologic estradiol exposures -results in an increased incidence and susceptibility to neoplastic transformation of the prostate gland in the aging male which may provide a fetal basis for this adult disease.