Upregulation of estrogen and androgen receptors modulate expression of FGF-2 and FGF-7 in human, cultured, prostatic stromal cells exposed to high concentrations of estradiol

Abstract

This study was performed to develop an experimental model in which expression of estrogen receptors (ER) by human prostatic stromal cells could be reproducibly enhanced relative to similar cells with low ER expression. The second aim was to characterise changes in expression of ER, androgen receptor (AR), FGF-2 and FGF-7 in stromal cells exposed to high and low concentrations of estradiol and testosterone mimicking the different sex hormone levels between young and elderly men. Five strains of human prostatic stromal cells, isolated from BPH resections, were grown in steroid-free medium plus 1 mmol 17b-estradiol. After 10 days, cells were passaged and grown in the same medium without estradiol until confluent. In a second study four cell strains were exposed to high and low concentrations of 17b-estradiol and testosterone for 10 days. Cells were labelled with fluorescent antibodies to ERa, AR, FGF-2 and FGF-7 and the fluorescence intensity measured by flow cytometry. Following exposure to 1 mmol estradiol, stromal cells showed reduced expression of AR and ERa but after passage without estradiol they showed a 25% increase in both receptors over controls. Different combinations of sex hormones induced inconsistent changes with respect to expression of ER, AR and FGFs in the various cell-strains. However, there was a highly significant correlation between AR, ER and FGF-2 and FGF-7, which was cell strain-specific. Thus, changes in sex hormone balance per se may not be solely responsible for the observed increases in prostatic ER levels in BPH. Since expression of ER is correlated with synthesis of FGF-2 and FGF-7, it is likely that increases in stromal ER may mediate the synthesis of stromallyderived growth factors which contribute to the aetiopathogenesis of benign prostatic hyperplasia.

Relationship between upregulated oestrogen receptors and expression of growth factors in cultured, human, prostatic stromal cells exposed to estradiol or dihydrotestosterone

“…This investigation confirms and extends our previous study 9 that showed that exposure of prostatic stromal cells to 1 mmol estradiol for 10 days followed by passage and growth in the absence of steroid hormones enhanced expression of ER. In the previous study, all stromal cell strains exhibited upregulation of ER to varying degrees.…”

“…With these data, cells treated with 1 mmol estradiol showed significant positive correlations between percentages of ERa and both FGF-2 and FGF-7. We have previously found highly significant correlations between immunofluorescence values of ERa and both FGF-2 and FGF-7 in the absence of ERa upregulation, 9 suggesting that there is an intrinsic relationship between ERa and the two growth factors in the prostatic stroma.…”

“…9. Stock cultures of stromal cells were seeded onto four, 9 cm diameter culture dishes (Nunc, Roskilde, Denmark), and grown in RPMI 1640 medium supplemented with 2 mmol L-glutamine, antibiotics and 10% fetal calf serum (FCS; Gibco, Invitrogen, Paisley, Scotland).…”

“…Recently, we described a simple experimental model in which expression of ERa protein is reliably upregulated in human prostatic stromal cells by exposing them to a high concentration of estradiol for 10 days followed by steroid deprivation. 9 In the current paper, this technique is utilised to determine the effect of ERa upregulation on the expression of six growth factors and hence gain some insight into the importance of ERa in the pathogenesis of BPH.…”

The role of estrogens at men. Part 2. Private clinical endocrinology and pathophysiology of estrogens at men

“…Сегодня эстрогены рас-сматриваются как важный участник патогенеза ДГПЖ. Согласно современным представлениям, роль эстро-генов в патогенезе простатической пролиферации и гиперплазии может быть двоякой [66,67]. С одной стороны, повышение уровня эстрогенов в простате за счет их избыточного поступления из крови или ак-тивации самостоятельной ароматазной активности стромы простаты приводит к стромальной гиперпла-зии предстательной железы.…”