Human prostate stromal cells stimulate increased PSA production in DHEA-treated prostate cancer epithelial cells

Abstract

Dehydroepiandrosterone (DHEA) is commonly used as a dietary supplement and may affect prostate pathophysiology when metabolized to androgens and/or estrogens. Human prostate LAPC-4 cancer cells with a wild type androgen receptor (AR), were treated with DHEA, androgens (DHT, T, or R1881), and E 2 and assayed for PSA protein and gene expression. In LAPC-4 monocultures, DHEA and E 2 induced little or no increase in PSA protein or mRNA expression compared to androgentreated cells. When prostate cancer-associated (6S) stromal cells were added in coculture, DHEA stimulated LAPC-4 cell PSA protein secretion to levels approaching induction by DHT. Also, DHEA induced 15-fold more PSA mRNA in LAPC-4 cocultures than in monocultures. LAPC-4 proliferation was increased 2-3 fold when cocultured with 6S stromal cells regardless of hormone treatment. DHEA-treated 6S stromal cells exhibited a dose-and time-dependent increase in T secretion, demonstrating stromal cell metabolism of DHEA to T. Coculture with non-cancerous stroma did not induce LAPC-4 PSA production, suggesting a differential modulation of DHEA effect in a cancerassociated prostate stromal environment. This coculture model provides a research approach to reveal detailed endocrine, intracrine, and paracrine signaling between stromal and epithelial cells that regulate tissue homeostasis within the prostate, and the role of the tumor microenvironment in cancer progression.

Prostate cancer stromal cells and LNCaP cells coordinately activate the androgen receptor through synthesis of testosterone and dihydrotestosterone from dehydroepiandrosterone

“…However, coculture with stromal cells, especially PCaSCs, strongly activated PSA promoter activity induced by DHEA. Although our results are consistent with Arnold et al (2008) observation that testosterone synthesized from DHEA in PCa-derived stromal cells contributed to PSA induction in LAPC4, we extended these studies further to elucidate which pathways were involved in testosterone synthesis. Specifically, we identified that the increased level of DHEAinduced AR activity by stromal cells was dependent on the synthesized level of testosterone and DHT achieved by coculture.…”

“…This activity could readily contribute to androgen deprivation-refractory PCa after ADT. Recently, Arnold et al (2008) have described a similar study using coculture of LAPC4 androgen-sensitive PCa cells with stromal cells. According to their study, PCa-derived stromal cells also increased PSA mRNA expression induced by DHEA.…”

Association of Prostate Specific Antigen Concentration with Lifestyle Characteristics in Korean Men

“…Considering that this study showed no association of vitamin intake with increased PSA, vitamin use might increase the risk of prostate cancer without elevation of serum PSA. Although DHEA exerts minimal effects on normal prostate, in cancer-associated tissues a reactive stromal microenvironment can promote prostate proliferation or PSA production in the presence of DHEA (Arnold et al, 2008). Although many kinds of nutritional supplements are increasingly consumed for their anti-aging effects, their effectiveness and long-term safety for prostate tissues are uncertain and rather risky.…”

The differential effects of prostate stromal cells derived from different zones on prostate cancer epithelial cells under the action of sex hormones

“…12,13 Many research groups have also shown that a dynamic stromal-epithelial interaction plays a critical role in the progression and metastasis of PCa. [14][15][16][17][18][19][20] Growth factors play a central role in mediating the interactions between epithelial and stromal cells. 21 The stromal-epithelial interaction is also critical for mediating the effects of these molecules on epithelial cells.…”