Androgen receptor in human prostate cancer-associated fibroblasts promotes prostate cancer epithelial cell growth and invasion

Abstract

The androgens and androgen receptor (AR) play key roles in the prostate cancer (PCa) development and progression via epithelium-stroma cross talk. Prostate cancer-associated fibroblasts (CAFs) are dominant components in PCa stroma and are essential in the malignant progression by supporting tumorigenesis and metastasis. However, the AR roles in CAFs are still obscure. We isolated and immortalized the CAFs from human PCa tissues and found the CAFs are AR positive. We then knocked down their AR with siRNA and co-cultured the resultant CAFs with PCa cell line PC3. The MTT, invasion, and colony formation assays were performed to study the PC3 biological behavior. The results showed that the PCa epithelial growth, invasion, and colony formation abilities decreased when knocking down the CAFs AR. By using the real-time quantitative polymerase chain reaction, we found the IGF1, FGF7, FGF10, SDF1, HGF, and TGFb2 expression levels decreased in the AR knocked down CAFs. These results suggested that the AR in CAFs promoted PCa epithelial growth and invasion via regulating a series of growth factors. Targeting the AR in CAFs might be a potential therapeutic option for PCa in future.

Influence of stromal–epithelial interactions on androgen action

“…Specific targeting of the stromal AR may yield different results. Yu et al (2013) have suggested that the expression of AR in CAFs regulates epithelial proliferation via various growth factors such as IGF1, FGF7, FGF10, SDF1, HGF, and TGFb2. This would indicate that preferential targeting of AR in the stroma might be a therapeutic option.…”

“…In the context of the stromal fibroblast ARKO mouse, FGF7 and FGF10 levels are reduced. This is associated with decreased epithelial proliferation and has been suggested as a possible therapeutic target (Yu et al 2013). The secretion of FGF7 is substantially higher in the cancer-associated peripheral zone than in the BPH-associated transitional zone (Jiang et al 2011).…”

“…Stromal ARKO mice exhibit reduced IGF1 expression. Lowered IGF1 expression in the stroma has been reported to be associated with a reduction in epithelial proliferation and maintenance (Yu et al 2013). IGF1 has been implicated in CRPC, but IGF1-mediated growth may also affect androgens by promoting ligandindependent androgen action (Mantzoros et al 1997).…”

“…AR may regulate tumorigenic properties and contribute to epithelialmesenchymal signaling in the breast, though the information is limited. There are many other wellcharacterized AR target tissues throughout the body, but specific information on the role of AR in epithelialmesenchymal interactions is minimal or non-existent (Chang et al 2013). This review focuses on the role of AR in the prostate and, to a lesser extent, in the breast, specifically in the context of interactions between the epithelium and the stroma.…”

WITHDRAWN: Mechanisms navigating the TGF-β pathway in prostate cancer

“…AR suppresses expression of TGF-b1 through a negative androgen-response region containing multiple negative androgen-response elements in the TGF-b1 promoter in androgen-independent and androgen-sensitive human prostate cancer cells [44]. AR knockdown in carcinoma-associated fibroblasts (CAFs) leads to decreased expression of TGF-b2, indicating that AR by regulating TGF-b promotes prostate cancer epithelial growth and invasion [45]. In addition, AR and miR-21 increase each other's expression and promote tumor growth by attenuating TGF-bRII expression and TGF-b-induced SMAD2/3 activation [46].…”