Departments of Pathology, Urology, and Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA.
EMBO Mol Med. 2012 Aug;4(8):791-807. doi: 10.1002/emmm.201101140. Epub 2012 Jun 29.
Stromal-epithelial interaction is crucial to mediate normal prostate and prostate cancer (PCa) development. The indispensable roles of mesenchymal/stromal androgen receptor (AR) for the prostate organogenesis have been demonstrated by using tissue recombination from wild-type and testicular feminized mice. However, the stromal AR functions in the tumour microenvironment and the underlying mechanisms governing the interactions between the epithelium and stroma are not completely understood. Here, we have established the first animal model with AR deletion in stromal fibromuscular cells (dARKO, AR knockout in fibroblasts and smooth muscle cells) in the Pten(+/-) mouse model that can spontaneously develop prostatic intraepithelial neoplasia (PIN). We found that loss of stromal fibromuscular AR led to suppression of PIN lesion development with alleviation of epithelium proliferation and tumour-promoting microenvironments, including extracellular matrix (ECM) remodelling, immune cell infiltration and neovasculature formation due, in part, to the modulation of pro-inflammatory cytokines/chemokines. Finally, targeting stromal fibromuscular AR with the AR degradation enhancer, ASC-J9®, resulted in the reduction of PIN development/progression, which might provide a new approach to suppress PIN development.
间质-上皮相互作用对于调节正常前列腺和前列腺癌（PCa）的发展至关重要。通过使用来自野生型和睾丸女性化小鼠的组织重组，已经证明了间质/基质雄激素受体（AR）对前列腺发生的不可或缺作用。然而，肿瘤微环境中的基质 AR 功能以及支配上皮和基质之间相互作用的潜在机制尚不完全清楚。在这里，我们在 Pten(+/-)小鼠模型中建立了第一个间质纤维肌肉细胞中 AR 缺失（dARKO，成纤维细胞和平滑肌细胞中的 AR 敲除）的动物模型，该模型可以自发发展前列腺上皮内瘤（PIN）。我们发现，间质纤维肌肉 AR 的缺失导致 PIN 病变发展受到抑制，上皮增殖和促进肿瘤的微环境得到缓解，包括细胞外基质（ECM）重塑、免疫细胞浸润和新血管形成，部分原因是促炎细胞因子/趋化因子的调节。最后，用 AR 降解增强剂 ASC-J9®靶向间质纤维肌肉 AR，导致 PIN 发展/进展减少，这可能为抑制 PIN 发展提供一种新方法。
