Division of Oncogenomics, The Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
Mol Oncol. 2018 Aug;12(8):1308-1323. doi: 10.1002/1878-0261.12327. Epub 2018 Jul 10.
Fibroblasts are abundantly present in the prostate tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs) which play a key role in cancer development. Androgen receptor (AR) signaling is the main driver of prostate cancer (PCa) progression, and stromal cells in the TME also express AR. High-grade tumor and poor clinical outcome are associated with low AR expression in the TME, which suggests a protective role of AR signaling in the stroma against PCa development. However, the mechanism of this relation is not clear. In this study, we isolated AR-expressing CAF-like cells. Testosterone (R1881) exposure did not affect CAF-like cell morphology, proliferation, or motility. PCa cell growth was not affected by culturing in medium from R1881-exposed CAF-like cells; however, migration of PCa cells was inhibited. AR chromatin immune precipitation sequencing (ChIP-seq) was performed and motif search suggested that AR in CAF-like cells bound the chromatin through AP-1-elements upon R1881 exposure, inducing enhancer-mediated AR chromatin interactions. The vast majority of chromatin binding sites in CAF-like cells were unique and not shared with AR sites observed in PCa cell lines or tumors. AR signaling in CAF-like cells decreased expression of multiple cytokines; most notably CCL2 and CXCL8 and both cytokines increased migration of PCa cells. These results suggest direct paracrine regulation of PCa cell migration by CAFs through AR signaling.
成纤维细胞在前列腺肿瘤微环境（TME）中大量存在，包括在癌症发展中起关键作用的癌相关成纤维细胞（CAF）。雄激素受体（AR）信号是前列腺癌（PCa）进展的主要驱动因素，TME 中的基质细胞也表达 AR。TME 中 AR 表达水平低与高级别肿瘤和不良临床结局相关，这表明 AR 信号在基质中对 PCa 发展具有保护作用。然而，这种关系的机制尚不清楚。在这项研究中，我们分离了表达 AR 的 CAF 样细胞。睾酮（R1881）暴露不会影响 CAF 样细胞的形态、增殖或运动性。PCa 细胞的生长不受 R1881 暴露的 CAF 样细胞培养物中培养的影响；然而，PCa 细胞的迁移受到抑制。进行了 AR 染色质免疫沉淀测序（ChIP-seq），并且 motif 搜索表明，在 R1881 暴露时，AR 通过 AP-1 元件结合 CAF 样细胞中的染色质，诱导增强子介导的 AR 染色质相互作用。CAF 样细胞中绝大多数染色质结合位点是独特的，与在 PCa 细胞系或肿瘤中观察到的 AR 位点不共享。CAF 样细胞中的 AR 信号降低了多种细胞因子的表达；最显著的是 CCL2 和 CXCL8，这两种细胞因子都增加了 PCa 细胞的迁移。这些结果表明，通过 AR 信号，CAF 对 PCa 细胞迁移的直接旁分泌调节。
