Format

Send to

Choose Destination
Mol Oncol. 2018 Aug;12(8):1308-1323. doi: 10.1002/1878-0261.12327. Epub 2018 Jul 10.

Loss of androgen receptor signaling in prostate cancer-associated fibroblasts (CAFs) promotes CCL2- and CXCL8-mediated cancer cell migration.

Author information

1
Division of Oncogenomics, The Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
2
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
3
Oncode Institute, The Netherlands.
4
Division of Molecular Genetics, The Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
5
Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands.
6
Division of Pathology, The Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
7
Division of Urology, The Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
8
Division of Medical Oncology, The Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.

Abstract

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.

KEYWORDS:

CCL2; CXCL8; EMT; androgen receptor; cancer cell migration; cancer-associated fibroblasts; prostate cancer

PMID:
29808619
PMCID:
PMC6068356
DOI:
10.1002/1878-0261.12327
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center