TY - JOUR
T1 - Loss of androgen receptor signaling in prostate cancer-associated fibroblasts (CAFs) promotes CCL2- and CXCL8-mediated cancer cell migration
AU - Cioni, Bianca
AU - Nevedomskaya, Ekaterina
AU - Melis, Monique H.M.
AU - van Burgsteden, Johan
AU - Stelloo, Suzan
AU - Hodel, Emma
AU - Spinozzi, Daniele
AU - de Jong, Jeroen
AU - Wessels, Lodewyk F.A.
AU - More Authors, null
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - androgen receptor
KW - cancer cell migration
KW - cancer-associated fibroblasts
KW - CCL2
KW - CXCL8
KW - EMT
KW - prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=85050822591&partnerID=8YFLogxK
U2 - 10.1002/1878-0261.12327
DO - 10.1002/1878-0261.12327
M3 - Article
C2 - 29808619
SN - 1574-7891
VL - 12
SP - 1308
EP - 1323
JO - Molecular Oncology
JF - Molecular Oncology
IS - 8
ER -