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

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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cancer-Associated Fibroblasts / metabolism
  • Cancer-Associated Fibroblasts / pathology*
  • Cell Movement*
  • Chemokine CCL2 / analysis
  • Chemokine CCL2 / metabolism*
  • Humans
  • Interleukin-8 / analysis
  • Interleukin-8 / metabolism*
  • Male
  • Middle Aged
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Receptors, Androgen / analysis
  • Receptors, Androgen / metabolism*
  • Signal Transduction*


  • CCL2 protein, human
  • CXCL8 protein, human
  • Chemokine CCL2
  • Interleukin-8
  • Receptors, Androgen