Abstract
The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy.
Highlights
The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment
We provide gene regulation data on AR signalling in human macrophages and show that activation of AR signalling in macrophages increases migration and invasion of PCa-derived cancer cells, mediated by upregulation of the Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) receptor and its downstream cytokines and promotion of tumourassociated macrophage (TAM) differentiation
To establish AR expression in macrophages at the protein level, formalin-fixed paraffin embedded (FFPE) prostatectomy specimen of untreated PCa patients were stained for AR and CD163, a marker of tissueresident macrophages including TAMs15
Summary
The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. During PCa development, stromal cells can change in phenotype to support tumour progression instead[3]. TAM infiltration into PCa was associated with disease progression after hormonal therapy and preclinical studies suggested that TAMs support PCa cell proliferation and migration[8,9,10]. We provide gene regulation data on AR signalling in human macrophages and show that activation of AR signalling in macrophages increases migration and invasion of PCa-derived cancer cells, mediated by upregulation of the Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) receptor and its downstream cytokines and promotion of TAM differentiation. Our study illustrates that AR signalling in macrophages might represent a druggable cascade in the treatment of PCa patients
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