Androgen receptor and immune inflammation in benign prostatic hyperplasia and prostate cancer

Abstract

Both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are frequent diseases in middle-aged to elderly men worldwide. While both diseases are linked to abnormal growth of the prostate, the epidemiological and pathological features of these two prostate diseases are different. BPH nodules typically arise from the transitional zone, and, in contrast, PCa arises from the peripheral zone. Androgen deprivation therapy alone may not be sufficient to cure these two prostatic diseases due to its undesirable side effects. The alteration of androgen receptor-mediated inflammatory signals from infiltrating immune cells and prostate stromal/epithelial cells may play key roles in those unwanted events. Herein, this review will focus on the roles of androgen/androgen receptor signals in the inflammation-induced progression of BPH and PCa.

Keywords: androgen receptor; benign prostate hyperplasia; immune inflammation; metastasis; prostate cancer.

Figure 1. Androgen/androgen receptor signaling and immune inflammation in benign prostatic hyperplasia

Androgen/AR signaling plays key roles to enhance cell growth in both stromal and epithelial cells. Some inflammatory cytokines are associated with androgen/AR signaling and contribute to benign prostatic hyperplasia development. Medical treatments targeting androgen/AR signaling and androgen/AR signaling-associated cytokines are shown as red outlined boxes and red bars. 5-ARI: 5-α reductase inhibitors; AR: Androgen receptor; CCL: CC chemokine ligand; DHT: dihydrotestosterone; IFN-γ: Interferon-γ; IL: Interleukin; LH-RH: Luteinizing hormone-releasing hormone; SARM: Selective androgen receptor modulators; TGF-β: Transforming growth factor-β. For color images please see online www.future-science.com/doi/full/10.4155/CLI.14.77

Figure 2. Treatment strategy of advanced prostate cancer

Androgen-deprivation therapy with combined androgen blockade (surgical or medical castration plus anti-androgen) is the standard therapy for advanced prostate cancer. If the patient has skeletal metastasis, addition of treatments targeting skeletal metastasis (green) is considered. In the castration-resistant phase, after confirmation of androgen withdrawal phenomenon, docetaxel, which is a conventional standard therapy, or recently developed therapies proven by randomized controlled Phase III studies, are applied according to the condition of the prostate cancer (blue). Before these standard therapies, alternative anti-androgen therapy may be considered. The best supportive care is applied after the sequence of standard therapies. However, treatments with less evidence may be applied before the best supportive care (orange). CRPC: Castration-resistant prostate cancer. For color images please see online www.future-science.com/doi/full/10.4155/CLI.14.77

Figure 3. Interaction of prostate cancer cells and macrophages

(A) Androgen receptor-CCL4-pSTAT3 signaling is a key regulator during prostate tumorigenesis. ASC-J9 and anti-CCL4 showed antitumorigenesis effects. (B) Migrated macrophages express a variety of pro-angiogenic and immunosuppressive mediators including MMP9. Zoledronic acid selectively suppressed the expression of MMP9 and could effectively drive the proliferation of activated γ-δ T lymphocytes and then inhibit cancer progression. (C) Bicalutamide or enzalutamide promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion via activation of PIAS3-pSTAT3-CCL2 signaling. ASC-J9 suppressed both macrophage migration and subsequent PCa cell invasion. (D) Androgen-deprivation therapy induced EMT in PCa via the activation of CCL2/CCR2-STAT3 signaling in the interaction of PCa cells and macrophages. CCR2 antagonists block CCL2 in both (C) and (D). The combination of ADT and anti-CCL2/CCR2-STAT3 signaling may be a better therapeutic approach to battle PCa progression and metastasis. ADT: Androgen-deprivation therapy; AR: Androgen receptor; CCL: CC chemokine ligand; MMP9: Matrix metallopeptidase 9; PCa: Prostate cancer; PIAS3: Endogenous protein inhibitor of activated STAT3; STAT3: Signal Tranducer and Activator of Transcription 3.