Prostate cancer as a dedifferentiated organ: androgen receptor, cancer stem cells, and cancer stemness

Cancer progression is characterized and driven by gradual loss of a differentiated phenotype and gain of stem cell-like features. In prostate cancer (PCa), androgen receptor (AR) signaling is important for cancer growth, progression, and emergence of therapy resistance. Targeting the AR signaling axis has been, over the decades, the mainstay of PCa therapy. However, AR signaling at the transcription level is reduced in high-grade cancer relative to low-grade PCa and loss of AR expression promotes a stem cell-like phenotype, suggesting that emergence of resistance to AR-targeted therapy may be associated with loss of AR signaling and gain of stemness. In the present mini-review, we first discuss PCa from the perspective of an abnormal organ with increasingly deregulated differentiation, and discuss the role of AR signaling during PCa progression. We then focus on the relationship between prostate cancer stem cells (PCSCs) and AR signaling. We further elaborate on the current methods of using transcriptome-based stemness-enriched signature to evaluate the degree of oncogenic dedifferentiation (cancer stemness) in pan-cancer datasets, and present the clinical significance of scoring transcriptome-based stemness across the spectrum of PCa development. Our discussions highlight the importance to evaluate the dynamic changes in both stem cell-like features (stemness score) and AR signaling activity across the PCa spectrum.